Biweekly Cetuximab Plus FOLFOX6 as First-Line Therapy in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The CEBIFOX Trial

BackgroundThe multicenter, single-arm, phase II study CEBIFOX evaluated the efficacy of a biweekly cetuximab administration in combination with FOLFOX6 as first-line therapy in KRAS (exon 2) wild-type (wt) metastatic colorectal cancer (mCRC).Patients and methodsPatients received FOLFOX6 with cetuximab (500 mg/m²) every second week. Primary endpoint was objective response rate (ORR), among others secondary endpoints were safety, progression-free survival (PFS), overall survival (OS), and patient-reported outcome (PRO). The impact on the treatment efficacy was evaluated in explorative subgroup analyses, including extended molecular profiling and primary tumor location.ResultsIn total, 57 were included in the intention-to-treat (ITT) analyses. New RAS mutations were detected in 14.0% by post hoc next-generation sequencing analysis in 43 patients. The ORR in the all RASwt population was 70.3% with a median PFS and OS of 10.9 (95% confidence interval [CI], 9.0-12.9) and 33.8 (95% CI, 21.1-45.5) months. Grade 3-5 adverse events occurred in 66.7% of the ITT, without significant impact on the PRO. Patients with right-sided primary tumors had a reduced ORR (54.5%), and median PFS and OS (10.1 and 23.8 months). BRAF mutations were detected in 11.3%. These patients had a significantly lower ORR, and median PFS and OS. Patients with RASwt/BRAFwt tumors had a notably high median PFS and OS of 14.3 and 38.9 months.ConclusionsThis study supports the efficacy and safety of biweekly cetuximab given in combination with FOLFOX6 in patients with RASwt/BRAFwt mCRC with left-sided primary tumor. CEBIFOX is the first trial reporting the complete dataset, including extended molecular profiling and tumor location of a biweekly administered cetuximab/FOLFOX6 in mCRC. Clinical trial number: NCT01051167.     

ATP6L promotes metastasis of colorectal cancer by inducing epithelial‐mesenchymal transition

ATP6L, the C subunit of the V‐ATPase V0 domain, is involved in regulating the acidic tumor micro‐environment and may promote tumor progression. However, the expression and functional role of ATP6L in tumors have not yet been well explored. In this study, we found that ATP6L protein overexpression was related to colorectal cancer histological differentiation (P < 0.001), presence of metastasis (P < 0.001) and recurrence (P = 0.02). ATP6L expression in the liver metastatic foci was higher than in the primary foci (P = 0.04). ATP6L expression was notably concomitant with epithelial‐mesenchymal transition (EMT) immunohistochemical features, such as reduced expression of the epithelial marker E‐cadherin (P = 0.021) and increased expression of the mesenchymal marker vimentin (P = 0.004). Results of in vitro and in vivo experiments showed that ATP6L expression could alter cell morphology, regulate EMT‐associated protein expression, and enhance migration and invasion. The effect of ATP6L on metastasis was further demonstrated in a tail vein injection mice model. In addition, the mouse xenograft model showed that ATP6L‐overexpressing HCT116 cells grew into larger tumor masses, showed less necrosis and formed more micro‐vessels than the control cells. Taken together, our results suggest that ATP6L promotes metastasis of colorectal cancer by inducing EMT and angiogenesis, and is a potential target for tumor therapy.     

Targeting glycosylated antigens on cancer cells using siglec-7/9-based CAR T-cells

Chimeric antigen receptor (CAR) T-cells treatment demonstrate the increasing and powerful potential of immunotherapeutic strategies, as seen mainly for hematological malignancies. Still, efficient CAR-T cell approaches for the treatment of a broader spectrum of tumors are needed. It has been shown that cancer cells can implement strategies to evade immune response that include the expression of inhibitory ligands, such as hypersialylated proteins (sialoglycans) on their surface. These may be recognized by sialic acid-binding immunoglobulin-type lectins (siglecs) which are surface receptors found primarily on immune cells. In this regard, siglec-7 and -9 are found on immune cells, such as natural killer cells, T-cells, and dendritic cells and they can promote immune suppression when binding to sialic acids expressed on target cells. In the present study, we hypothesized that it is possible to use genetically engineered T-cells expressing siglec-based CARs, enabling them to recognize and eliminate tumor cells, in a non-histocompatibility complex molecule restricted way. Thus, we genetically modified human T-cells with different chimeric receptors based on the exodomain of human siglec-7 and -9 molecules and selected optimal receptors. We then assessed their antitumor activity in vitro demonstrating the recognition of cell lines from different histologies. These results were confirmed in a tumor xenograft model exemplifying the potential of the present approach. Overall, this study demonstrates the benefit of targeting cancer-associated glycosylation patterns using CAR based on native immune receptors and expressed in human primary T-cells.     

SOX6 represses tumor growth of clear cell renal cell carcinoma by HMG domain-dependent regulation of Wnt/β-catenin signaling

Sex-determining region Y box (SOXs) are expressed in various cells and control cell fate and differentiation in a multitude of physiologic processes. SOX6, a main representative of SOXs, is involved in the regulation of carcinogenesis in various human malignancies. However, the role of SOX6 in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, SOX6 expression in ccRCC and its clinical significance were investigated. In vitro and in vivo assays were used to explore the tumor-related function and the underlying molecular mechanism of SOX6 in ccRCC. We confirmed that SOX6 was frequently downregulated in ccRCC tissues and cell lines. Besides, downregulation of SOX6 was significantly associated with larger tumor sizes, advanced tumor stage, higher Fuhrman grades, and its expression could act as an independent prognostic factor for ccRCC (hazards ratio = 0.590, P = .026). Gain/loss-of-function experiments demonstrated that SOX6 could remarkably inhibit tumor cell growth and foci formation in vitro and xenograft tumorigenesis in vivo, respectively. Mechanistically, SOX6 could influence cell cycle by regulating the G1/the S phase transition and had an inhibitory effect on Wnt/β-catenin signaling as well as its target genes, c-Myc and cyclin D1. Interesting, the tumor-suppressive function of SOX6 was proved to be dependent on its specific high-mobility-group (HMG) domain. In general, our findings indicated that SOX6 was a novel tumor suppressor and prognostic biomarker in ccRCC. SOX6 could inhibit tumor growth by negatively regulating the Wnt/β-catenin signaling pathway in an HMG domain-dependent manner in ccRCC, which might provide a novel therapeutic approach for ccRCC.     

Treatment of generalized infantile myofibromatosis with sorafenib and imatinib: A case report

Infantile myofibromatosis (IM) is characterized by solitary musculoskeletal nodules presenting during infancy but can manifest as multiple lesions with visceral involvement. Multicentric IM with visceral involvement carries a high risk of mortality and there is no consensus on treatment. We present a case of a patient with multicentric IM and pulmonary involvement who progressed on several chemotherapeutic regimens and subsequently had a complete response to sorafenib and later imatinib. This report describes the novel use of sorafenib and imatinib to treat generalized IM and the role of continued tyrosine kinase inhibitor therapy to maintain remission.     

大承气汤足浴和足底穴位按摩护理干预改善肿瘤切除术后化疗引起便秘临床观察

目的观察大承气汤足浴和足底穴位按摩护理干预对改善肿瘤切除术引起便秘的效果。方法选择2017年1月—2018年1月收治的60例住院患者,进行肿瘤切除术后随机均分为观察组和对照组,对照组给予一般护理干预,观察组在对照组的基础上使用大承气汤足浴和足底穴位按摩辅助治疗,观察患者术后便秘情况的发生率和治疗效果,对数据进行统计分析。结果对照组和观察组患者的便秘发生率有显著差异(P<0.05),对照组和观察组患者的粪便性状有显著差异(P<0.05)。结论应用大承气汤足浴和足底穴位按摩护理干预可改善肿瘤切除术后引起的便秘情况,值得推广使用。     

原发性卵巢非霍奇金淋巴瘤1例及相关文献复习

目的:探讨原发性卵巢弥漫性大B细胞淋巴瘤的病因、临床表现、诊断、治疗及预后。方法:报道1例原发性卵巢弥漫性大B细胞淋巴瘤的临床病理资料及术后免疫组化结果，并阅读及复习国内外相关文献。结果:该例患者为（右）卵巢弥漫性大B细胞淋巴瘤，积极治疗后现考虑肿瘤复发。结论:原发性卵巢弥漫性大B细胞淋巴瘤罕见，确诊依赖于术后病理及免疫组化，预后不佳，常采用以手术为主，辅以化疗和放疗的综合治疗。     

miRNA调控实体肿瘤发生发展机制研究进展

microRNA（miRNA）是广泛存在于动物、植物、微生物体内，在转录后水平调控mRNA翻译和降解的内源性染色体编码的小分子RNA。研究证实miRNA对实体肿瘤细胞的发生、增殖、分化、侵袭及转移均具有重要意义。目前miRNA与肿瘤相关性的研究主要集中在检测实体肿瘤组织或体液中miRNA的表达量，明确其对于肿瘤发生、发展的意义；寻找具有临床意义的miRNA靶点，并通过调控其表达抑制肿瘤增殖与转移。miRNA检测方法的进步，也为临床检测miRNA提供了可能。本文对miRNA在实体肿瘤发生发展的作用及其调控机制、以及未来研究方向作综述。     

The role of transforming growth factor-beta in immune suppression and chronic inflammation of squamous cell carcinomas

Despite a decline in the incidence of squamous cell carcinomas (SCCs) over the past 20 years, their survival rate has remained nearly the same, indicating that treatment options have not improved relative to other cancer types. Immunotherapies have a high potential for a sustained effect in SCC patients, but their response rate is low. Here, we review the suppressive role of transforming growth factor-beta (TGFβ) on the antitumor immune response in SCC and present its potential as a therapeutic target in combination with the current range of immunotherapies available for SCC patients. We conclude that SCCs are an optimal cancer type to study the effectiveness of TGFβ inhibition due to the prevalence of dysregulated TGFβ signaling in them.