Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study

Chronic myelogenous leukemia (CML) is caused by expression of the BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Patients with CML in accelerated phase have rapidly progressive disease and are characteristically unresponsive to existing therapies. Imatinib (formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl kinase. A total of 235 CML patients were enrolled in this study, of whom 181 had a confirmed diagnosis of accelerated phase. Patients were treated with imatinib at 400 or 600 mg/d and were evaluated for hematologic and cytogenetic response, time to progression, survival, and toxicity. Imatinib induced hematologic response in 82% of patients and sustained hematologic responses lasting at least 4 weeks in 69% (complete in 34%). The rate of major cytogenetic response was 24% (complete in 17%). Estimated 12-month progression-free and overall survival rates were 59% and 74%, respectively. Nonhematologic toxicity was usually mild or moderate, and hematologic toxicity was manageable. In comparison to 400 mg, imatinib doses of 600 mg/d led to more cytogenetic responses (28% compared to 16%), longer duration of response (79% compared to 57% at 12 months), time to disease progression (67% compared to 44% at 12 months), and overall survival (78% compared to 65% at 12 months), with no clinically relevant increase in toxicity. Orally administered imatinib is an effective and well-tolerated treatment for patients with CML in accelerated phase. A daily dose of 600 mg is more effective than 400 mg, with similar toxicity.     

Computed tomography appearances of the lung parenchyma in pulmonary hypertension

Computed tomography (CT) is a valuable tool in the workup of patients under investigation for pulmonary hypertension (PH) and may be the first test to suggest the diagnosis. CT parenchymal lung changes can help to differentiate the aetiology of PH. CT can demonstrate interstitial lung disease, emphysema associated with chronic obstructive pulmonary disease, features of left heart failure (including interstitial oedema), and changes secondary to miscellaneous conditions such as sarcoidosis. CT also demonstrates parenchymal changes secondary to chronic thromboembolic disease and venous diseases such as pulmonary venous occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH). It is important for the radiologist to be aware of the various manifestations of PH in the lung, to help facilitate an accurate and timely diagnosis. This pictorial review illustrates the parenchymal lung changes that can be seen in the various conditions causing PH.     

恩替卡韦与拉米夫定治疗HBeAg阴性慢性乙型肝炎的对照研究

Ⅱ期临床试验已经证实恩替卡韦是一种治疗HBeAg阴性慢性乙型肝炎有效和可选择的抗病毒药物。采用双盲法将648例未曾接受过核苷类药物治疗的HBeAg阴性慢性乙型肝炎随机分配进入恩替卡韦（0．5mg／d）治疗组或拉米夫定（100mg／d）治疗组，疗程至少52wk。     

Repeat hepatic surgery for colorectal cancer metastasis to the liver.

OBJECTIVE: The authors addressed whether a repeat hepatic operation is warranted in patients with recurrent isolated hepatic metastases. Are the results as good after second operation as after first hepatic operation? SUMMARY BACKGROUND DATA: Five-year survival after initial hepatic operation for colorectal metastases is approximately 33%. Because available alternative methods of treatment provide inferior results, hepatic resection for isolated colorectal metastasis currently is well accepted as the best treatment option. However, the main cause of death after liver resection for colorectal metastasis is tumor recurrence. METHODS: Records of 95 patients undergoing initial hepatic operation and 10 patients undergoing repeat operation for isolated hepatic metastases were reviewed for operative morbidity and mortality, survival, disease-free survival, and pattern of failure. The literature on repeat hepatic resection for colorectal metastases was reviewed. RESULTS: The mean interval between the initial colon operation and first hepatic resection was 14 months. The mean interval between the first and second hepatic operation was 17 months. Operative mortality was 0%. At a mean follow-up of 33 +/- 27 months, survival in these ten patients was 100% at 1 year and 88% +/- 12% at 2 years. Disease-free survival at 1 and 3 years was 60% +/- 16% and 45% +/- 17%, respectively. After second hepatic operation, recurrence has been identified in 60% of patients at a mean of 24 +/- 30 months (median 9 months). Two of these ten patients had a third hepatic resection. Survival and disease-free survival for the 10 patients compared favorably with the 95 patients who underwent initial hepatic resection. CONCLUSIONS: Repeat hepatic operation for recurrent colorectal metastasis to the liver yields comparable results to first hepatic operations in terms of operative mortality and morbidity, survival, disease-free survival, and pattern of recurrence. This work helps to establish that repeat hepatic operation is the most successful form of treatment for isolated recurrent colorectal metastases.     

The emergence of resistance to targeted cancer therapeutics

Drug resistance has always been a concern in cancer treatment, often blamed on the genetic complexity and instability of tumor cells. While studies of cancer cell lines have implicated an array of potential mechanisms, it has been difficult to translate these insights into clinically meaningful improvements in cancer treatment. The successful deployment of molecularly targeted therapeutics in some cancers has led to widespread optimism that this approach will become broadly applicable. Despite their early promise in the clinic, the novel therapeutics are often plagued with the age old problem of acquired drug resistance. Progress in understanding why certain patients respond and why some develop resistance can be made rapidly through studies of the drug target in tumor tissue from patient. One important lesson is that many cancers, even in the most advanced stages, continue to rely on a limited number of critical oncogenic signals for maintenance of the malignant phenotype. This article reviews the mechanisms of drug resistance to a variety of cancer therapeutics and provides an approach for how measures of drug target activity can be incorporated into clinical trial design.     

TMEFF2 is an androgen-regulated gene exhibiting antiproliferative effects in prostate cancer cells

We have identified a gene that is highly expressed in the androgen-dependent prostate cancer cell line, LNCaP. Sequence analysis revealed that it was identical to a recently cloned gene designated TMEFF2, which encodes a transmembrane protein containing an epidermal growth factor (EGF)-like motif and two follistatin domains. This gene was highly expressed only in primary samples of normal prostate and prostate cancer as well as normal brain. Expression of the gene was controlled by androgen as shown by dihydrotestosterone markedly increasing TMEFF2 expression in LNCaP cells. Also, androgen-dependent human prostate cancer xenografts (CWR22) expressed high levels of TMEFF2 and these levels markedly decreased by day 10 after castration of the mice. Furthermore, a large number of androgen-dependent xenografts (CWR22, LuCaP-35, LAPC-4AD, LAPC-9AD) exhibited higher levels of TMEFF2 mRNA than androgen-independent xenografts (CWR22R, LAPC-3AI, LAPC-4AI, LAPC-9AI). Ectopic expression of TMEFF2 in DU145 and PC3 cells resulted in their prominent inhibition of growth. Taken together, the results demonstrate that TMEFF2 is a androgen-regulated gene, which can suppress growth of prostate cancer cells and our xenograft data show that escape of prostate cancer cells from androgen modulation causes them to decrease their expression of this gene, which may result in their more malignant behavior.     

Identification of the key amino acids of gliai cell line-derived neurotrophic factor family receptor alpha 1 involved in its biological function

Glial cell line-derived neurotrophic factor （GDNF） plays a critical role in neurodevelopment and survival of midbrain dopaminergic and spinal motor neurons in vitro and in vivo. The biological actions of GDNF are mediated by a two-receptor complex consisting of a glycosylphosphatidylinositol-linked cell surface molecule, the GDNF family receptor alpha 1 （GFR alpha 1）, and receptor protein tyrosine kinase Ret. Although structural analysis of GDNF has been extensively examined, less is known about the structural basis of GFR alpha 1 function. In this study, based on evolutionary trace method and relative solvent accessibility prediction of residues, a set of trace residues that are solvent-accessible was selected for site-directed mutagenesis. A series of GFR alpha 1 mutations was made, and PC12 cell lines stably expressing different GFR alpha 1 mutants were generated. According to the survival and differentiation responses of these stable PC12 cells upon GDNF stimulation and the GDNF- GFR alpha 1-Ret interaction assay, residues 152NN153, Arg259, and 316SNS318 in the GFR alpha 1 central region were found to be critical for GFR alpha 1 binding to GDNF and eliciting downstream signal transduction. The single mutation R259A in the GFR alpha 1 molecule simultaneously lost its binding ability to GDNF and Ret. However N152A/N153A or S316A/N317A/ S318A mutation in the GFR alpha 1 molecule still retained the ability to bind with Ret. These findings suggest that distinct structural elements in GFR alpha 1 may be involved in binding to GDNF and Ret.