Comparison of clinical and MRI features of brain metastases between ALK+ and ALK- NSCLC.

BACKGROUND: Non-small-cell lung cancer (NSCLC) is the primary cause of brain metastases (BM). This study aimed to investigate differences in clinical and magnetic resonance imaging (MRI) features of BM between anaplastic lymphoma kinase (ALK) gene fusion (ALK+) and ALK wild-type (ALK-) NSCLC, and to preliminarily assess the efficacy of radiotherapy for treating BM. METHODS: A retrospective analysis included 101 epidermal growth factor receptor (EGFR)- NSCLC patients with BM: 41 with ALK gene fusion and 60 being ALK-. The brain MRI and clinical features were compared between different ALK status using the multivariate analysis, and a nomogram was constructed to predict ALK gene fusion. Fifty-six patients who did not undergo cerebral surgery and had complete pre- and post- treatment data were further divided based on whether they received radiotherapy. Log-rank test was used to compare the short-term effect of treatment between the two groups under different genotypes. RESULTS: ALK+ BM exhibited decreased peritumoral brain edema size, lower peritumoral brain edema index (PBEI), and a more homogeneous contrast enhancement pattern compared to ALK- BM. Age (OR = 1.04; 95%CI: 1.02-1.06), time to BM (OR = 1.50; 95% CI: 1.04-2.14), PBEI (OR = 1.26; 95% CI: 0.97-1.62), smoking status (smoking index >400 vs. non-smoking status: OR = 1.42; 95% CI: 0.99-2.04) and contrast enhancement pattern (OR = 1.89; 95% CI: 1.28-2.78) were associated with ALK gene fusion. A nomogram based on these variables demonstrated acceptable predictive efficiency (AUC = 0.844). In the ALK+ group, patients who received radiotherapy did not show increased disease control rate (DCR) or progression-free survival (PFS). In contrast, in the ALK- group, those who received radiotherapy had improved objective response rate (ORR), DCR, and PFS compared to those who were only treated with systemic therapy. CONCLUSIONS: The clinical and MRI features of BM can indicate the status of ALK in NSCLC. In the ALK- group, patients who received radiotherapy showed higher ORR, DCR, and PFS compared to those who did not.

Case report: Robust response to sintilimab in advanced distal cholangiocarcinoma with PD-L1 expression and DNA damage repair.

Cholangiocarcinoma (CCA) is a highly heterogeneous tumor that occurs in the bile duct epithelium; adenosquamous carcinoma is a rare pathological subtype of CCA. The clinical treatment of patients with metastatic distal CCA poses significant challenges. We report a 53-year-old female diagnosed with a stage III adenosquamous carcinomas of distal CCA. Metastasis occurred 4 months postoperatively and she was diagnosed with stage IV disease. The patient was treated with Gemcitabine + Oxaliplatin (GEMOX) and Capecitabine + Oxaliplatin (CAPEOX), followed by sintilimab monotherapy. After two cycles of treatment, the patient achieved partial response (PR) and the lesion continued to shrink. After 37 months of follow-up, the patient's liver metastasis had almost completely disappeared, and complete response (CR) was achieved. Moreover, she had more than 46 months of disease progression-free survival (PFS). Immunohistochemical testing showed high expression of PD-L1, and next-generation sequencing revealed the presence of mutations in DNA damage repair (DDR) pathway genes. To the best of our knowledge, this is the first reported case of the successful treatment of metastatic distal adenosquamous CCA with sintilimab alone. Remarkably, patients of CCA with high PD-L1 expression and DDR pathway gene mutations may benefit from sintilimab treatment.

Demineralized bone matrix for repair and regeneration of maxillofacial defects: A narrative review.

OBJECTIVES: Demineralized bone matrix (DBM) is a well-established bone graft material widely accepted by dentists and the public for its favorable osteoconductivity and osteoinductive potential. This article aimed to provide a narrative review of the current therapeutic applications and limitations of DBM in maxillofacial bone defects. STUDY SELECTION, DATA, AND SOURCES: Randomized controlled trials, prospective or retrospective clinical studies, case series and reports, and systematic reviews. MEDLINE, PubMed, and Google Scholar were searched using keywords. CONCLUSIONS: Some evidence supported the therapeutic application of DBM in periodontal intrabony defects, maxillary sinus lifts, ridge preservation, ridge augmentation, alveolar cleft repair, orthognathic surgery, and other regional maxillofacial bone defects. However, the limitations of DBM should be considered when using it, including potential low immunogenicity, instability of osteoinductive potential, handling of the graft material, and patient acceptance. CLINICAL SIGNIFICANCE: With the increasing demand for the treatment of maxillofacial bone defects, DBM is likely to play a greater role as a promising bone graft material. Safe and effective combination treatment strategies and how to maintain a stable osteoinductive potential will be the future challenges of DBM research.

Significance of thyroid transcription factor 1 and Napsin A for prompting the status of EGFR mutations in lung adenocarcinoma patients.

Background: To evaluate the prompting value of thyroid transcription factor 1 (TTF-1) and Napsin A for the status of epidermal growth factor receptor (EGFR) mutations in an independent cohort of lung adenocarcinomas (LUADs) when genetic testing is unavailable. Methods: In this study, 976 untreated primary LUADs were retrospectively reviewed. The clinical and pathological data, including age, gender, smoking history, predictive values of TTF-1 and Napsin A, EGFR status, and tumor-node-metastasis (TNM) stage were obtained through medical records available in Shanxi Province Cancer Hospital. All patients were divided into 2 groups, a mutant group (n=362) and wild-type group (n=614), according to their EGFR status. The clinical data and the expression of TTF-1 and Napsin A were compared between the 2 groups. TTF-1 and Napsin A are detected by fully automated IHC.PCR was carried out to detect the EGFR mutation. Univariate and multivariate logistic regression analyses were undertaken to distinguish independent factors of EGFR mutations. Results: A total of 362 cases (37.1%) of EGFR mutations were detected, which were more frequent in females, never smokers, lymphatic metastasis, distant metastasis, and the positive expression of TTF-1 and Napsin A. Multivariate analysis indicated that females [odds ratio (OR), 1.950; 95% confidence interval (CI): 1.2958 to 2.938; P=0.001], never smokers (OR, 2.040; 95% CI: 1.345 to 3.094; P=0.001), and the positive expression of TTF-1 (OR, 2.366; 95% CI: 1.440 to 3.887; P=0.001) and Napsin A (OR, 2.295; 95% CI: 1.448 to 3.638; P<0.001) were effective prompting for EGFR mutations. Conclusions: The positive expression of TTF-1 and Napsin A had the prompting value for EGFR mutations in patients with LUAD, and the indicators could be combined with other clinical characteristics to enhance the prediction of the EGFR status in LUAD.

Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor.

Tropomyosin receptor kinases (TRKs) are a family of TRKA, TRKB and TRKC isoforms. It has been widely reported that TRKs are implicated in a variety of tumors with several Pan-TRK inhibitors currently being used or evaluated in clinical treatment. However, off-target adverse events frequently occur in the clinical use of Pan-TRK inhibitors, which result in poor patient compliance, even drug discontinuation. Although a subtype-selectivity TRK inhibitor may avert the potential off-target adverse events and can act as a more powerful tool compound in the biochemical studies on TRKs, the high sequence similarities of TRKs hinder the development of subtype-selectivity TRK inhibitors. For example, no selective TRKC inhibitor has been reported. Herein, a selective TRKC inhibitor (L13) was disclosed, with potent TRKC inhibitory activity and 107.5-/34.9-fold selectivity over TRKA/B (IC50 TRKA/B/C = 1400 nM, 454 nM, 13 nM, respectively). Extensive molecular dynamics simulations illustrated that key interactions of L13 with the residues and diversely conserved water molecules in the ribose regions of different TRKs may be the structural basis of selectivity. This will provide inspiring insights into the development of subtype-selectivity TRK inhibitors. Moreover, L13 could serve as a tool compound to investigate the distinct biological functions of TRKC and a starting point for further research on drugs specifically targeting TRKC.

Differentiating Central Lung Tumors from Atelectasis with Contrast-Enhanced CT-Based Radiomics Features.

OBJECTIVES: To evaluate the utility of radiomics features in differentiating central lung cancers and atelectasis on contrast-enhanced computed tomography (CT) images. This study is retrospective. MATERIALS AND METHODS: In this study, 36 patients with central pulmonary cancer and atelectasis between July 2013 and June 2018 were identified. A total of 1,653 2D and 2,327 3D radiomics features were extracted from segmented lung cancers and atelectasis on contrast-enhanced CT. The refined features were investigated for usefulness in classifying lung cancer and atelectasis according to the information gain, and 10 models were trained based on these features. The classification model is trained and tested at the region level and pixel level, respectively. RESULTS: Among all the extracted features, 334 2D features and 1,507 3D features had an information gain (IG) greater than 0.1. The highest accuracy (AC) of the region classifiers was 0.9375. The best Dice score, Hausdorff distance, and voxel AC were 0.2076, 45.28, and 0.8675, respectively. CONCLUSIONS: Radiomics features derived from contrast-enhanced CT images can differentiate lung cancers and atelectasis at the regional and voxel levels.

Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations.

Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitor resistance that presents a significant clinical challenge. Herein, a series of pyrazole-3-amine derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. The structure-activity relationship and molecular dynamics simulation studies illustrated that the ribose region of FLT3 could be occupied to help address the obstacle of secondary mutations. Among those derivatives, compound 67 exhibited potent and selective inhibitory activities against FLT3-ITD-positive acute myeloid leukemia (AML) cells and possessed equivalent potency against transformed BaF3 cells with a variety of secondary mutations. Besides, cellular mechanism assays demonstrated that 67 strongly inhibited phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and apoptosis in MV4-11 cells. In the MV4-11 xenograft models, 67 exhibited potent antitumor potency without obvious toxicity. Taken together, these results demonstrated that 67 might be a drug candidate for the treatment of FLT3-ITD-positive AML.

Applicability of graded prognostic assessment of lung cancer using molecular markers to lung adenocarcinoma patients with brain metastases.

Several scoring systems are available to estimate prognosis and assist in selecting treatment methods for non-small cell lung cancer (NSCLC) patients with brain metastasis, including recursive partitioning analysis (RPA), basic score for brain metastases (BS-BM), and diagnosis-specific graded prognostic assessment (DS-GPA). Lung-molGPA is an update of the DS-GPA that incorporates EGFR and/or ALK mutation status. The present study tested the applicability of these four indexes in 361 lung adenocarcinoma patients with brain metastasis. Potential predictive factors in our independent multivariate analysis included patient age, Karnofsky performance status, EGFR and ALK mutation status, and use of targeted therapy. In the log-rank test, all four systems predicted overall survival (OS) (P<0.001). Harrell's C indexes were 0.732, 0.724, 0.729, and 0.747 for RPA, BS-BM, DS-GPA, and Lung-molGPA, respectively. Our results confirmed that the Lung-molGPA index was useful for estimating OS in our patient cohort, and appeared to provide the most accurate predictions. However, the independent prognostic factors identified in our study were not entirely in agreement with the Lung-molGPA factors. In an era of targeted therapy, Lung-molGPA must be further updated to incorporate more specific prognostic factors based on additional patient data.

Assessment of prognostic scores of brain metastases from lung adenocarcinoma with EGFR mutations.

The aim of this study was to analyze prognostic factors and evaluate the value of four prognostic scores including RPA, DS-GPA BS-BM, GGS for the EGFR mutant BM patients from lung adenocarcinoma treated with EGFR-TKI. Data of NSCLC were retrospectively reviewed from August 2010 to June 2015 using the medical database of Shanxi Provincial Cancer Hospital. Patients with BM from lung adenocarcinoma with mutant EGFR treated by EGFR-TKI or a combination of EGFR-TKI and WBRT were included. Potential prognostic factors were statistically examined. The C-index of each prognostic score was calculated. A total of 1063 BM patients with lung adenocarcinoma that had been identified with EGFR mutations were reviewed. A total of 104 patients that had been diagnosed with BM were confirmed to have mutant EGFR in primary tumors. These patients received treatment with EGFR-TKI or EGFR-TKI with WBRT to BM. The potential predictive factors in multivariable analysis included KPS (70 vs.70-80 vs. 90-100) and number of brain metastatic lesions. In the log-rank test, the indexes of RPA, DS-GPA BS-BM, and GGS were all significant predictors of OS. The C-indexes of each prognostic score were 0.79, 0.76, 0.77, and 0.74 in DS-GPA, RPA, GGS, and BS-BM, respectively. The indexes of RPA, DS-GPA BS-BM, GGS were applicable for asessing survival stratification in brain metastases from lung adenocarcinoma with presented EGFR mutations in our independent population. The DS-GPA appears to be the best predictive value. However, all four of the indexes could not evaluate the exact independent prognostic factors in multivariable analysis. A prognostic index specific for this group of patients was needed for targeted lung cancer therapy.