The new (Version 9) American Joint Committee on Cancer tumor, node, metastasis staging for cervical cancer

The American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) staging for all cancer sites has been periodically updated as a published manual for many years. The last update, the eighth edition AJCC Cancer Staging Manual went into use on January 1, 2018. The AJCC has since restructured and updated its processes, and all AJCC staging-related data are now housed on its new application programming interface. Consequently, the next AJCC TNM staging update, AJCC version 9 TNM staging, will be published electronically and will be released chapter by chapter. The first chapter of version 9 AJCC TNM staging is the updated cervical cancer staging, which is now published. This article highlights the changes to the AJCC TNM cervical cancer staging; these changes align with the International Federation of Gynecology and Obstetrics staging. The most important of the changes are: 1) the incorporation of imaging and surgical findings, 2) the elimination of lateral spread from T1a, 3) the addition of a subcategory to T1b (T1b3), and 4) histopathology is updated to reflect human papillomavirus-associated and human papillomavirus-independent carcinomas

Interleukin-4 deficiency enhances Th1 responses and crescentic glomerulonephritis in mice

Interleukin-4 deficiency enhances Th1 responses and crescentic glomerulonephritis in mice. Evidence suggests that crescentic glomerulonephritis (GN) is due to T helper cell 1 (Th1) directed delayed-type hypersensitivity (DTH)-like injury. As endogenous interleukin (IL)-4, (the pivotal cytokine in Th2 responses) may attenuate Th1 responses in this disease, we compared the development of crescentic GN, induced by a planted antigen, in mice genetically deficient in IL-4 (IL-4−/−) with disease in normal mice (IL-4+/+). IL-4−/− mice developed more severe GN with increased renal impairment (CCr 35 ± 7 μl/min vs. 133 ± 14 μl/min, P < 0.002) and crescent formation (55.7 ± 8.4% vs. 4.9 ± 1.2%, P < 0.002). This was associated with increased glomerular fibrin deposition, glomerular CD4+ T cell infiltration and macrophage recruitment. Systemically, IL-4−/− mice showed an increased antigen specific Th1 response indicated by increased skin DTH, and increased IgG3 and IgG2b. Decreased IgG1 levels indicated a reduced Th2 response. These results demonstrate a protective role for endogenous IL-4 in crescentic GN. They show that IL-4 deficiency promotes crescentic glomerular injury and amplifies local and systemic Th1 responses. They support the hypothesis that crescent formation results from Th1 immune responses to antigens in the glomerulus

Novel treatment option for MUC16-positive malignancies with the targeted TRAIL-based fusion protein Meso-TR3

BACKGROUND: The targeted delivery of cancer therapeutics represents an ongoing challenge in the field of drug development. TRAIL is a promising cancer drug but its activity profile could benefit from a cancer-selective delivery mechanism, which would reduce potential side effects and increase treatment efficiencies. We recently developed the novel TRAIL-based drug platform TR3, a genetically fused trimer with the capacity for further molecular modifications such as the addition of tumor-directed targeting moieties. MUC16 (CA125) is a well characterized biomarker in several human malignancies including ovarian, pancreatic and breast cancer. Mesothelin is known to interact with MUC16 with high affinity. In order to deliver TR3 selectively to MUC16-expressing cancers, we investigated the possibility of targeted TR3 delivery employing the high affinity mesothelin/MUC16 ligand/receptor interaction. METHODS: Using genetic engineering, we designed the novel cancer drug Meso-TR3, a fusion protein between native mesothelin and TR3. The recombinant proteins were produced with mammalian HEK293T cells. Meso-TR3 was characterized for binding selectivity and killing efficacy against MUC16-positive cancer cells and controls that lack MUC16 expression. Drug efficacy experiments were performed in vitro and in vivo employing an intraperitoneal xenograft mouse model of ovarian cancer. RESULTS: Similar to soluble mesothelin itself, the strong MUC16 binding property was retained in the Meso-TR3 fusion protein. The high affinity ligand/receptor interaction was associated with a selective accumulation of the cancer drug on MUC16-expressing cancer targets and directly correlated with increased killing activity in vitro and in a xenograft mouse model of ovarian cancer. The relevance of the mesothelin/MUC16 interaction for attaching Meso-TR3 to the cancer cells was verified by competitive blocking experiments using soluble mesothelin. Mechanistic studies using soluble DR5-Fc and caspase blocking assays confirmed engagement of the extrinsic death receptor pathway. Compared to non-targeted TR3, Meso-TR3 displayed a much reduced killing potency on cells that lack MUC16. CONCLUSIONS: Soluble Meso-TR3 targets the cancer biomarker MUC16 in vitro and in vivo. Following attachment to the tumor via surface bound MUC16, Meso-TR3 acquires full activation with superior killing profiles compared to non-targeted TR3, while its bioactivity is substantially reduced on cells that lack the tumor marker. This prodrug phenomenon represents a highly desirable property because it has the potential to enhance cancer killing with fewer side-effects than non-targeted TRAIL-based therapeutics. Thus, further exploration of this novel fusion protein is warranted as a possible therapeutic for patients with MUC16-positive malignancies

Mesothelin\u27s minimal MUC16 binding moiety converts TR3 into a potent cancer therapeutic via hierarchical binding events at the plasma membrane

TRAIL has been extensively explored as a cancer drug based on its tumor-selective activity profile but it is incapable per se of discriminating between death receptors expressed by normal host cells and transformed cancer cells. Furthermore, it is well documented that surface tethering substantially increases its biologic activity. We have previously reported on Meso-TR3, a constitutive TRAIL trimer targeted to the biomarker MUC16 (CA125), in which the entire ectodomain of human mesothelin was genetically fused to the TR3 platform, facilitating attachment to the cancer cells via the MUC16 receptor. Here, we designed a truncation variant, in which the minimal 64 amino acid MUC16 binding domain of mesothelin was incorporated into TR3. It turned out that the dual-domain biologic Meso64-TR3 retained its high MUC16 affinity and bound to the cancer cells quickly, independent of the TR3/death receptor interaction. Furthermore, it was substantially more potent than Meso-TR3 and TR3 in vitro and in a preclinical xenograft model of MUC16-dependent ovarian cancer. Phenotypically, Meso64-TR3 is more closely related to non-targeted TR3, evident by indistinguishable activity profiles on MUC16-deficient cancers and similar thermal stability characteristics. Overall, Meso64-TR3 represents a fully human, MUC16-targetd TRAIL-based biologic, ideally suited for exploring preclinical and clinical evaluation studies in MUC16-dependent malignancies

AXL modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer

The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro, genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer