Fusion variations of neurotrophic receptor tyrosine kinase (NTRK) are oncogenic drivers in various solid tumors such as breast cancer, salivary gland carcinoma, infant fibrosarcoma, etc. Gene rearrangements involving NTRK1/2/3 lead to constitutive activation of the tropomyosin receptor kinase (TRK) domain, and the expressed fusion proteins drive tumor growth and survival. NTRK fusions are estimated to occur at a frequency of approximately 0.1% to 1% in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) mutations are prevalent in NSCLC, but the frequency of EGFR G719A mutation is relatively low (about 2%), and EGFR mutations are typically mutually exclusive with NTRK fusion variants. The study presented the first documented case of lung adenocarcinoma harboring both EGFR G719A mutation and LMNA-NTRK1 fusion. A review of the literature was conducted to elucidate the role of NTRK fusion mutations in NSCLC and their relationship with EGFR mutations, aiming to enhance the understanding of NTRK fusion mutations in NSCLC.
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Humans ; Adenocarcinoma/genetics* ; Adenocarcinoma of Lung ; ErbB Receptors/genetics* ; Lamin Type A/genetics* ; Lung Neoplasms/genetics* ; Mutation ; Oncogene Proteins, Fusion/genetics* ; Receptor, trkA/metabolism*

Background::There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients.Methods::In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12.Results::At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P <0.001) and Physician’s Global Assessment (60.9% [67/110] vs. 10.0% [11/110]; difference, 49.1% [95% CI, 38.64, 59.62]; P <0.001) compared to placebo. PASI 75 response continued to improve over time in both tildrakizumab and placebo-switching to tildrakizumab groups, reaching maximal efficacy after 28 weeks (86.8% [92/106] vs. 82.4% [89/108]) and maintained up to 52 weeks (91.3% [95/104] vs. 87.4% [90/103]). Most treatment-emergent adverse events were mild and not related to tildrakizumab. Conclusion::Tildrakizumab demonstrated durable efficacy through week 52 and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.Trial registration::ClinicalTrials.gov, NCT05108766.

Marsdenia tenacissima injection, a standard Marsdenia tenacissima extract (MTE), has been approved as an adjuvant therapeutic agent for various cancers. Our previous study showed that MTE inhibited the proliferation and metastasis of prostate cancer (PCa) cells. However, the underlying mechanisms and active ingredients of MTE against PCa were not completely understood. This study revealed that MTE induced significant decreases in cell viability and clonal growth in PCa cells. In addition, MTE induced the apoptosis of DU145 cells by reducing the mitochondrial membrane potential and increasing the expression of Cleaved Caspase 3/7, Cyt c, and Bax. In vivo, DU145 xenografted NOD-SCID mice treated with MTE showed significantly decreased tumor size. TUNEL staining and Western blot confirmed the pro-apoptotic effects of MTE. Network pharmacology analysis collected 196 ingredients of MTE linked to 655 potential targets, and 709 PCa-associated targets were retrieved, from which 149 overlapped targets were screened out. Pathway enrichment analysis showed that the HIF-1, PI3K-AKT, and ErbB signaling pathways were closely related to tumor apoptosis. Western blot results confirmed that MTE increased the expression of p-AKT^Ser473 and p-GSK3β^Ser9, and decreased the expression of p-STAT3^Tyr705in vitro and in vivo. A total of 13 compounds in MTE were identified by HPLC-CAD-QTOF-MS/MS and UPLC-QTOF-MS/MS. Molecular docking analysis indicated that six compounds may interact with AKT, GSK3β, and STAT3. In conclusion, MTE induces the endogenous mitochondrial apoptosis of PCa by regulating the AKT/GSK3β/STAT3 signaling axis, resulting in inhibition of PCa growth in vitro and in vivo.
Mice ; Animals ; Male ; Humans ; Mice, Inbred NOD ; Mice, SCID ; Marsdenia ; Proto-Oncogene Proteins c-akt ; Glycogen Synthase Kinase 3 beta ; Molecular Docking Simulation ; Phosphatidylinositol 3-Kinases ; Tandem Mass Spectrometry ; Prostatic Neoplasms ; Apoptosis ; STAT3 Transcription Factor

Purpose: We aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)–mutated patients with or without concomitant alterations. Materials and Methods: This multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non–small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR–tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint. Results: The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment. Conclusion EGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Colonoscopy with endoscopic resection of detected colonic adenomas interrupts the adenoma-carcinoma sequence and reduces the incidence of colorectal cancer and cancer-related mortality. In the past decade, there have been significant developments in instruments and techniques for endoscopic polypectomy. Guidelines have been formulated by various professional bodies in Europe, Japan and the United States, but some of the recommendations differ between the various bodies. An expert professional workgroup under the auspices of the Academy of Medicine, Singapore, was set up to provide guidance on the endoscopic management of colonic polyps in Singapore. A total of 23 recommendations addressed the following issues: accurate description and diagnostic evaluation of detected polyps; techniques to reduce the risk of post-polypectomy bleeding and delayed perforation; the role of specific endoscopic resection techniques; the histopathological criteria for defining endoscopic cure; and the role of surveillance colonoscopy following curative resection.
Adenoma/surgery* ; Colonic Neoplasms/surgery* ; Colonic Polyps/surgery* ; Colonoscopy/methods* ; Colorectal Neoplasms/pathology* ; Humans ; Singapore ; United States

Objective:To explore the differential diagnosis and different treatment methods of chylothorax and pseudochylothorax after lung cancer surgery.Methods:Clinical data of 1 584 surgical patients with non-small cell lung cancer from January 2016 to December 2021 were analyzed, 21 cases of chylothorax and 8 cases of pseudochylothorax were identified and analyzed to compare the differences in pleural fluid chyle test, pleural effusion biochemical values, total cholesterol, triglycerides, total cholesterol/triglyceride ratio, leukocyte count, bacterial culture and treatment.Results:The incidence of chylothorax after lung cancer surgery was 1.3%, and the incidence of pseudochylothorax was 0.5%; 80.9%% of chylothorax on the right side was significantly higher than 19.1% of chylothorax on the left side, and the difference was statistically significant( P<0.05). Pseudochylothorax occurred on the right side(100%). The difference between chylothorax and pseudochylothorax in pleural fluid tests for cholesterol and triglyceride was statistically significant( P<0.05), the leukocyte count was significantly higher in pseudochylothorax than chylothorax, and the difference was statistically significant( P<0.05). The differences in drainage before treatment, postoperative drainage time and postoperative hospitalization time between the two groups were statistically significant( P<0.05). The success rate was 61.9% in 13 cases of chylothorax treated conservatively and 38.1% in 8 cases of thoracic duct clamping; all cases of pseudochylothorax were treated conservatively with a success rate of 100%. Conclusion:In naddition to pleural fluid chyle test and pleural effusion biochemical values, total cholesterol, triglyceride and total cholesterol to triglyceride ratio in pleural fluid should be tested to identify chylothorax and pseudochylothorax, high triglyceride in pleural fluid diagnosed as chylothorax; Pseudochylothorax is diagnosed with a cholesterol/triglyceride ratio >1 in the pleural fluid, pseudochylothorax is usually treated conservatively. Chylothorax is treated conservatively and surgically according to different conditions. If the drainage flow is greater than 800 ml/day for 3 consecutive days or if it causes serious electrolyte disorders, it is recommended to perform thoracoscopic-assisted thoracic duct clamping via right-sided approach.

In this paper, we aim to provide professional guidance to clinicians who are managing patients with chronic liver disease during the current coronavirus disease 2019 (COVID-19) pandemic in Singapore. We reviewed and summarised the available relevant published data on liver disease in COVID-19 and the advisory statements that were issued by major professional bodies, such as the American Association for the Study of Liver Diseases and European Association for the Study of the Liver, contextualising the recommendations to our local situation.
COVID-19/epidemiology* ; Carcinoma, Hepatocellular/therapy* ; Chronic Disease ; Hepatitis B, Chronic/therapy* ; Hepatitis C, Chronic/therapy* ; Humans ; Liver Cirrhosis/therapy* ; Liver Diseases/therapy* ; Liver Neoplasms/therapy* ; Liver Transplantation ; Singapore/epidemiology*

Objective To explore the association of synovial fluid vasoactive intestinal peptide levels with cartilage damage,radiological changes and symptomatic severity in patients with ankle post-traumatic osteoarthritis. Methods 74 patients with ankle traumatic osteoarthritis undergoing ankle anthroscopic debridement or joint replacement and 69 healthy controls receiving body check were enrolled in the this study. Serum and synovial fluid VIP concentrations were measured by a special radioimmunoassay method. Cartilage degradation biomarker colla-gen type Ⅱ(CTX-II)and inflammatory marker interleukin-6 were determined by enzyme-linked immunosorbent assay (ELISA). The symptomatic and functional severity was evaluated using Teeny & Wiss and AOFAS ankle-hindfoot rating scale. The radiographic progression of PTAOA was identified according to the modified ankle osteoar-thritis Kellgren-Lawrence (K-L) grading system. The mankin score was used for assessing the histopathological severity for cartilage lesions. Receiver operating characteristic (ROC) curve was conducted and the area under curve(AUC)was used to evaluate the diagnostic value of VIP,IL-6 and CTX-II levels for the prediction of the modified K-L grading by comparing with other biomarkers. Results There were no significant differences in serum VIP levels between PTAOA patients and controls. VIP levels in synovial fluid showed a negative correlation with modified ankle K-L grading,Mankin scores,CTX-Ⅱand IL-6. In addition,VIP levels were also positively associated with Teeny&Wiss and AOFAS ankle-hindfoot scores. The AUC area of VIP was similar to CTX-Ⅱat early stage of the disease. Conclusions Synovial fluid VIP levels show an independent and negative correlation with disease severity in patients with PTAOA. Low level of VIP in SF can be used as a potential biomarker for reflecting disease progression.

Objective A retrospective cohort study was carried out to observe the long-term effect of ESD in treating early gastrointestinal cancer or precancerous lesions. Methods The clinical and follow-up data of 73 patients were collected. Kaplan-Meier, Log-rank and Breslow test and Cox's proportional hazards regression model were used to analyze the data. Results The median survival time in the gastric and colo-rectal early cancer or precancerous lesions is longer than 65 months in our study, respectively. For esophagus, the median survival time was 44.5 months; the disease free survival time (DFS) after ESD was significantly reduced in the esophagus, compared to the stomach and colo-rectum (χ2 = 12.61, P = 0.000; χ2 = 7.09, P = 0.008); the degree of atypia (or infiltration), and lesion size were considered to be two factors to influence the DFS after ESD (P = 0.027, OR^ =2.38, 95%CI:1.10 ~ 5.12, P = 0.074, 95%CI; OR^ =0.90, 95%CI: 0.80 ~ 1.01). Conclusion ESD is an effective curative treatment in the resection of early upper gastrointestinal cancer and precancerous lesions. The degree of atypia (or infiltration) was concluded as an independent risk factor for the DFS post-ESD, and the size of lesion was a valuable parameter with regard to the recurrence after ESD procedure.

Objective To discuss the methods and effects of arthroscopic treatment of posterior and anterior ankle impingement syndrome through anterior approach,tarsal sinus approach plus posterolateral approach.Methods The study enrolled 12 patients with posterior and anterior ankle impingement syndrome treated from January 2012 to March 2014.There were 8 males and 4 females,agedl7-65 years (mean,45 years).Left ankle injury was noted in 9 patients and right ankle injury in 3 patients.Eight patients had a history of obvious ankle injury (5 acute and 3 chronic sprains).Arthroscopic surgery was performed to manage the posterior and anterior ankle impingement syndrome through the combined anterior,tarsal sinus and posterolateral approaches,and prone position and posteromedial incision were not used during operation.Postoperative outcome was evaluated using the American Orthopedic Foot and Ankle Society (AOFAS) score.Results Operation time was 45-80 min (mean,62 min).Arthroscopy confirmed anterior bone impingement in all patients.Three patients suffered from posterior bony impingement of the talus,while nine patients os trigonum injury.Duration of follow-up was 10-18 months (mean,14 months).AOFAS score was (91.4-± 6.5) points after operation,significantly higher (34.4 ± 12.6) points before operation (t =14.607,P ＜0.01).All patients had normal ankle range of motion after operation.There were no complications such as neurovascular injury.All the surgical incisions achieved primary healing.Conclusion The procedure avoids body position shift and posteromedial incision during operation,and attains a good vision to the anterior and posterior portions and satisfactory short-term outcome.