Anaplastic lymphoma kinase inhibitors in phase I and phase II clinical trials for non-small cell lung cancer

Introduction: Crizotinib is a first-in-class ALK tyrosine kinase inhibitor (TKI), which has proven its superiority over standard platinum-based chemotherapy for the first-line therapy of ALK-rearranged non-small cell lung cancer (NSCLC) patients. The development of acquired resistance to crizotinib represents an ongoing challenge with the central nervous system being one of the most common sites of relapse. Ceritinib and alectinib are approved second-generation ALK TKIs. Several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib, are currently in development.

Areas covered: This review will focus on new ALK inhibitors, currently in phase 1 or 2 clinical studies. We will also comment on the mechanisms of resistance to ALK inhibition and the strategies to delay or overcome resistance.

Expert opinion: The therapeutic management of ALK-rearranged NSCLC has been greatly improved. Next-generation ALK inhibitors have shown differential potency against ALK rearrangements and ALK resistance mutations. The molecular profile of the tumor at the time of disease progression to crizotinib is crucial for the sequencing of novel ALK TKIs. Ongoing clinical studies will address key issues, including the optimal therapeutic algorithm and whether combinational approaches are more effective than single ALK inhibition for the outcome of ALK-rearranged NSCLC patients.     

甲基莲心碱对豚鼠心房生理特性及异丙肾上腺素和Ca2+量—效反应的影响

甲基莲心碱1～100μmol/L浓度依赖性地抑制豚鼠左心房收缩性,延长功能性不应期,降低兴奋性;30μmol/L甲基莲心碱能明显提高肾上腺素诱发左心房自律性的阈浓度。对异丙肾上腺素量—效反应的影响,不同于β-受体阻滞剂普萘洛尔,表现为非竞争性拮抗作用,对Ca²⁺量—效反应的影响,与抗钙剂维拉帕米类似,呈竞争性和非竞争性双重拮抗作用。     

Neu／c─erbB─2癌基因在颊粘膜上皮良性及恶性病变中的表达及其定量研究

目的：观察Ｎｅｕ／ｃ－ｅｒｂＢ－２癌基因在颊粘膜上皮良性、癌前以及癌变状态下的表达，并确立图像分析系统定量的方法．方法：用三种抗Ｎｅｕ抗体，通过微波暴露抗原，进行标准化的ＥｌｉｔｅＡＢＣ染色，并通过半定量及图像分析系统确立Ｎｅｕ基因在不同标本病变中的表达．结果：Ｎｅｕ基因在恶变组有高表达（６３．５％），以转移和复发的病变反应强度最高．此外，在癌前病变中也有较高的表达（５６．３％）．结论：本研究建立的免疫组化定量方法检测Ｎｅｕ基因表达的系统精确、可靠、重复性好，选取的指标可充分反映Ｎｅｕ基因表达的量以及细胞的阳性表达率．结果证实了Ｎｅｕ基因与口腔鳞癌的癌变关系密切，在癌变的早期以及转移和复发的病变中有较高的表达．     

Early sequelae of gunshot wounds to the spine: radiologic diagnosis

During a 6-month period, 11 consecutive patients who had delayed neurologic deterioration after sustaining a gunshot wound to the spine were prospectively evaluated clinically, radiologically, and surgically. The patients had dysesthetic burning pain in an anesthetic area, hyperhidrosis, flexor spasm, and additional motor deficit above the level of cord injury 2-22 weeks after injury. Radiologic evaluation consisted of plain radiography of the spine and metrizamide myelography followed by computed tomography. A syringomyelic cavity was found in seven patients, an arachnoid cyst in three, and osteomyelitis in one. Seven of these patients also had cord atrophy. Postoperatively, dysesthetic pain was relieved in all the patients. There was no recurrence during a 2-year follow-up. These results emphasize the need for immediate radiologic investigation in patients with gunshot wounds of the spine who have further deterioration superimposed on their initial deficit.     

Expression of the c-myc oncoprotein in human metaplastic epithelial cells of fibrocystic disease

Sections derived from fibrocystic disease in human breast tissue were examined for the presence of the c-myc oncoprotein by using the c-myc specific monoclonal antibody 9E10 (1). The results obtained revealed that the c-myc gene was not expressed in normal epithelial cells either of ducts or lobules. It was expressed mainly in mucous metaplastic cells and very rarely in apocrine cells. The c-myc protein was observed at a higher level in mucous metaplastic cells of epitheliosis and multiple papillomas. The number and intensity of positive mucous metaplastic cells was significantly increased after pretreating the sections with neuraminidase. We suggest that elevated expression of the c-myc nuclear oncoprotein in human breast metaplastic epithelial cells play a role in the early stages of malignant cell transformation.     

Extrarenal abnormalities in Tc-99m-DTPA renal blood flow studies

We observed extrarenal abnormalities during renal flow scintigraphy and retrospectively reviewed 90 patient studies to determine the types and frequencies of such abnormal findings. For each routine Tc-99m-DTPA renal flow study, we obtained nine 2-second sequential images, which included the heart, abdominal aorta, spleen and kidneys. Eighty abnormalities, observed in 62 patients, were divided into three categories: aortic, 37 cases (aneurysms, ectasia, thrombosis, tortuosity, and abruptly decreased flow); splenic, 40 cases (enlarged, small, or absent spleen); and miscellaneous, 3 cases (hepatic arterialization and very slow circulation). Other correlative studies including Tc-99m sulfur colloid-spleen scintigraphy, ultrasonography (US), CT, aortography, and surgical and/or autopsy findings were available for corroboration in 56 of 80 lesions.     

Seminal plasma alpha-glucosidase activity and male infertility

Measurement of alpha-glucosidase (alpha-GLUC) activity by means of a simple colorimetric test using a commercial kit (EpiScreen; FertiPro, Lotenhulle, Belgium) yielded results that were strongly correlated with the values obtained for the neutral iso-enzyme measured by a fluorimetric reference method (r=0.85, P=0.003, n=13). The former method was characterized by a low intra- and inter-coefficient of variation (6.6 and 4.3% respectively). Vasectomized men with azoospermia (n=27) had a significantly lower alpha-GLUC activity in semen than vasectomized men with residual spermatozoa present (n=11, P < 0.01) and men with azoospermia of primary testicular origin (n=33, P < 0.01). Receiver operating curve (ROC) analysis showed alpha-GLUC measurement to be reasonably accurate in differentiation between cases with obstructive versus testicular azoospermia at criterion value 13.5 U/l (sensitivity=82%, specificity= 70%). In cases with spermatozoa present, alpha-GLUC activity and output per ejaculate were positively correlated with sperm concentration (r=0.53 and 0.38, n=472), linear velocity (r=0.35 and 0.30, n=224), curvilinear velocity (r=0.32 and r=0.29, n=224), semen adenosine triphosphate (r=0.35 and 0.26, n=64), the concentration of 5alpha-dihydrotestosterone (r=0.31 and 0.29, n=74), and gamma-glutamyltransferase activity (r=0.62 and 0.32, n=275) in seminal plasma. The activity of alpha-GLUC was inversely correlated with ROS generation after 12-myristate, 13-acetate phorbol ester stimulation (r=-0.27, n=104), and both alpha-GLUC activity and total output were inversely correlated with the concentration of peroxidase- positive white blood cells among samples with > or =1x10(6)/ml of these cells (r=-0.30 and -0.19, n=165). It is concluded that simple photometric measurement of alpha-GLUC activity in seminal plasma reflects the functional state of the epididymis and may be helpful for the differential diagnosis of certain cases with azoospermia.      

Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis

Smit DL, Mensenkamp AR, Badeloe S, Breuning MH, Simon MEH, van Spaendonck KY, Aalfs CM, Post JG, Shanley S, Krapels IPC, Hoefsloot LH, van Moorselaar RJA, Starink TM, Bayley J‐P, Frank J, van Steensel MAM, Menko FH. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Heterozygous fumarate hydratase (FH) germline mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer. The main objective of our study was to evaluate clinical and genetic data from families suspected of HLRCC on a nationwide level. All families referred for FH mutation analysis in the Netherlands were assessed. We performed FH sequence analysis and multiplex ligation‐dependent probe amplification. Families with similar FH mutations were examined for haplotype sharing. In 14 out of 33 families, we identified 11 different pathogenic FH germline mutations, including 4 novel mutations and 1 whole‐gene deletion. Clinical data were available for 35 FH mutation carriers. Cutaneous leiomyomas were present in all FH mutation carriers older than 40 years of age. Eleven out of 21 female FH mutation carriers underwent surgical treatment for symptomatic uterine leiomyomas at an average of 35 years. Two FH mutation carriers had papillary type 2 renal cancer and Wilms' tumour, respectively. We evaluated the relevance of our findings for clinical practice and have proposed clinical diagnostic criteria, indications for FH mutation analysis and recommendations for management.