Enantioselective Nickel-Catalyzed Reductive Aryl/Alkenyl-Cyano Cyclization Coupling to All-Carbon Quaternary Stereocenters.

An enantioselective nickel-catalyzed intramolecular reductive cross-coupling of C(sp2) electrophiles and cyano groups is reported. Enantioenriched CN-containing all-carbon quaternary stereocenters are assembled by desymmetrizing cyclization of aryl/alkenyl halide-tethered malononitriles. The use of an organic reductant, (EtO)2MeSiH, is crucial to the enantioselectivity and reactivity. Applications of the method are demonstrated through the synthesis of bioactive molecules and their cyanated analogues and the total synthesis of the natural product diomuscinone. This study exhibits the potential of desymmetrizing reductive coupling strategies to access structurally rigid and synthetically versatile molecules from readily available starting materials.

Enantioselective Synthesis of α-All-Carbon Quaternary Center-Containing Carbazolones via Amino-palladation/Desymmetrizing Nitrile Addition Cascade.

An enantioselective Pd(II)-catalyzed amino-cyclization and desymmetrizing nitrile addition cascade reaction of alkyne-tethered malononitriles is reported. This reaction forms two rings and one quaternary carbon center in a single step and serves as an efficient strategy for the construction of α-quaternary carbazolones with high enantioselectivities (up to 98:2 er). The utility of this method is demonstrated by product derivatization into a diverse array of heterocycles and a nitrile-containing leucomidine A analog.

Genomic Study of Chinese Quadruple-negative GISTs Using Next-generation Sequencing Technology.

PURPOSE: Approximately 10% of gastrointestinal stromal tumors (GISTs) are devoid of KIT, PDGFRA (platelet-derived growth factor-alpha), BRAF, and SDH alterations. The aim of this study was to characterize molecular drivers in Chinese patients with quadruple-negative GISTs. PATIENTS AND METHODS: In 1022 Chinese patients with GIST, mutations of KIT and PDGFRA were analyzed by direct sequencing. Of these mutations, 142 KIT/PDGFRA wild-type (WT) GISTs were detected, and succinate dehydrogenase (SDH) deficiency was determined using immunohistochemistry analysis of succinate dehydrogenase B. In 78 KIT/PDGFRA/SDH cases, we performed targeted 425 cancer-related gene analysis using next-generation sequencing. The correlation between molecular findings and clinicopathologic features was also analyzed. RESULTS: We defined 72 quadruple-negative GISTs from enrollments. They featured nongastric localization with histologic characteristics of spindle cells and male predilection. An overall 27.78% (20/72) of quadruple-negative tumors carried TP53, and 25.00% (18/72) carried RB1 mutations, which were frequently associated with high mitotic index and large size. TP53 analyses demonstrated coexistence with mutational activation of other oncogenes in 12 of 20 cases. A total of 18 RB1-mutated cases were independent of TP53. Further, no tumors carried NF1 and BRAF mutations. CONCLUSIONS: We report the genomic analysis of Chinese quadruple-negative patients. These databases may help advance our understanding of quadruple-negative GISTs' progression. Next-generation sequencing from GISTs is feasible to provide relevant data for guiding individualized therapy.

Epidermal Growth Factor Receptor Gene Mutation Status in Primary Lung Adenocarcinoma and Corresponding Bone Metastases.

BACKGROUND: The aim of this study was to compare epidermal growth factor receptor (EGFR) mutations between primary tumors and corresponding bone metastases (BMs) in lung adenocarcinoma. MATERIALS AND METHODS: In total, 115 paired primary lung adenocarcinoma and corresponding BM tumors were analyzed for EGFR mutations by Amplification Refractory Mutation System. RESULTS: EGFR mutations were detected in 61 primary lung adenocarcinomas (53.04%) and in 67 corresponding metastases (58.26%), respectively. The EGFR mutation rate was significantly higher in female and in never-smoker patients. The consistency of EGFR mutations between the 115 matched BMs and primary tumor tissue samples reached to 80.87%, and the disparity was 19.13%. Mutations in exons 19 (19-del) and 21 (point mutation L858R) were the predominant mutation type. CONCLUSIONS: The concordance rate demonstrated the feasibility of EGFR mutations in corresponding metastases using Amplification Refractory Mutation System when the primary tumor tissue is unavailable in the lung adenocarcinoma patients, and the inconsistency indicates that corresponding metastasis being screened simultaneously with the primary tumor samples may present some supplementary information for the patients.

Comparison of Epidermal Growth Factor Receptor Gene Mutations Identified Using Pleural Effusion and Primary Tumor Tissue Samples in Non-Small Cell Lung Cancer.

BACKGROUND: Although the use of pleural effusion samples for epidermal growth factor receptor (EGFR) testing in lung cancer is increasing, the accuracy rate and effectiveness of identifying EGFR mutations using these samples, rather than primary tumor tissue samples, is not established. MATERIALS AND METHODS: One hundred ninety-two advanced, non-small cell lung cancer patients were enrolled into this study. All patients had primary tumor tissue and corresponding pleural effusion samples, and we employed the Amplification Refractory Mutation System to detect EGFR gene mutations in these samples. RESULT: The number of EGFR mutations detected in primary tumor tissue and pleural effusion samples was 119 (61.98%) and 113 (58.85%), respectively. The EGFR-mutation rate was significantly higher in female than in male patients, and in adenocarcinoma than in nonadenocarcinoma patients (P=0.000). Single mutations in exons 19 and 21 were the predominant observed mutation type, and the overall concordance rate of EGFR-mutation status between the 192 matched pleural effusion and primary tumor tissue samples was 86.98%. CONCLUSIONS: We observed a high concordance rate between EGFR mutations identified using primary tumor tissue and corresponding pleural effusion samples by Amplification Refractory Mutation System. Thus, it is likely that pleural effusion sampling from advanced non-small cell lung cancer patients, especially those with adenocarcinoma, may be effective in EGFR-mutation screening.