Self-polymerized platinum (II)-Polydopamine nanomedicines for photo-chemotherapy of bladder Cancer favoring antitumor immune responses.

Systemic administration of platinum-based drugs has obvious limitations in the treatment of advanced bladder cancer (BC) owing to lower tumor accumulation and uncontrolled release of chemotherapeutics. There is an urgent need for advanced strategies to overcome the current limitations of platinum-based chemotherapy, to achieve maximal therapeutic outcomes with reduced side effects. In this study, self-polymerized platinum (II)-polydopamine nanocomplexes (PtPDs) were tailored for efficient chemo-photoimmunotherapy of BC. PtPDs with high Pt loading content (11.3%) were degradable under the combination of a reductive tumor microenvironment and near-infrared (NIR) light irradiation, thus controlling the release of Pt ions to achieve efficient chemotherapy. In addition, polydopamine promoted stronger photothermal effects to supplement platinum-based chemotherapy. Consequently, PtPDs provided effective chemo-photothermal therapy of MB49 BC in vitro and in vivo, strengthening the immunogenic cell death (ICD) effect and robust anti-tumoral immunity response. When combined with a PD-1 checkpoint blockade, PtPD-based photochemotherapy evoked systemic immune responses that completely suppressed primary and distant tumor growth without inducing systemic toxicities. Our work provides a highly versatile approach through metal-dopamine self-polymerization for the precise delivery of metal-based chemotherapeutic drugs, and may serve as a promising nanomedicine for efficient and safe platinum-based chemotherapy for BC.

Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases-a multicenter retrospective study.

BACKGROUND: Central nervous system (CNS) metastases in patients with ALK-positive non-small cell lung cancer (NSCLC) are a cause of substantial morbidity and mortality. Although alectinib had demonstrated promising intracranial efficacy in several clinical trials, data were limited on its CNS activity in real-world settings. METHODS: In this retrospective study, ALK-positive NSCLC patients with brain metastases (BM) or leptomeningeal metastases (LM) from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib. ALK-TKI-naive patients were enrolled in cohort 1, cohort 2 included patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib, and cohort 3 included patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs. The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Sixty-five patients were eligible and included in our study (cohort 1: 20, cohort 2: 32, cohort 3: 13). For the overall population and patients with uncontrolled CNS metastases, similar intracranial response in CNS target lesions was observed: cohort 1: 81.8% and 80%; cohort 2: 76.5% and 86.7%; cohort 3: 42.8% and 33.3%. For patients in these three cohorts, 75% (6/8), 78.6% (11/14), and 83.3% (5/6) were reported to have significant improvement in CNS-related symptoms respectively. The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib (p < 0.001), and there was also a steep fall-over in the number of patients with ECOG ≥2 points before and after the administration of alectinib (p = 0.003). All patients (8/8) diagnosed with LM ± BM experienced substantial alleviation in CNS-related symptoms. In cohort 1 and cohort 2, no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone. CONCLUSIONS: Our study substantiated the potent CNS activity of alectinib in real-world settings. Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively, which indicated that alectinib alone might defer the timing of local treatment. However, our results should be treated cautiously owing to limited sample size.

Structural characterizations on the degradation of 2D organic-inorganic hybrid perovskites and its enlightenment to improved stability.

Despite the demonstrated high-efficiency of solar cells and light-emitting devices based on two-dimensional (2D) perovskites, intrinsic stability of the 2D perovskites is yet far from satisfactory. In this work, we find the 2D (BA)2PbI4perovskite crystals rapidly degrade in the ambient conditions and the photoluminescence (PL) nearly completely quenches in 6 d. Moreover, the PL shoulder band due to defects and absorption band of PbI2gradually rise during degradation, suggesting the precipitation of PbI2. Besides, rod structures are observed in the degraded crystals, which are attributed to the formation of one-dimensional (1D) (BA)3PbI5perovskites. And the degradation can be largely retarded by decreasing the humidity during storage. Therefore, a chemical reaction for the degradation of (BA)2PbI4is proposed, revealing the interactions between water molecules and undercoordinated defects are very critical for understanding the degradation. Enlightened by these findings, dimethyl itaconate (DI) treatment is developed to passivate the defects and block the intrusion of moisture to improve the stability of the (BA)2PbI4. After storage in the ambient environment for 16 d, the DI treated (BA)2PbI4only shows a slight surface degradation without formation of any nanorod-like structures, and the PL intensity retains about 70%. Therefore, our systematic study provides a comprehensive understanding on the degradation dynamics of 2D perovskites, which will promote future development of intrinsically stable 2D perovskites.

Successful Treatment of Afatinib Reversing Epidermal Growth Factor Receptor Exon19Deletion/G724S Mutation Resistance Guided by Protein-Drug Docking.

G724S is a rare mutation induced by different generations of tyrosine kinase inhibitors (TKIs). No clinical effective drugs toward G724S mutation have been reported till now. We analyzed the interaction of three drugs (afatinib, gefitinib, osimertinib) with epidermal growth factor receptor (EGFR) from three aspects: the spatial structure of the binding region, the scoring function value, and the interaction force between drug molecules and active center of EGFR. Our results indicate that afatinib remains effective to patients with EGFR Exon19Deletion(Ex19Del) and G724S mutations whereas osimertinib and gefitinib are not, which is consistent with other reports. Afatinib is reported to be effective against G724S mutation, but no long-term clinical survival has been reported till now. A patient with stage IV adenocarcinoma was found to have Ex19Del/G724S mutation. Treated with afatinib, he received a progression-free survival of more than 1 year. With the guidance of this case report, we provide the clinical evidence of using afatinib for patients with G724S mutations and obtaining long-term clinical survival. KEY POINTS: Guided by protein-drug docking, afatinib is more effective to EGFR G724S mutation compared with osimertinib and gefitinib. A patient with Ex19Del/G724S mutation obtained long-term survival with afatinib treatment.

Serum Copper Level and the Copper-to-Zinc Ratio Could Be Useful in the Prediction of Lung Cancer and Its Prognosis: A Case-Control Study in Northeast China.

BACKGROUND: The association between lung cancer and trace element levels, such as serum copper (Cu) and zinc (Zn) levels and the Cu:Zn ratio, vary among different demographic groups; however, it is unknown whether variations in serum Cu and Zn levels and Cu:Zn ratios are related to the prediction and prognosis of lung cancer. We aimed to clarify this relationship in the Han Chinese population of Northeast China. METHODS: We recruited 146 patients with lung cancer and 146 age- and resident area-matched cancer-free controls. RESULTS: Increased serum Cu and Zn levels and the Cu:Zn ratio were positively associated with lung cancer (OR: 72.243, 95% CI 24.159-216.030; OR: 3.513, 95% CI, 1.476-8.358, and; OR: 58.582, 95% CI, 20.023-171.395, respectively). The critical serum Cu level for the prediction of lung cancer was 1.37 mg/L (sensitivity, 77.4%; specificity, 84.9%), while the critical Cu:Zn ratio was 1.45 (sensitivity, 69.9; specificity, 88.4%). Patients with stage IV non-small-cell lung cancer (NSCLC) had higher serum Cu levels and a higher Cu:Zn ratio than patients with stage I, II, or III NSCLC. CONCLUSIONS: The serum Cu level and the Cu:Zn ratio are effective predictive indicators of lung cancer and may help evaluate the prognosis of patients with NSCLC.

Successful treatment of Afatinib plus Apatinib using for a lung adenocarcinoma patient with HER-2 V659D mutation: a rare case report.

Lung cancer is one of the most important and lethal cancers in the world. Human epidermal growth factor 2 (HER2) is a member of the erbB receptor tyrosine kinase family. The incidence of HER2 kinase domain mutations in adenocarcinoma of lung ranges from 1% to 3%. HER2 V659D mutation is located in the trans-membrane domain (TMD) with only a few cases reported before, and importantly, there were no more standard and effective ways for this kind of diseases until now. Afatinib irreversibly blocks all kinase-competent HER family members. Apatinib is one of the small-molecule oral anti-angiogenesis-targeted agents developed firstly in China, and it's a highly selective inhibition of the activity of VEGFR-2. This report presents an advanced lung adenocarcinoma patient with HER2 V659D mutation who was treated with combination of Afatinib and Apatinib. He achieved good efficacy and tolerable adverse reactions.

Identification of a new GLDC gene alternative splicing variant and its protumorigenic roles in lung cancer.

Aim: To clarify the regulatory roles of GLDCV1, the first identified truncated glycine decarboxylase (GLDC), on cancer stem cells and tumorigenesis. Materials & methods: RT-PCR or RT-qPCR, immunoblotting and immunohistochemical staining were applied to assess gene expression. MTT, BrdU incorporation and colony formation assays were used to examine cell proliferation capacity. Soft agar colony formation and in vivo transplantation were applied to evaluate cellular transformation and tumorigenesis. Results & conclusion: Expression of GLDCV1 or GLDC was enhanced in non-small-cell lung cancer cell line and clinical samples. GLDCV1 overexpression induced MRC5 cell proliferation, transformation and tumorigenesis. Additionally, GLDCV1 increased lactate production and cancer stem cell marker expression and activated ERK and P38 pathways. Our study gained deeper insight into GLDC oncogene.

Lung squamous cell carcinoma with solitary ocular metastasis and its successful treatment with thoracic surgery and chemotherapy: an interesting and rare case report.

BACKGROUND: The incidence of ocular metastasis from lung cancer is reported to be 0.1-7%, with adenocarcinoma and small cell lung cancer accounting for the highest proportions of these cases. The majority of cases involves metastasis to more than one other distal organ in addition to the eye. Here, we report for the first time, a case of lung squamous cell carcinoma with solitary symptomatic ocular metastasis as the initial manifestation that was managed by a multidisciplinary treatment (MDT). CASE PRESENTATION: A woman presented at the ophthalmology department of hospital with a 1-week history of left eye pain and blurred vision. Systemic examination led to the diagnosis of central lung cancer in the right lower lobe with ocular metastasis. After consultations with an MDT, including specialists from the surgery, internal medicine, ophthalmology, radiotherapy and imaging departments, the patient underwent surgery and chemotherapy. Her eye symptoms disappeared, and the ocular lesion was well controlled without any specific ocular treatment. The patient demonstrated a prolonged progression-free survival. CONCLUSION: This is the first report of a rare case with solitary ocular metastasis as the initial manifestation of lung squamous cell carcinoma. This rare patient was treated based on evidence-based medicine, indicating the importance of cooperation within an MDT. The successful treatment of this case was reported as a new therapeutic reference for clinicians who encounter similar cases in the future.

[Efficacy of adjuvant therapy in 110 patients with N1 lymph node metastasis of esophageal squamous cell carcinoma].

OBJECTIVE: The aim of this study was to evaluate the effect of postoperative adjuvant therapy on the survival in patients with N1 lymph node metastasis of esophageal squamous cell carcinoma (ESCC). METHODS: 110 patients with positive N1 lymph node metastasis of esophageal squamous carcinoma were included in this study. The surgery group included 46 cases and the postoperative adjuvant therapy group included 64 cases (24 cases in the adjuvant chemotherapy subgroup and 40 cases in the adjuvant concurrent chemoradiotherapy). The disease-free survival (DFS) and overall survival (OS) of the two groups were compared and the prognostic factors were analyzed by multivariate Cox model. RESULTS: In the postoperative adjuvant therapy group, the DFS (16.8 months) and OS (21.3 months) were significantly prolonged compared with those in the surgery group (10.6 months, P=0.007) and (13.7 months, P=0.001), respectively. Postoperative adjuvant chemotherapy significantly extended the OS (31.1 months) of N1-positive patients compared with 13.7 months (P=0.002) in the surgery group. But there were no significant differences between the DFS in the two subgroups (16.3 and 16.8 months, P=0.346) and between the OS (23.4 and 21.3 months, P=0.491). Postoperative adjuvant therapy was an independent prognostic factor in the ESCC patients with N1 lymph node metastasis. CONCLUSION: Postoperative adjuvant therapy can improve the prognosis and prolong the survival time in ESCC patients with positive N1 lymph node metastasis.

[Relationship between the efficacy of gemcitabine/cisplatin adjuvant chemotherapy and RRM1 protein expression in postoperative NSCLC patients].

OBJECTIVE: The purpose of this study was to investigate the relationship between the expression of ribonucleotide reductase subunit M1 (RRM1) protein and the efficacy of gemcitabine/cisplatin (GP) adjuvant chemotherapy in postoperative non-small cell lung cancer (NSCLC) patients. METHODS: A total of 68 patients with NSCLC after radical surgery were included in this study. The expression of RRM1 protein in tumor specimens was assayed by streptavidin-peroxidase (SP) immunohistochemistry retrospectively. Correlation between the expression of RRM1 protein and the efficacy of GP chemotherapy was analyzed. Disease-free survival rate was taken as the main outcome measure. RESULTS: Among the 68 patients, 31 cases had recurrence or metastasis. The expression rate of RRM1 was 54.4%. The 1-year and 3-year disease-free survival rates were 82.7% and 61.5% for patients with RRM1-negative expression, and 78.1% and 36.8% for patients with RRM1-posivive expression, respectively (P = 0.044). In the subgroup analysis of stage IB cases, the 1-year and 3-year disease-free survival rates were 100% and 82.3% for patients with RRM1-negative expression, and 84.5% and 24.6% for patients with RRM1-positive expression, respectively (P = 0.047). In the analysis of squamous cell carcinoma subgroup, the 1-year and 3-year disease-free survival rates were 92.3% and 83.7% for patients with RRM1-negative expression, and 83.1% and 43.9% for patients with RRM1-posivive expression, respectively (P = 0.005). Univariate analysis and multivariate analysis indicated that smoking history, pathological type, clinical stage and expression of RRM1 significantly influenced the therapeutic efficacy (P < 0.05). CONCLUSIONS: RRM1 protein may be a valuable predictive factor for gemcitabine/cisplatin adjuvant chemotherapy in NSCLC patients.

Small cell lung cancer with dermatomyositis: a case report.

Dermatomyositis represents an autoimmune disorder characterized by notable skin and muscular manifestations. The annual incidence of dermatomyositis stands at approximately (5~10)/1 million individuals. Notably, patients with malignant tumors exhibit an elevated risk of developing dermatomyositis compared to the general population. However, in cases where dermatomyositis co-occurs with malignancy, the efficacy of hormone therapy alone tends to be suboptimal. Moreover, reports addressing the correlation between tumor treatment and the management of dermatomyositis are scarce. A 60-year-old male patient presented with dermatomyositis, initially manifesting through symptoms such as rash, muscle weakness, and dysphagia. Despite undergoing standard hormone therapy, there was no discernible improvement in the dermatomyositis symptoms. Considering the patient's concomitant troublesome cough, further investigations were conducted, including CT, PET-CT, and pathological biopsy. These assessments confirmed the diagnosis of limited-stage small cell lung cancer (T1cN3M0 IIIB). Notably, in this patient, dermatomyositis was suspected to be a paraneoplastic syndrome associated with small cell lung cancer. Standard chemotherapy and radiotherapy were employed to treat the small cell lung cancer, resulting in partial remission after two treatment cycles. As the malignancy regressed, a notable improvement in dermatomyositis symptoms was observed, subsequently leading to a gradual reduction in the prescribed hormone dosage. In conclusion, we present a comprehensive case study of dermatomyositis as a paraneoplastic syndrome throughout the treatment process. The response to tumor therapy coincided with the amelioration of dermatomyositis symptoms. Therefore, diligent malignancy screening is imperative for patients diagnosed with dermatomyositis.

Imaging findings can't mean everything in the era of immunotherapy: a case report and literature review.

Immune-checkpoint inhibitors (ICIs) play an important role in the treatment of cancers. However, immunotherapy can also induce atypical response patterns, including pseudoprogression, which is challenging to clinicians. We reported a case of non-small-cell lung cancer showing so-called pseudoprogression during the treatment of pembrolizumab and the patient benefited clinically from continued treatment with ICIs. Therefore, beside imaging evaluation, the assessment of Eastern Cooperative Oncology Group performance status score, numerical rating scale score of cancer pain, tumor markers levels, and neutrophil-to-lymphocyte ratio should be used for response evaluation of tumors in the era of immunotherapy. And more accurate evaluation methods and reliable information are urgently needed to better understand the pseudoprogression.

Sometimes drugs can kill cancer cells but rather than getting smaller, as expected, the tumor size increases. This is called 'pseuoprogression', meaning false progression. Here, we report pseudoprogression in a lung cancer patient receiving immunotherapy. The tumor initially got larger, but with continued treatment, it decreased in size.

Tumor microenvironment(TME) and single-source dual-energy CT(ssDECT) on assessment of inconformity between RECIST1.1 and pathological remission in neoadjuvant immunotherapy of NSCLC.

BACKGROUND: The inconformity (IC) between pathological and imaging remissions after neoadjuvant immunotherapy in patients with NSCLC can affect the evaluation of curative effect of neoadjuvant therapy and the decision regarding the chance of surgery. MATERIALS AND METHODS: Patients who achieved disease control(CR/PR/SD) after neoadjuvant chemoimmunotherapy from a clinical trial (NCT04326153) and after neoadjuvant chemotherapy during the same period were enrolled in this study. All patients underwent radical resection and systematic mediastinal lymphadenectomy after neoadjuvant treatments. The pathological remission, immunohistochemistry (CD4, CD8, CD20, CD56, FoxP3, CD68, CD163, CD11b tumor-infiltrating lymphocytes, or macrophages), and single-source dual-energy computed tomography (ssDECT) scans were assessed. The IC between imaging remission by CT and pathological remission was investigated. The underlying cause of IC, the correlation between IC and DFS, and prognostic biomarkers were explored. RESULTS: After neoadjuvant immunotherapy, enhanced immune killing and reduced immunosuppressive performance were observed. 70 % of neoadjuvant chemoimmunotherapy patients were in high/medium IC level. Massive necrosis and repair around and inside the cancer nest were the main pathological changes observed 30-45 days post-treatment with PD1/PD-L1 antibody and were the main causes of IC between the pathology and imaging responses after neoadjuvant immunotherapy. High IC and preoperative CD8 expression (H score ≥ 3) indicate a high pathological response rate and prolonged DFS. Iodine material density ssDECT images showed that the iodine content in the lesion causes hyperattenuation in post-neoadjuvant lesion in PCR patient. CONCLUSIONS: Compared to chemotherapy and targeted therapy, the efficacy of neoadjuvant immunotherapy was underestimated based on the RECIST criteria due to the unique antitumor therapeutic mechanism. Preoperative CD8+ expression and ssDECT predict this IC and evaluate the residual tumor cells. This is of great significance for screening immune beneficiaries and making more accurate judgments about the timing of surgery.

Liver mechanosignaling as a natural anti-hepatitis B virus mechanism.

The mechanisms underlying the natural control of hepatitis B virus (HBV) infection have long been an intriguing question. Given the wide physiological range of liver stiffness and the growing attention to the role of mechanical microenvironment in homeostasis and diseases, we investigated how physical matrix cues impact HBV replication. High matrix stiffness significantly inhibited HBV replication and activated YAP in primary hepatocyte culture system, a key molecule in mechanosignaling. YAP activation notably suppressed HBV transcription and antigen expression. Several YAP-induced genes exhibited strong anti-HBV effects. Single-cell analysis of liver tissue from male individuals with active HBV replication revealed a strong significant negative correlation between YAP signature activation and HBV transcript levels. Intraperitoneal administration of YAP small molecule agonist potently controls HBV in male mouse models. These findings unveil a mechanism that involves the mechanical environment of hepatocytes and YAP to clear hepatotropic viral infection in the liver, providing new perspectives for HBV cure studies and antiviral development.

Maintenance therapy with anlotinib after induction therapy with platinum-based chemotherapy for advanced non-small-cell lung cancer: A pooled analysis of 2 single-arm trials.

BACKGROUND: Maintenance therapy could significantly improve the prognosis of patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. Anlotinib is effective, tolerable, and convenient in administration as a third-line treatment for NSCLC. This study aimed to evaluate the efficacy and safety of maintenance therapy with anlotinib after platinum-based induction chemotherapy for patients with advanced NSCLC. METHODS: This pooled analysis of 2 multicenter, open-label, single-arm, phase 2 clinical trials (ALTER-L014 and ALTER-L011) enrolled patients with locally advanced or metastatic NSCLC and without known sensitive mutations in China between September 2018 and January 2021. The primary outcome was progression-free survival. The secondary outcomes were objective response rate, disease control rate, overall survival, and safety. RESULTS: The data of 23 patients were pooled, with 15 from ALTER-L014 and 8 from ALTER-L011. At the cutoff date of June 13, 2021, the median progression-free survival since the start of maintenance therapy was 5.95 (95% confidence interval, 4.30-8.80) months. Nineteen patients had stable disease, 1 had a partial response and 3 had progressive disease. The objective response rate was 4.35%, while disease control rate was 86.96%. The median overall survival of the patients since the start of maintenance therapy was 18.60 (95% confidence interval, 6.87-22.80) months. The incidence of adverse events of grade ≥ 3 was 21.7%. CONCLUSION: Anlotinib might offer a new option for maintenance treatment in patients with locally advanced or metastatic NSCLC without known sensitive mutations after standard first-line platinum-based chemotherapy.

Efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy in potentially resectable stage IIIA/IIIB non-small cell lung cancer: Neo-Pre-IC, a single-arm phase 2 trial.

Background: Some locally advanced (IIIA/IIIB) non-small cell lung cancers (NSCLCs) might have surgical options available. However, information regarding the effectiveness of neoadjuvant immunotherapy for potentially resectable IIIA/IIIB NSCLC is limited. The intent of this investigation was to offer a more favourable alternative to the standard approach of chemoradiotherapy (concurrent or sequential chemoradiotherapy) followed by immunotherapy for potentially resectable stage III NSCLC. Methods: This prospective, single-arm, phase 2 clinical trial (NCT04326153) enrolled treatment-naïve patients with 'potentially resectable' IIIA/IIIB NSCLC who were deemed unsuitable for complete (R0) resection upon initial diagnosis. The study period was between March 20, 2020, and August 20, 2021. Patients underwent neoadjuvant chemoimmunotherapy (sintilimab combined with nab-paclitaxel and carboplatin) for two to three cycles prior to surgical resection of the lung carcinoma and systematic nodal dissection within 30-45 days. The primary endpoint was the 2-year disease-free survival (DFS) rate, with secondary endpoints encompassing major pathological response (MPR) rate, pathological complete response (pCR) rate, overall survival, objective response rate (ORR), downstaging rate, and adverse events (AEs). Tumour immune cell infiltrates, identified via immunohistochemistry, were assessed as biomarkers at baseline and after surgery. Findings: Among 30 patients who received neoadjuvant chemoimmunotherapy, 20 underwent complete resection. The disease control rate was 96.7% (95% CI: 90.3%-99.99%), with an ORR of 55% (95% CI: 37.2%-72.8%) and a downstaging rate of 80% (95% CI: 65.7%-94.3%). In the subgroup of 20 patients who underwent surgery, the MPR rate was 65% (95% CI: 43.3%-82.9%), and the pCR rate was 40% (95% CI: 21.2%-46.3%). The 2-year DFS rate in the surgical group was 75% (95% CI 56%-94%). Notably, the MPR group demonstrated significantly prolonged DFS compared with the non-MPR group (p = 0.00024). A significant increase in pretreatment CD8 expression correlated with improved DFS (p = 0.00019). Three patients (10%) experienced grade 3 or higher immune-related AEs-one case of grade 3 elevated myocardial enzymes, one case of grade 3 interstitial pneumonia, and one case of grade 5 bronchopleural fistula. Interpretation: Neoadjuvant immunotherapy markedly enhanced the rate of pathological response and 2-year DFS in patients with potentially resectable IIIA/IIIB NSCLC. Overexpression of CD8 before treatment (H score≥3) may serve as a potential predictive biomarker for DFS. Consequently, the treatment landscape for potentially resectable IIIA/IIIB NSCLC could undergo changes. Funding: This study did not receive any financial support.

Updated overall survival and circulating tumor DNA analysis of ensartinib for crizotinib-refractory ALK-positive NSCLC from a phase II study.

BACKGROUND: The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. METHODS: In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. RESULTS: At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. CONCLUSION: Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and ALK-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

PI3K is required for the physical interaction and functional inhibition of NF-κB by ß-catenin in colorectal cancer cells.

Activation of ß-catenin and PI3K pathways are crucial for the oncogenesis of colorectal cancer (CRC). It remains controversial whether these two pathways function independently or cooperatively in the development and progression of CRC. We showed previously that ß-catenin inhibited NF-κB activation by interacting with p65 and this inhibitory interaction involved an unidentified cellular protein. In this study, we found that the PI3K effect on NF-κB activity is dependent on the level of ß-catenin in CRC cells. PI3K promoted NF-κB activity in the ß-catenin-low RKO cells; whereas it inhibited NF-κB activity in the ß-catenin-high HCT116, DLD-1, and SW480 cells. We showed that PI3K is required for the physical interaction and functional inhibition of NF-κB by ß-catenin. Inhibition of PI3K released NF-κB suppression in ß-catenin-high CRC cells, which conferred these cells with susceptibility to TNFα- and Fas-induced apoptosis. This is consistent with the observation showing that the level of ß-catenin and activated Akt are both inversely correlated with the expression of Fas, a downstream target of NF-κB, in CRC specimens. Mechanistically, the PI3K subunit p85 formed a complex with ß-catenin and NF-κB. Inhibition of PI3K disrupted the complex formation, leading to NF-κB activation. Our study not only provides new insight into the cross-talk among PI3K, ß-catenin and NF-κB signaling pathways but also indicates that targeting PI3K may yield therapeutic efficacy in treating ß-catenin-high CRC.

A real-world study of the efficacy and safety of furmonertinib for patients with non-small cell lung cancer with EGFR exon 20 insertion mutations.

BACKGROUND: Furmonertinib is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). A phase Ib study (FAVOUR, NCT04858958) initially demonstrated the efficacy of furmonertinib in non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins). This study aimed to investigate the real-world efficacy and safety of furmonertinib in patients with advanced NSCLC with EGFR ex20ins. METHODS: We retrospectively examined patients with advanced NSCLC with EGFR ex20ins having complete follow-up data, who were treated with furmonertinib from April 14, 2021, to March 15, 2022, at our institution and multiple hospitals in China. Objective response rate (ORR), disease control rate (DCR), 6-month progression-free survival (PFS) rates and treatment related adverse events (TRAEs) were assessed. RESULTS: This study included 53 patients with advanced NSCLC with EGFR ex20ins. A767_V769dup (28.3%) and S768_D770dup (11.3%) are the major variants. The ORR and DCR were 37.7% (20/53) and 92.5% (49/53), respectively. The 6-month PFS rate was 69.4% (95% CI 53.7-85.1%). The ORR of patients in the 240 mg once-daily dosage group was higher (42.9%) than that of patients in the 80 mg once-daily (25.0%) and 160 mg once-daily (39.5%) groups, but with no statistically significant difference (P = 0.816). The ORR of furmonertinib is not dependent on insertion location (P = 0.893). Patients with central nervous system (CNS) metastases at baseline responded similarly to those without CNS metastases (ORR: 33.3% vs. 40.6%, P = 0.773). The most common AEs were diarrhea (26.4%) and rash (26.4%). No grade ≥ 3 TRAEs were observed. No statistically significant difference was observed in the incidence of TRAEs between dosage groups (P = 0.271). CONCLUSIONS: Furmonertinib has shown encouraging antitumor activity and CNS activity in patients with advanced NSCLC with EGFR ex20ins. Moreover, furmonertinib had a good safety profile and no dose-dependent toxicity.

Genome-Wide Extrachromosomal Circular DNA Profiling of Paired Hepatocellular Carcinoma and Adjacent Liver Tissues.

Hepatocellular carcinoma (HCC) develops through multiple mechanisms. While recent studies have shown the presence of extrachromosomal circular DNA (eccDNA) in most cancer types, the eccDNA expression pattern and its association with HCC remain obscure. We aimed to investigate this problem. The genome-wide eccDNA profiles of eight paired HCC and adjacent non-tumor tissue samples were comprehensively elucidated based on Circle-seq, and they were further cross-analyzed with the RNA sequencing data to determine the association between eccDNA expression and transcriptome dysregulation. A total of 60,423 unique eccDNA types were identified. Most of the detected eccDNAs were smaller than 1 kb, with a length up to 182,363 bp and a mean sizes of 674 bp (non-tumor) and 813 bp (tumor), showing a greater association with gene-rich rather than with gene-poor regions. Although there was no statistical difference in length and chromosome distribution, the eccDNA patterns between HCC and adjacent non-tumor tissues showed significant differences at both the chromosomal and single gene levels. Five of the eight HCC tissues showed significantly higher amounts of chromosome 22-derived eccDNA expression compared to the non-tumor tissue. Furthermore, two genes, SLC16A3 and BAIAP2L2, with a higher transcription level in tumor tissues, were related to eccDNAs exclusively detected in three HCC samples and were negatively associated with survival rates in HCC cohorts from public databases. These results indicate the existence and massive heterogeneity of eccDNAs in HCC and adjacent liver tissues, and suggest their potential association with dysregulated gene expression.