Radiotherapy in brain metastases from EGFR-mutated non-small cell lung cancer

Epidermal growth factor receptor (EGFR) mutations are present in 20–40% of non-small cell lung cancers (NSCLCs). Brain metastasis (BM) is more common in EGFR-mutated NSCLC (25–45%) compared to EGFR wild-type (15–30%). First and second-generation tyrosine kinase inhibitors (TKIs), such as erlotinib and afatinib have proven to be superior to chemotherapy in the front-line treatment of EGFR-mutated NSCLC. Osimertinib, a third-generation EGFR TKI, has demonstrated better blood brain barrier (BBB) penetration, higher rate of intracranial response (66% vs. 43%) and a lower rate of CNS progression when compared to first generation EGFR TKI. Evidence on upfront radiation vs. upfront osimertinib is limited, but rapidly evolving and being tested in ongoing comparative trials. Stereotactic radiation (SRS) is very effective in the control of BMs and has been increasingly used and consequently replacing resection of BMs. SRS also has been increasingly used in the treatment of multiple BMs. Considering the effectiveness of targeted agents such as third generation EGFR inhibitors clinicians now are more frequently faced with the decision, if systemic therapy is safe and effective enough to withhold SRS. Third generation EGFR inhibitors also have fewer adverse events as previous generations. This review discusses the current literature available for management of BM in EGFR-mutated NSCLC.     

高聚金葡素治疗糖尿病的临床观察

采用超抗原生物制剂高聚金葡素的两种剂型（ＢＭ口服液和ＢＭ胶囊），分别协同治疗２０例糖尿病。结果：ＢＭ口服液组治后的血糖比治前下降３０．８９％，Ｐ＜０．００１；ＨｂＡ１Ｃ比治前下降３７．３３％，Ｐ＜０．００１。ＢＭ胶囊组治后的血糖比治前下降１３．７３％，Ｐ＜０．０５；ＨｂＡ１Ｃ比治前下降２９．３７％，Ｐ＜０．００１。胰岛素（３６例）治后增加５１．３％，Ｐ＜０．０１；４０例患者中Ｃ肽治后增加１９．３４％，Ｐ＜０．０５；４０例的Ｔ细胞亚群ＣＤ３治后增加１３．２％，Ｐ＜０．０１；ＣＤ４增加１７．４％，Ｐ＜０．００１；ＣＤ８减少１９．４％，Ｐ＜０．００１；ＣＤ４／ＣＤ８比值由１．０４转为１．５０，达到正常水平。表明高聚金葡素与降血糖药物合用对治疗糖尿病有明显的协同作用。其机理可能是通过超抗原的生物调节因子，调节机体内环境和细胞免疫功能所致。值得进一步深入研究。     

1,5-Diaryl-2-ethyl pyrrole derivatives as antimycobacterial agents: Design, synthesis, and microbiological evaluation

During the search of novel antitubercular drugs related to BM 212, new diarylpyrroles were designed and synthesized on the basis of a structure–activity relationship analysis of many pyrroles previously described by us. Among them, 1-(4-fluorophenyl)-2-ethyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole (2b) proved to be particularly active, with a minimum inhibitory concentration (MIC, expressed as μg/mL) and a protection index (PI) better than or comparable to those of reference compounds. Also the remaining compounds were very active, although their MIC and PI were in general lower than those of their parent 2-methyl analogues.     

不同贫血病时C-erbB1胚系扩增与骨髓再生和白血病发生

目的：证明上皮生长因子受体(EGFR)基因与白血病发生和骨髓再生的相关性。方法：应用鸡原始红细胞增多症病毒癌基因V-erbB作探针，进行Southern印迹杂交，对8例不同贫血状态下的血液病，包括5例骨髓增生异常综合征(MDS)，1例家族性急性髓细胞白血病及其亲属，1例缺铁性贫血(IDA)和1例范柯尼贫血(FA)等进行检测，并以7例AL、MDS和AA父母为对照。结果：MDS和AL有C-erbB1重排／扩增。患者父母仅有C-erbB1重排，大多数无胚系扩增；MDS和IDA有C-erbB1胚系扩增，但IDA无C-erbB1重排；正常人大多数与其父母一样，既无C-erbB1胚系扩增，也无C-erbB1重排。结论：C-erbB1即EGFR基因重排／扩增与MDS和AL有关，且其胚系扩增可能还与骨髓再生相关。白血病的发生还可能与骨髓再生有负相关，且对EGF不依赖。     

Role of spectral domain optical coherence tomography in the diagnosis and prognosis of papilledema

Purpose:The study of papilledema with a novel noninvasive technique such as spectral domain-optical coherence tomography (SD-OCT) provides minute and detailed cross-sectional changes thus giving an insight into the application of biomechanical principles and pathophysiology of disc edema.Methods:We measured average retinal nerve fiber layer (RNFL) thickness and the retinal pigment epithelium/Bruch’s membrane (RPE/BM) angle at the temporal and nasal borders of the neural canal opening (NCO) in 30 eyes with papilledema, 30 eyes with papillitis, and 80 control eyes. The inward angulation was considered as positive and the outward as negative. Follow-up was done at 1, 2, 3, and 6 months. The main outcome measures are the average RNFL thickness and the RPE/BM angle.Results:29 eyes (96.6%) with papilledema had a positive RPE/BM angle (+8.11 ± 3.13). 29 eyes (96.6%) with papillitis had a negative RPE/BM angle (−1.04 ± 3.27). On follow-up at 1 month, both RNFL thickness (P = 0.01) and RPE-BM angle (P = 0.001) reduced significantly in eyes with papilledema; in eyes with papillitis, there was a significant reduction in the RNFL thickness (P = 0.02), but not in the RPE-BM angle (P > 0.05). RNFL thickness in papilledema cases normalized at 3 months whereas RPE/BM normalized at 6 months of follow-up. To detect papilledema, OCT has a sensitivity of 96.66% and specificity of 99.09% on both nasal and temporal sides.Conclusion:After appropriate treatment, the RPE/BM angle in papilledema decreased much later than the RNFL thickness. Hence, the RPE/BM angle in papilledema (positive) can be used to differentiate it from papillitis (negative) and also to monitor the activity of the disease.     

花宝金教授“调气解毒”理论治疗小细胞肺癌脑转移经验

花宝金教授从事中医防治肿瘤复发转移工作数十载,结合中医学气机升降理论和现代医学发展特点凝练总结,提出“调气解毒”理论,并将其思想引入临床实践。现通过总结分析花宝金教授“调气解毒”理论治疗小细胞肺癌(SCLC)脑转移经验,结合SCLC脑转移的治疗现状,结合临床医案,从病因病机、学术思想、用药特点等方面,阐述“调气解毒”理论指导下的中医治疗在改善SCLC脑转移临床症状、提高患者生命质量、延缓疾病进展等方面的积极作用,为SCLC脑转移的中医治疗提供依据。     

GM-CSF intrinsically controls eosinophil accumulation in the setting of allergic airway inflammation

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Detection of MYD88 L265P mutations in formalin-fixed and decalcified BM biopsies from patients with lymphoplasmacytic lymphoma

The diagnosis of bone marrow (BM) infiltration by Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) poses a diagnostic challenge in hematopathology. No definitive morphology or immunophenotype is able to distinguish between infiltration of paraffin-embedded BM sections by WM/LPL and other indolent lymphomas, in particular those of the splenic marginal zone (SMZL) which may also show plasmacytic maturation. An oncogenic gain-of-function mutation (L265P) in the human MYD88 gene has been found to be present in most cases of WM/LPL, yet is absent in most other cases of B-cell chronic lymphoproliferative disorders (LPD), including SMZL. Here, we compare two newly developed diagnostic protocols for detection of this mutation in paraffin-embedded archival tissues which are particularly applicable to decalcified BM biopsies. Sanger sequencing can easily detect levels of BM infiltration above 15% by WM lymphoplasmacytic cells, while the allele-specific PCR can detect the L265P mutation in BM infiltrations below 1% of lymphoma cells. We show that these methods are easily applicable to archival BM specimens and markedly improve diagnostic accuracy of BM infiltrations by indolent B-cell lymphomas.     

Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting

The identification of proliferation/survival pathways constitutively activated by genetic alterations in multiple myeloma (MM), or sustained by the bone marrow (BM) microenvironment, provides novel opportunities for the development of targeted therapies. The deregulated function of protein tyrosine kinases plays a critical role in driving MM malignant phenotype. We investigated the effects of the multi-target tyrosine kinase inhibitor RPI-1 in a panel of human MM cell lines, including t(4;14) positive cell lines expressing the TK receptor FGF-R3. Cells harboring FGF-R3 activating mutations (KMS11 and OPM2) displayed the highest sensitivity to RPI-1 antiproliferative effect. The stimulating effect of the aFGF ligand was abrogated in cells harboring a non-constitutively active receptor. Drug treatment inhibited activation and expression of the FGF-R3^Y373C mutant as well as aFGF-dependent signaling involving AKT and ERKs. Inhibition of JAK2, an additional RPI-1 target, resulted in STAT3 inactivation. Blockade of these proliferation/survival pathways was associated with caspase-dependent apoptosis. Moreover, drug treatment abrogated proliferative and pro-invasive stimuli provided by conditioned medium from mesenchymal stromal cells. Gene expression profile of KMS11 cells showed 22 upregulated and 52 downregulated genes upon RPI-1 treatment, with an early modulation of genes implicated in MM pathobiology such as SAT-1, MYC, MIP-1α/β, FGF-R3, and the growth factor receptor B-cell maturation antigen (BCMA). Thus, concomitant blockade of FGF-R3 and JAK2 results in inhibition of several MM-promoting pathways, including BCMA-regulated signaling, and downregulation of disease-associated proteins. These data may have therapeutic implications in the design of treatment strategies resulting in the concomitant inhibition of FGF-R3 and JAK2 signaling pathways in t(4;14) MM.