The triptolide derivative MRx102 inhibits Wnt pathway activation and has potent anti-tumor effects in lung cancer.

BACKGROUND: The natural compound triptolide has been shown to decrease cell proliferation and induce apoptosis and cellular senescence. We previously demonstrated that triptolide decreases tumor formation and metastasis of human non-small cell lung cancer cells (NSCLC). Due to the toxicity of triptolide, derivatives of the natural compound have been developed that show more favorable toxicity profiles and pharmacokinetics in animal models. The purpose of this study was to evaluate MRx102 as a novel therapeutic for lung cancer. METHODS: Mice injected subcutaneously with H460 lung cancer cells were treated with MRx102 or carboplatin to determine the effect of MRx102 on tumor formation in comparison to standard treatment. Patient-derived xenografts (PDX) with different WIF1 expression levels were treated with MRx102 or cisplatin. We tested the effects of MRx102 treatment on migration and invasion of lung cancer cells using Transwell filters coated with fibronectin and Matrigel, respectively. Tail vein injections using H460 and A549 cells were performed. RESULTS: Here we report that the triptolide derivative MRx102 significantly decreases NSCLC proliferation and stimulates apoptosis. Further, MRx102 potently inhibits NSCLC haptotactic migration and invasion through Matrigel. In vivo, NSCLC tumor formation and metastasis were greatly decreased by MRx102 treatment. The decrease in tumor formation by MRx102 in the patient-derived xenograft model was WIF1-dependent, demonstrating that MRx102 is a potent inhibitor of the Wnt pathway in low WIF1 expressing NSCLC patient tumors. CONCLUSIONS: These results indicate that MRx102 has potent antitumor effects both in vitro and in vivo, and is a potential novel therapy for the treatment of NSCLC.

Kikuchi-Fujimoto disease complicated by aseptic meningitis and hemophagocytosis successfully treated with intrathecal dexamethasone.

Kikuchi-Fujimoto disease (KFD) is thought to be a self-limited disease featuring fever and cervical lymphadenopathy; most cases having a favorable outcome. Severe disease and death are occasionally reported. Here we report a case of KFD complicated by hemophagocytosis and aseptic meningitis. The symptoms and laboratory parameters improved after systemic glucocorticoids, intravenous immunoglobulin and one dose of intrathecal dexamethasone. Clinicians should aware of this disease and make early diagnosis by lymph node biopsy to avoid over-treatment.

Identification of Tissue-Specific DNA Methylation Signatures for Thyroid Nodule Diagnostics.

PURPOSE: Thyroid cancer is frequently difficult to diagnose due to an overlap of cytologic features between malignant and benign nodules. This overlap leads to unnecessary removal of the thyroid in patients without cancer. While providing some improvement over cytopathologic diagnostics, molecular methods frequently fail to provide a correct diagnosis for thyroid nodules. These approaches are based on the difference between cancer and adjacent thyroid tissue and assume that adjacent tissues are the same as benign nodules. However, in contrast to adjacent tissues, benign thyroid nodules can contain genetic alterations that can be found in cancer.Experimental Design: For the development of a new molecular diagnostic test for thyroid cancer, we evaluated DNA methylation in 109 thyroid tissues by using genome-wide single-base resolution DNA methylation analysis. The test was validated in a retrospective cohort containing 65 thyroid nodules. RESULTS: By conducting reduced representation bisulfite sequencing in 109 thyroid specimens, we found significant differences between adjacent tissue, benign nodules, and cancer. These tissue-specific signatures are strongly linked to active enhancers and cancer-associated genes. Based on these signatures, we developed a new epigenetic approach for thyroid diagnostics. According to the validation cohort, our test has an estimated specificity of 97% [95% confidence interval (CI), 81-100], sensitivity of 100% (95% CI, 87-100), positive predictive value of 97% (95% CI, 83-100), and negative predictive value of 100% (95% CI, 86-100). CONCLUSIONS: These data show that epigenetic testing can provide outstanding diagnostic accuracy for thyroid nodules.See related commentary by Mitmaker et al., p. 457.

Transjugular liver biopsy with an automated trucut-type needle: comparative study with percutaneous liver biopsy.

OBJECTIVE: Transjugular liver biopsy using the suction method usually produces small specimens with excessive fragmentation, hence the diagnosis adequacy of specimens and the clinical impact of performing the biopsy have been questioned. An alternative biopsy needle, the Quick-Core needle system, which uses an automated trucut-type mechanism, has been shown to produce non-fragmented tissue specimens. The aim of the present study was to evaluate the safety, adequacy and clinical impact of the transjugular liver biopsy by comparing it with the standard percutaneous liver biopsy. DESIGN: We recruited all patients who underwent liver biopsies by percutaneous or transjugular routes in the Department of Medicine, Princess Margaret Hospital, Hong Kong between January 1998 and December 1999. METHOD: We recorded demographics and clinical features of patients, indications and complications, and the clinical impact of the liver biopsy procedure. All liver biopsy specimens were reviewed by the histopathologist, who was blinded to the approach of taking the biopsy. All variables between patients undergoing transjugular and percutaneous liver biopsies were compared. RESULTS: During the study period, 50 percutaneous and 18 transjugular liver biopsies were performed. All transjugular liver biopsies were performed successfully with adequate tissue for diagnosis. Although specimens obtained by the transjugular technique tended to be shorter (10 mm v. 18 mm by the percutaneous approach, P < 0.001), the presence of fragmentation was similar to that in biopsies obtained by the percutaneous approach. Respectively, 100% and 98% of specimens obtained by the transjugular and percutaneous approaches were considered to be adequate for histological assessment. The clinical impact of transjugular and percutaneous liver procedures was comparable (89% v. 76%, P = 0.25). CONCLUSION: Specimens obtained by a transjugular automated trucut needle are sufficient for histological assessment, and carry clinical impact in patient management.