Phosphorylation of tyrosine 1248-ERBB2 measured by chemiluminescence-linked immunoassay is an independent predictor of poor prognosis in primary breast cancer patients

ERBB2 (HER2/Neu) gene amplification and overexpression is associated with increased risk of metastases and shorter survival in breast cancer. Tyrosine 1248 is a major phosphorylation site of ERBB2 and reflects the activation status of the receptor. The aim of this study was to investigate the relationships between quantitative levels of pY1248-ERBB2 (p-ERBB2) and the expression of epidermal growth factor receptor (EGFR)-family members, and whether p-ERBB2 could provide additional prognostic value compared with established prognostic markers. For this purpose we developed a highly sensitive chemiluminescence-linked immunoassay (CLISA) and detected p-ERBB2 levels in 70 primary breast cancer biopsies. Phosphorylated ERBB2 correlated with EGFR and ERBB2, and inversely with oestrogen receptor (ER), progesterone receptor (PgR) and ERBB4 expression levels. Additionally, p-ERBB2 was associated with poor clinical outcome in univariate and multivariate Cox regression analysis. Further studies are needed to evaluate the predictive value of p-ERBB2.     

小细胞肺癌作为第二原发肿瘤的临床特征

目的探讨小细胞肺癌作为第二原发肿瘤的临床特征。方法回顾分析美国康州Hartford医院Helen＆Harry Gray癌症中心10年诊治的355例小细胞肺癌，其中经正规治疗者165例。作为第二原发肿瘤发生于其他恶性肿瘤之后的小细胞肺癌48例，经正规治疗者28例。结果48例小细胞肺癌诊断之前患有其他恶性肿瘤，占13．5％，其中包括头颈部癌4例（8．3％），皮肤癌11例（22．9％，其中2例为三原发肿瘤），非小细胞肺癌2例（4．2％），乳腺癌6例（12．5％），胃肠肿瘤5例（10．4％），妇科肿瘤3例（6．3％），男性泌尿生殖道肿瘤5例（10．4％），前列腺癌13例（27．1％），血液系统肿瘤2例（4．2％）。三原发肿瘤5例（10．4％）。有吸烟史者93％（40／43例）。发生在前列腺癌后的患者与发生在皮肤癌后的患者相比，年龄较大，正规治疗者较少，生存期较短（分别为3．5月和15月）。在28例正规治疗患者中，11例完全缓解（39．3％），12例部分缓解（42．9％），其生存期为5．1～77．7月（中位11．3月）；20例未治疗患者的生存期为0．5～34．0月（中位2．0月）。165例经正规治疗过的第一原发SCLC的中位生存期（13．5月）、缓解率（77．6％）与28例第二原发SCLC（11．3月，82．1％）均无显著差异。（P〉0．05）。结论小细胞肺癌作为第二原发肿瘤的发生率为13．5％，其中三原发肿瘤为10．4％。其治疗有效率和生存期与一般小细胞肺癌均无差异。发生在前列腺癌后的患者可能比发生在皮肤癌后的患者预后差。     

Identification of human platelet glycoprotein VI-specific IgG autoantibody and its fragments.

Glycoprotein VI (GPVI), as a major receptor for collagen on the platelet surface, mediates the initial platelet contact with collagen, and causes platelet aggregation and thrombosis. Agents of anti-GPVI can inhibit the adhesion, activation and aggregation function of platelets, which can be used for preventing thrombotic diseases. To make humanized monoclonal antibodies by phage surface display technology, we studied plasmas from 44 patients with chronic idiopathic thrombocytopenic purpura using modified monoclonal antibody immobilization of platelet antigen assays. GPVI-specific antibodies were found in six (13.6%) patients. Among these, only one showed significant inhibition of platelet aggregation induced by collagen. The IgG antibody and F(ab')2 fragments of this patient's plasma were further purified and their immunoreactivities and effects on platelet aggregation were reanalyzed. It was found that purified IgG and its F(ab')2 fragments from the patient not only retained the ability to bind to platelet GPVI, but also inhibited collagen-induced platelet aggregation. In this study, therefore, the specific anti-platelet GPVI autoantibody that inhibits collagen-induced platelet aggregation has been successfully screened out, which can be used to develop completely humanized anti-GPVI phage antibody.     

Anlotinib Monotherapy for Refractory Metastatic Colorectal Cancer: A Double-Blinded,Placebo-Controlled,Randomized Phase III Trial (ALTER0703)

Background

Treatment options for refractory metastatic colorectal cancer (mCRC) were limited. Anlotinib is a novel multitarget tyrosine kinase inhibitor. ALTER0703 study was conducted to assess efficacy and safety of anlotinib for patients with refractory mCRC.

Materials and Methods

This was a multicenter, double-blinded, placebo-controlled, randomized phase III trial involving 33 hospitals in China. Patients had taken at least two lines of therapies were 2:1 randomized to receive oral anlotinib (12 mg/day; days 1–14; 21 days per cycle) or placebo, plus best supportive care. Randomization was stratified by previous VEGF-targeting treatments and time from diagnosis to metastases. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), and safety.

Results

A total of 419 patients (anlotinib: 282; placebo: 137) were treated from December 2014 to August 2016. The median PFS was improved in anlotinib group (4.1 months; 95% confidence interval [CI], 3.4–4.5) over placebo group (1.5 months; 95% CI, 1.4–1.5), with a hazard ratio (HR) of 0.34 (95% CI, 0.27–0.43; p < .0001). However, median OS was similar between two groups (8.6 months; 95% CI, 7.8–9.7 vs. 7.2 months; 95% CI, 6.2–8.8; HR, 1.02; p = .870). Improvements of ORR and DCR were observed in anlotinib over placebo. The most common grade ≥ 3 anlotinib related adverse events were hypertension (20.92%), increased γ-GT (7.09%), and hand-foot skin reaction (6.38%).

Conclusion

Anlotinib was tolerated in Chinese patients with refractory mCRC. Although OS did not reach significant difference, anlotinib still provided clinical benefits by substantially prolonged PFS in these patients.

Implications for Practice

In this randomized clinical trial that included 419 patients with refractory metastatic colorectal cancer, substantial prolonged in progression-free survival was noted in patients who received anlotinib compared with those given placebo. Improvements on objective response rate and disease control rate was also observed in anlotinib group. However, overall survival was similar between the two groups. In a word, in third-line or above treatment of Chinese patients with refractory metastatic colorectal cancer, anlotinib provided clinical benefit by significantly prolonged progression-free survival.

     

Primary Care Physicians’ Perspectives in Leading Breast Cancer Follow-Up Care

IntroductionLimited data exist on the barriers associated with transitioning breast cancer follow-up care to primary care physicians (PCPs). This study aimed to describe the current perspectives of PCPs in managing breast cancer follow-up.MethodAn online survey was distributed to PCPs in Toronto, ON, Canada. Questions examined PCPs’ view of transitioning breast cancer follow-up care to their practices.ResultsOf 800 PCPs invited, 126 responded (response rate: 15.7%). The types of practice models amongst respondents included blended capitation (42.9%), blended salary (27%), and fee-for-service (17.5%). Seventy-seven percent of respondents stated they provided follow-up care. Approximately half of the respondents stated they were somewhat comfortable providing follow-up care. PCP-led follow-up care was considered either very (49.2%) or somewhat appropriate (30.2%). When asked about financial remuneration, 43.7% of respondents stated it was somewhat important. The factors that influenced the feasibility of PCP-led follow-up care included receipt of a detailed follow-up care plan provided by the specialist after discharge (81%), the ability to re-refer to specialists rapidly (56.3%), and the ability to obtain regular updates of best practice changes (59.5%). The preferred means of educational updates included E-mail (40.5%), continuing medical education events (30.2%), and electronic medical records (19.8%). When the fee model was taken into consideration there was no significant difference in opinions regarding follow-up care.ConclusionsTransitioning to a PCP-led model was supported by most of the PCPs who participated in this study. Their perspective on PCP-led follow up care and barriers associated with implementation of this model of care needs to be further explored with future studies that include larger sample size and a more diverse PCP population.     

Emerging Strategies in Treating Double Hit Lymphomas

Double hit lymphomas (DHLs) are a new category in the World Health Organization newest classification for lymphoid malignancies. DHL encompasses various histologies of lymphomas where the MYC oncogene and either BCL2 or BCL6 oncogenes are present concomitantly. Several observational studies and retrospective series have demonstrated that patients with DHL carry a poor prognosis and respond less and for a shorter duration to standard R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin, and prednisone). These studies have also proposed that dose intensification (with Burkitt-like regimens such as DA-EPOCH-R [dose-adjusted rituximab, etoposide, vincristine, Adriamycin, cyclophosphamide, and prednisone]) might offer patients with DHL better outcomes and improved prognosis. In this timely review, we discuss incidence of DHL, testing implications of MYC translocation, current treatment strategies, and future directions. Understanding this entity and its therapeutic consequences is essential to improve patients' outcomes.