In vitro elimination of epidermal growth factor receptor-overexpressing cancer cells by CD32A-chimeric receptor T cells in combination with cetuximab or panitumumab

Cetuximab and panitumumab bind the human epidermal growth factor receptor (EGFR). Although the chimeric cetuximab (IgG1) triggers antibody-dependent-cellular-cytotoxicity (ADCC) of EGFR positive target cells, panitumumab (a human IgG2) does not. The inability of panitumumab to trigger ADCC reflects the poor binding affinity of human IgG2 Fc for the FcγRIII (CD16) on natural killer (NK) cells. However, both human IgG1 and IgG2 bind the FcγRII (CD32A) to a similar extent. Our study compares the ability of T cells, engineered with a novel low-affinity CD32A^131R-chimeric receptor (CR), and those engineered with the low-affinity CD16^158F-CR T cells, in eliminating EGFR positive epithelial cancer cells (ECCs) in combination with cetuximab or panitumumab. After T-cell transduction, the percentage of CD32A^131R-CR T cells was 74 ± 10%, whereas the percentage of CD16^158F-CR T cells was 46 ± 15%. Only CD32A^131R-CR T cells bound panitumumab. CD32A^131R-CR T cells combined with the mAb 8.26 (anti-CD32) and CD16^158F-CR T cells combined with the mAb 3g8 (anti-CD16) eliminated colorectal carcinoma (CRC), HCT116^FcγR+ cells, in a reverse ADCC assay in vitro. Crosslinking of CD32A^131R-CR on T cells by cetuximab or panitumumab and CD16^158F-CR T cells by cetuximab induced elimination of triple negative breast cancer (TNBC) MDA-MB-468 cells, and the secretion of interferon gamma and tumor necrosis factor alpha. Neither cetuximab nor panitumumab induced Fcγ-CR T antitumor activity against Kirsten rat sarcoma (KRAS)-mutated HCT116, nonsmall-cell-lung-cancer, A549 and TNBC, MDA-MB-231 cells. The ADCC of Fcγ-CR T cells was associated with the overexpression of EGFR on ECCs. In conclusion, CD32A^131R-CR T cells are efficiently redirected by cetuximab or panitumumab against breast cancer cells overexpressing EGFR.     

Birth weight,weight over the adult life course and risk of breast cancer

Breast cancer has been suggested to potentially have prenatal origins. We examined associations between birth weight, body mass index (BMI) at four-time points over 25 years of adulthood, and risk of postmenopausal breast cancer, with emphasis on whether the association between birth weight and risk of breast cancer was mediated by weight and height changes over the adult life course. Postmenopausal women (n = 70,397) aged 50–79 years without breast cancer at enrollment (1993–1998) were followed up to 25 years. Weight and height were measured at baseline. Birth weight, and weights at ages 18, 35 and 50 were self-reported. Breast cancer cases were centrally adjudicated. Compared to women with birth weight of 6–8 pounds, women with birth weight of <6 pounds had lower risk of breast cancer (HR = 0.88 95% CI: 0.79–0.99). 44% and 21% of the relationship between birth weight and breast cancer risk was mediated by adult height and weight at baseline, respectively. Birth weight of 8 pounds or more was not associated with risk of postmenopausal breast cancer. Weight gain in adulthood was associated with increased risk of breast cancer regardless of time periods. In conclusion, lower birthweight was associated with lower risk of postmenopausal breast cancer, and this reduction in risk was significantly mediated by childhood or adolescent growth, especially by adult height. Our data suggest that reaching and maintaining a healthy weight during adulthood is key in the prevention of breast cancer.     

Theoretical potential for endometrial cancer prevention through primary risk factor modification: Estimates from the EPIC cohort

Endometrial cancer (EC) incidence rates vary ~10-fold worldwide, in part due to variation in EC risk factor profiles. Using an EC risk model previously developed in the European EPIC cohort, we evaluated the prevention potential of modified EC risk factor patterns and whether differences in EC incidence between a European population and low-risk countries can be explained by differences in these patterns. Predicted EC incidence rates were estimated over 10 years of follow-up for the cohort before and after modifying risk factor profiles. Risk factors considered were: body mass index (BMI, kg/m²), use of postmenopausal hormone therapy (HT) and oral contraceptives (OC) (potentially modifiable); and, parity, ages at first birth, menarche and menopause (environmentally conditioned, but not readily modifiable). Modeled alterations in BMI (to all ≤23 kg/m²) and HT use (to all non-HT users) profiles resulted in a 30% reduction in predicted EC incidence rates; individually, longer duration of OC use (to all ≥10 years) resulted in a 42.5% reduction. Modeled changes in not readily modifiable exposures (i.e., those not contributing to prevention potential) resulted in ≤24.6% reduction in predicted EC incidence. Women in the lowest decile of a risk score based on the evaluated exposures had risk similar to a low risk countries; however, this was driven by relatively long use of OCs (median = 23 years). Our findings support avoidance of overweight BMI and of HT use as prevention strategies for EC in a European population; OC use must be considered in the context of benefits and risks.     

基于现代医学诊疗模式的非小细胞肺癌中医证型梳理与浅析

肺癌为中国常见的呼吸道恶性肿瘤，其发病率及病死率常年占据中国恶性肿瘤首位，随着现代分子生物学研究进展，综合治疗使得肺癌患者的生存时间明显延长。基于西医的综合治疗方案，中国中西医结合的综合治疗因中医独特的辨证观和整体观在提高疗效、改善患者生活质量、减轻不良反应、延长生存期方面发挥着积极的作用，因此基于现代医学诊疗方案下患者的证型研究尤为重要。文章将梳理非小细胞肺癌（NSCLC）患者现代医学诊疗模式下的中医证型，以此指导今后中西医结合的综合治疗，从而更好地提高非小细胞肺癌患者的生存及生活质量。     

人乳头瘤病毒致癌关键因素的研究进展

人乳头瘤病毒（human papillomavirus，HPV）感染与多种疾病相关，特别是高危型人乳头瘤病毒更是与头颈部鳞癌、生殖器官癌等多种癌症关系密切，其中与宫颈癌的相关性尤为显著。人乳头瘤病毒基因组共分为早期基因编码区（E）、晚期基因编码区（L）和长控制区（LCR），这些基因各自发挥功能，并与宿主细胞相互作用使正常宫颈组织发生癌变。因此大量的研究工作围绕此展开，本文将对目前关于HPV基因组各功能区基因作用及致癌机制的研究成果加以综述。     

Assessing the Clinical Benefit of UBC Rapid in the Surveillance and Initial Diagnosis of Bladder Cancer

IntroductionSeveral studies have shown that abnormal urine levels of cytokeratins 8 and 18 are associated with bladder cancer. However, the clinical benefit of the UBC (urinary bladder cancer) Rapid assay has remained unclear.Patients and MethodsWe performed the UBC Rapid assay and voided cytology in 336 patients—297 in surveillance for non–muscle-invasive bladder cancer and 39 with newly diagnosed bladder cancer. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated by contingency. We also controlled for the patients with positive UBC Rapid findings but negative cystoscopy findings to prove the former’s ability to provide an anticipatory diagnosis.ResultsWe diagnosed 27 recurrences (9.8%). Overall, the sensitivity of the UBC Rapid assay was better for the higher risk groups and after adding the cytology findings. The only independent predictor of a positive UBC Rapid assay was the tumor size. Of the 81 patients with positive UBC Rapid findings without positive cystoscopy findings, 8 (10%) had developed a recurrence within the first year. Avoiding cystoscopy for the patients with UBC Rapid negative results could avoid 184 cystoscopies (66%) but would result in missing 7 of 13 high-risk recurrences.ConclusionsThe performance of the UBC Rapid assay improved with increasing tumor size. Limiting cystoscopies to patients with UBC Rapid positive results could result in a reduction in surveillance cystoscopies but could result in missing high-risk recurrences. Finally, the UBC Rapid assay was not useful for anticipatory diagnoses.     

乳腺癌21基因检测的研究进展

乳腺癌是一类具有异质性的肿瘤，不同患者的治疗方法和疗效都不相同。尽管目前仍在努力为激素受体（hormone receptor，HR）阳性（+）、人表皮生长因子受体2（human epidermal growth factor receptor 2,HER-2）阴性（-）、淋巴结（axillary lymph node，ALN）阴性（-）的早期乳腺癌患者寻找合适的治疗方法，但其术后是否需要化疗仍然是肿瘤科医生面临的一个难题。以往治疗主要依赖于经典的组织病理学和免疫组织化学技术，随着精准医疗时代的到来，我们需要更定量的诊断方法和合理的个体化治疗。虽然化疗可降低疾病复发风险并提高生存率，但它带来的不良反应事件会降低患者的生活质量，尤其低复发风险（recurrence risk,RS)有可能超过化疗益处。21基因检测不仅可以预测这类早期乳腺癌化疗疗效及评估预后，还可提供精准的个体化治疗方案指导用药，为患者增添信心。本文就乳腺癌21基因检测的研究进展进行综述。