Zhejiang Cancer Hospital
Recent publications
WX-0593 (Iruplinalkib) is a novel, highly selective oral ALK and ROS1 tyrosine kinase inhibitor (TKI). In this study, the safety, antitumor activity, and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer (NSCLC) patients with ALK or ROS1 rearrangement. In the dose-escalation phase and dose-expansion phase, patients were treated with WX-0593 until disease progression, unacceptable toxicity, or subject withdrawal. In the dose-escalation phase, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety assessed by investigators. In the dose-expansion phase, the primary endpoint was objective response rate (ORR) assessed by investigators. Between September 25, 2017 and October 15, 2018, a total of 153 patients received WX-0593 treatment. Two dose-limiting toxicities (DLTs) including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient. MTD was not reached. Overall, 140 of the 152 (92%) patients experienced treatment-related adverse events (TRAEs) and 35 of the 152 (23%) patients had TRAEs ≥grade 3. The overall ORR was 59.3% (32 of 54) for the dose-escalation phase and 56.6% (56 of 99) for the dose-expansion phase. For patients who were ALK -rearranged and ALK TKI naive, the ORR were 81.0% (17 of 21) in the dose-escalation phase and 76.3% (29 of 38) in the dose-expansion phase, and for patients who previously received crizotinib as the only ALK TKI, the ORR were 38.1% (8 of 21) and 45.7% (21 of 46) for the two phases, respectively. For patients who were ROS1 -rearranged, the ORR were 30.0% (3 of 10) in the dose-escalation phase and 44.4% (4 of 9) in the dose-expansion phase. WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement.
Due to their biological activities in regulating dosage compensation, epigenetics, and cell differentiation, long non-coding RNAs (lncRNA) have been recognized as important regulators of the beginning and development of human malignancies. LncRNA dysregulation has a significant impact on a range of cellular functions, including proliferation, migration, invasion, and anti-apoptosis activity. Recently, aberrant expression of the long non-coding RNA zinc finger protein multitype 2 antisense RNA 1 (ZFPM2-AS1) was observed in a range of solid tumors and correlated significantly with tumor size, histological differentiation, lymph node metastasis, malignant tumor (TNM) stage, short survival, and prognosis. Additional mechanical analysis indicated that ZFPM2-AS1 was involved in several cellular activities, including proliferation, migration, invasion, cell cycle progression, and apoptosis, through microRNAs (miRNAs), signaling pathways, and other biological components or proteins. This review summarizes the current status of research on ZFPM2-AS1 in various human malignancies and discusses its mechanism of action and clinical significance in tumor development and progression.
Sequential recommender systems aim to model users’ changing interests based on their historical behavior and predict what they will be interested in at the next moment. In recent years, approaches to modeling users’ long-term/short-term preferences have achieved promising results. Previous works typically model historical interactions through an end-to-end neural network incorporating rich side information, which relies on a final loss function to optimize all parameters. However, they tend to concatenate side information and item ID into a vector representation, leading to irreversible fusion. We propose a two-stage sequence recommendation framework to address this problem. The first stage aims to enhance the representation ability of sequence through a non-invasive bidirectional self-attentive item embedding. In the second stage, we use a time-interval aware Gated Recurrent Units with attention to capture the user’s latest intents, while predicting long-term preferences based on the first stage. To integrate the long-term/short-term preferences, we generate the final preference representation using an attention-based adaptive fusion module. We conduct extensive experiments on four benchmark datasets and the results demonstrate the effectiveness of our proposed model.
Gastric cancer (GC) is a common malignant tumor worldwide and poses a serious threat to human health. As a traditional Chinese medicine, Huaier (Trametes robiniophila Murr.) has been used in the clinical treatment of GC. However, the mechanism underlying the anticancer effect of Huaier remains poorly understood. In this study, we used in vivo imaging technology to determine the anticancer effect of the Huaier n-butanol extract (HBE) on orthotopic and hepatic metastasis of GC mouse models. We found that HBE suppressed tumor growth and metastasis without causing apparent host toxicity. Proteomic analysis of GC cells before and after HBE intervention revealed syntenin to be one of the most significantly downregulated proteins after HBE intervention. We further demonstrated that HBE suppressed the growth and metastasis of GC by reducing the expression of syntenin and the phosphorylation of STAT3 at Y705 and reversing the epithelial-mesenchymal transition (EMT). In addition, we confirmed that syntenin was highly expressed in GC tissue and correlated with metastasis and poor prognosis. In conclusion, our results suggest that Huaier, a clinically used anticancer drug, may inhibit the growth and liver metastasis of GC by inhibiting the syntenin/STAT3 signaling pathway and reversing EMT.
TGF-β is essential for inducing systemic tumor immunosuppression; thus, blocking TGF-β can greatly enhance antitumor immunity. However, there are still no effective TGF-β inhibitors in clinical use. Here, we show that the clinically approved compound ursodeoxycholic acid (UDCA), by degrading TGF-β, enhances antitumor immunity through restraining Treg cell differentiation and activation in tumor-bearing mice. Furthermore, UDCA synergizes with anti-PD-1 to enhance antitumor immunity and tumor-specific immune memory in tumor-bearing mice. UDCA phosphorylates TGF-β at T282 site via TGR5-cAMP-PKA axis, causing increased binding of TGF-β to carboxyl terminus of Hsc70-interacting protein (CHIP). Then, CHIP ubiquitinates TGF-β at the K315 site, initiating p62-dependent autophagic sorting and subsequent degradation of TGF-β. Notably, results of retrospective analysis shows that combination therapy with anti-PD-1 or anti-PD-L1 and UDCA has better efficacy in tumor patients than anti-PD-1 or anti-PD-L1 alone. Thus, our results show a mechanism for TGF-β regulation and implicate UDCA as a potential TGF-β inhibitor to enhance antitumor immunity. TGF-β can function to increase Treg cell function and reduce anti-tumour immunity. Here the authors show that UDCA is a potential mediator that can reduce TGF-β activity and promote anti-tumour immune responses in mice and can be additive to other checkpoint inhibitors.
Background Neoadjuvant chemoradiation followed by esophagectomy has been established as the first-line treatment for locally advanced esophageal cancer. Postoperative enteral nutrition has been widely used to improve perioperative outcomes. However, whether to implement preoperative nutritional intervention during neoadjuvant therapy is yet to be verified by prospective studies. Methods POINT trial is a multicenter, open-labeled, randomized controlled trial. A total of 244 patients with surgically resectable esophageal cancer are randomly assigned to nutritional therapy group (arm A) or control group (arm B) with a 2:1 ratio. Both groups receive neoadjuvant chemotherapy with concurrent radiotherapy based on the CROSS regimen followed by minimally invasive esophagectomy. The primary endpoint is the rate of nutrition and immune-related complications after surgery. Secondary endpoints include completion rate of neoadjuvant chemoradiation and related adverse events, rate of pathological complete response, perioperative outcomes, nutritional status, overall survival, progression-free survival and quality of life. Discussion This trial aims to verify whether immunonutrition during neoadjuvant chemoradiation can reduce the rate of complications and improve perioperative outcomes. Frequent communication and monitoring are essential for a multicenter investigator-initiated trial. Trial registration: ClinicalTrials.gov: NCT04513418. The trial was prospectively registered on 14 August 2020, https://www.clinicaltrials.gov/ct2/show/NCT04513418 .
Background Reconstruction of soft tissue defects following surgical tumor resection is important for quality of life in cancer patients with oral and oropharyngeal squamous cell carcinoma (SCC). This study presents a novel computer-aided reconstruction of soft tissue (CARST) technology employed with these patients. Methods We first described the CARST technology in detail in a report of a 34-year-old male patient with locally invasive right-sided tongue SCC following a nearly total glossectomy and reported the postoperative outcomes. This digital technology was applied to construct a 3D model from CT images, which was used to delineate surgical resection boundaries and design a personalized reconstruction of the soft tissue defect. A nonuniform rational B-spline (NURBS) was generated and applied to transform the 3D model into a 2D flap-cutting guide printed out using a 3D printer. We then reported a case-series study on oral and oropharyngeal SCC patients who were randomly assigned to receive the CARST ( n = 15) or a traditional soft tissue reconstruction ( n = 15). Clinicopathological features and short- and long-term postoperative outcomes between the two groups were compared. Results The patient with the tongue SCC had a successful CARST following surgical tumor resection without any complications. His speech and swallowing functions recovered well after surgery and he experienced no significant changes to his appearance following recovery. There was no recurrence within a 3-year follow-up period. Results of the case-series study showed that the CARST group had significantly shorter operative and post-operation hospital-stay time, a higher flap utilization rate, and a trend of less and milder postoperative complications, and they experienced no significant difference in intraoperative blood loss and long-term outcomes compared to the traditional group. Conclusion CARST is a safer and more efficient personalized technology of soft tissue reconstruction following surgical tumor resection in patients with oral and oropharyngeal SCC.
Objective: To observe the clinical effect of acupuncture for perimenopausal early-wake insomnia. Methods: A total of 60 patients with perimenopausal early-wake insomnia were randomly divided into an observation group (30 cases, 3 cases dropped off) and a control group (30 cases, 2 cases dropped off, 2 cases were removed). In the observation group, acupuncture was applied at Baihui (GV 20), Yintang (GV 24+), Anmian (Extra), Hegu (LI 4), Shenmen (HT 7), Taichong (LR 3), Taixi (KI 3), etc., once every other day, 3 times a week. In the control group, oryzanol tablets were taken orally, 20 mg each time, 3 times a day. Both groups were treated for 4 weeks. Before and after treatment, the sleep actigraphy (ACT) was used to measure the effective sleep time, sleep quality, wake-up time, wake-up frequency, each wake-up time, and the Pittsburgh sleep quality index (PSQI) score and early-wake score were compared in the two groups, and the clinical effect was assessed. Results: After treatment, compared before treatment, the effective sleep time was prolonged and the sleep quality was improved (P<0.05), the wake-up time, each wake-up time were shortened and wake-up frequency was decreased (P<0.05), the PSQI score and early-wake score were decreased (P<0.05) in the observation group. After treatment, the wake-up frequency, PSQI score and early-wake score were decreased in the control group (P<0.05). The effective sleep time, sleep quality, wake-up time, wake-up frequency, each wake-up time, PSQI score and early-wake score after treatment in the observation group were superior to the control group (P<0.05). The total effective rate was 88.9% (24/27) in the observation group, which was higher than 38.5% (10/26) in the control group (P<0.05). Conclusion: Acupuncture can increase the effective sleep time and improve sleep quality in patients with perimenopausal early-wake insomnia.
OBJECTIVE: This study aimed to examine the correlation between polymorphisms in vitamin D receptor (VDR) gene and serum vitamin D, and to determine their role in predicting childhood Autism Spectrum Disorder (ASD). METHODS : A total of 269 children with ASD and 320 age- and gender- matched healthy controls were recruited from the Chinese Han population. Their serum 25(OH) vitamin D was measured using competitive chemiluminescent immunoassays. The TaqMan probe approach was applied to analyze the common VDR SNPs rs731236 (Taq1), rs11568820 (Cdx2), rs1544410 (BsmI), rs2228570 (FokI) and rs7975232 (API). Both linear and logistic regressions were applied in data analysis. RESULTS: Children with ASD had significantly lower levels of serum vitamin D and a significantly higher rate of vitamin D deficiency (< 20 ng/ml) compared to healthy controls (67.7% vs 34.1%). All these examined VDR SNPs were not correlated with serum vitamin D concentrations or vitamin D deficiency. Logistic regression analysis revealed that rs731236 and serum vitamin D were associated with childhood ASD. The area under the receiver operating characteristic (ROC) curve was 0.7285 for serum vitamin D. Children with both T/C genotype of rs731236 and vitamin D deficiency had a higher risk of being diagnosed with ASD. CONCLUSION: All examined common VDR SNPs are not correlated with serum vitamin D concentrations or vitamin D deficiency. The combination of T/C phenotype of rs731236 and vitamin D deficiency are associated with a higher risk of childhood ASD. Vitamin D is a promising target in the prevention and treatment of this disease.
To analyze the application value of computed tomography (CT) based on a three-dimensional reconstruction algorithm in perioperative nursing research and prognosis analysis of non-muscle-invasive bladder cancer (NMIBC), a retrospective study was performed on 124 patients with NMIBC who underwent surgical treatment in the hospital. All patients underwent CT examination based on the three-dimensional reconstruction algorithm before surgery, and transurethral resection of the bladder tumor was performed. The patients receiving conventional care were classified as the control group, and those receiving comprehensive care were classified as the case group, and the recovery status and recurrence of the two groups were compared. The results showed that the accuracy, specificity, and sensitivity of CT imaging information based on the three-dimensional reconstruction algorithm for NMIBC patients were 89.38, 93.77, and 84.39, respectively. The incidence of bladder spasm (9.68%), bladder flushing time (1.56 d), and retention of drainage tube time (2.68 d) in the case group were obviously lower compared with the control group (30.65%, 2.32 d, and 5.19 d) (P
Background Liver fibrosis is an outcome of restoring process in chronic liver injury. Human amniotic mesenchymal stem cells (hAMSCs) derived from amniotic membrane have multilineage differentiation, immunosuppressive, and anti-inflammatory potential which makes them suitable for treating liver fibrosis. This study aimed to explore the effect and mechanism of hAMSCs on liver fibrosis. Methods hAMSCs were transplanted into carbon tetrachloride (CCl 4 )-induced liver fibrosis mice via tail vein, and the effects of hAMSCs on hepatic fibrosis were assessed. The effects of hAMSCs and hAMSCs conditional medium (CM) on the activation of hepatic stellate cells (HSCs) were investigated in vivo and in vitro. Antibody array assay was used to identify the cytokines secreted by hAMSCs that may inhibit the activation of HSCs. Finally, the underlying mechanisms were explored by assessing IGF-1R/PI3K/AKT and GSK3β/β-catenin signaling pathways in the activated HSCs (LX-2) with hAMSCs and hAMSCs transfected with corresponding siRNAs. Results Our results showed that hAMSCs possessed the characterizations of mesenchymal stem cells. hAMSCs significantly reduced liver fibrosis and improved liver function in mice by inhibiting HSCs activation in vivo. Both hAMSCs and hAMSC-CM remarkably inhibited the collagen deposition and activation of LX-2 cells in vitro. Antibody array assay showed that insulin-like growth factor binding protein-3 (IGFBP-3), Dickkopf-3 (DKK-3), and Dickkopf-1 (DKK-1) were highly expressed in the co-culture group and hAMSC-CM group compared with LX-2 group. Western blot assay demonstrated that IGFBP-3, DKK-3, and DKK-1 derived from hAMSCs inhibit LX-2 cell activation through blocking canonical Wnt signaling pathway. Conclusions Our results demonstrated that IGFBP-3, Dkk3, and DKK-1 secreted by hAMSCs attenuated liver fibrosis in mice through inhibiting HSCs activation via depression of Wnt/β-catenin signaling pathway, suggesting that hAMSCs or hAMSC-CM provides an alternative therapeutic approach for the treatment of liver fibrosis.
Seizure is one of the manifestations of central nervous system (CNS) inflammatory demyelinating diseases, which mainly include multiple sclerosis (MS), aquaporin 4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). "Acute symptomatic seizures secondary to MS / AQP4-NMOSD / MOGAD" occur in the acute phase of the diseases, and are more frequent in MOGAD. In contrast, recurrent non-provoked seizures, mainly attributed to "autoimmune-associated epilepsy", occur in the non-acute phase of the diseases. Seizures in MS / AQP4-NMOSD / MOGAD mostly have a focal-onset. MS patients with concomitant systemic infections, an earlier onset and a higher disease activity are more likely to have seizures, whereas factors such as higher MS severity, the presence of status epilepticus and cortical damage indicate a greater risk of developing epilepsy. In MOGAD, cerebral cortical encephalitis, acute disseminated encephalomyelitis (ADEM)-like phenotypes (predominately ADEM and multiphasic disseminated encephalomyelitis) indicate a higher seizure risk. Multiple relapses with ADEM-like phenotypes predict epilepsy in pediatrics with MOGAD. Pathophysiologically, acute symptomatic seizures in MS are associated with neuronal hyperexcitability secondary to inflammation and demyelination. Chronic epilepsy in MS is largely due to gliosis, neuronal dysfunction and synaptic abnormalities. The mainstay of treatment for seizures secondary to MS / AQP4-NMOSD / MOGAD include immunotherapy along with antiseizure medications. This critical review discusses the most-updated evidence on epidemiology, clinical correlates, and inflammatory mechanisms underlying seizures and epilepsy in MS / AQP4-NMOSD / MOGAD. Treatment cautions including drug-drug interactions and the impact of treatments on the other are outlined. We also highlight pitfalls and challenges in managing such patients and future research perspectives to address unsolved questions.
Purpose: Recurrent or metastatic cervical cancer patients have limited treatment options after platinum-containing treatment. We initiated a phase 1 study to assess SHR-1701, a novel bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, in solid tumors (NCT03774979). Here, results from the cervical cancer cohort are presented. Patients and methods: Patients with recurrent or metastatic cervical cancer who progressed during or after platinum-based therapy were enrolled to receive SHR-1701 at 30 mg/kg every three weeks. Primary endpoint was objective response rate (ORR) per RECIST v1.1. Results: Totally, 32 patients were recruited. ORR was 15.6% (95% CI, 5.3-32.8) and disease control rate was 50.0% (95% CI, 31.9-68.1). Responses were still ongoing in 80.0% of the responders; 6-month duration of response rate was 80.0% (95% CI, 20.4-96.9). Median progression-free survival (PFS) was 2.7 months (95% CI, 1.4-4.1). Of note, as assessed by imRECIST, median PFS was 4.1 months (95% CI, 1.6-4.3). 12-month overall survival rate was 54.6% (95% CI, 31.8-72.7). Treatment-related adverse events of grade 3 or 4 were reported in 11 (34.4%) patients. No treatment-related deaths occurred. No difference in ORR was found between patients with PD-L1 CPS {greater than or equal to}1 or <1; patients with high pSMAD2 level in immune cells or tumor cells had numerically higher ORR. Conclusion: SHR-1701 exhibits encouraging antitumor activity and controllable safety in patients with recurrent or metastatic cervical cancer after platinum-based regimens, might providing another treatment option for this population.
Background This phase II study evaluated camrelizumab in different PD-L1 expression cohorts of patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC; NCT03085069, registered March 21, 2017). Methods Patients who progressed during/after chemotherapy were enrolled and divided into four cohorts based on PD-L1 tumor proportion score (TPS). Patients with EGFR/ALK alterations and PD-L1 TPS ≥ 50% were also eligible. All enrolled patients received camrelizumab at 200 mg IV Q2W. The primary endpoint was objective response rate. Results A total of 146 patients were enrolled. As of data cutoff on Aug 20, 2020, the median follow-up was 29.5 months (95% CI 27.4–30.8). Objective response rate was 17.8% (95% CI 12.0–25.0) and improved with the increasing PD-L1 TPS (TPS < 1%, 12.2% [95% CI 5.7–21.8]; ≥ 1–< 25%, 19.4% [95% CI 7.5–37.5]; ≥ 25–< 50%, 36.4% [95% CI 10.9–69.2]; ≥ 50%, 23.3% [95% CI 9.9–42.3]). No response was observed in the five patients harboring EGFR mutations. Median progression-free survival was 3.2 months (95% CI 2.0–3.4), and patients with positive PD-L1 TPS had longer progression-free survival. Median overall survival was 14.8 months (95% CI 10.2–18.7). Treatment-related adverse events (TRAEs) of any grade occurred in 87.7% of patients, and 21.2% had grade ≥ 3 TRAEs. Conclusion Camrelizumab showed improved efficacy compared with historical data of the second-line chemotherapy in pre-treated advanced/metastatic NSCLC. Patients with positive PD-L1 expression derived greater benefit from camrelizumab. Camrelizumab has a manageable safety profile.
The examination of patients' handwriting has become an important auxiliary method for the diagnosis and treatment of Parkinson's disease which can be used for early self-diagnosis of patients with Parkinson's disease. However, at present, the recognition of writing disorders based on artificial intelligence technology mainly relies on pattern templates and intelligent dynamic acquisition equipment, which has some design limitations. And professional acquisition equipment is not suitable for ordinary home patients. In order to facilitate the diagnosis of Parkinson's disease and get more accurate diagnostic results, this paper is devoted to studying various features of spiral hand drawing of Parkinson's disease and developing an auxiliary diagnosis scheme based on hand drawing. Firstly, through the ablation experiment with open dataset, it is verified that the visual information of hand drawing can better reflect the characteristics of hand drawing of patients with Parkinson's disease than the original dynamic information. Secondly, an Archimedes spiral hand drawing dataset is established that can accurately reflect the tremor, shape and spacing characteristics of the image, with no limitation of the application scenario. Finally, Continuous Convolution Network (CC-Net) is proposed to reduce the pooling layer. Compared with the traditional classification network, CC-Net can accurately extract diversified features of hand drawings and maximize the retention of image information, and obtain a higher classification accuracy with qualified stability (the classification accuracy on the dataset of this paper is about 89.3%, MCC is about 0.733, and average AUC is about 0.934).
The protein encoded by CD3D is part of the T-cell receptor/CD3 complex (TCR/CD3 complex) and is involved in T-cell development and signal transduction. Previous studies have shown that CD3D is associated with prognosis and treatment response in breast, colorectal, and liver cancer. However, the expression and clinical significance of CD3D in gastric cancer are not clear. In this study, we collected 488 gastric cancer tissues and 430 paired adjacent tissues to perform tissue microarrays (TMAs). Then, immunohistochemical staining of CD3D, CD3, CD4, CD8 and PD-L1 was conducted to investigate the expression of CD3D in gastric cancer and the correlation between the expression of CD3D and tumor infiltrating lymphocytes (TILs) and PD-L1. The results showed that CD3D was highly expressed in gastric cancer tissues compared with paracancerous tissues (P<0.000). Univariate and multivariate analyses showed that CD3D was an independent good prognostic factor for gastric cancer (P=0.004, HR=0.677, 95%CI: 0.510-0.898 for univariate analyses; P=0.046, HR=0.687, 95%CI: 0.474-0.994 for multivariate analyses). In addition, CD3D was negatively correlated with the tumor location, Borrmann type and distant metastasis (P=0.012 for tumor location; P=0.007 for Borrmann type; P=0.027 for distant metastasis). In addition, the expression of CD3D was highly positively correlated with the expression of CD3, CD4, CD8, and PD-L1, and the combination of CD3D with CD3, CD4, CD8 and PD-L1 predicted the best prognosis (P=0.043). In summary, CD3D may play an important regulatory role in the tumor immune microenvironment of gastric cancer and may serve as a potential indicator of prognosis and immunotherapy response.
Hepatorenal syndrome (HRS) could occur when patients get decompensated liver cirrhosis. Meanwhile, hepatitis B virus (HBV) infection raises the risk of mortality of the end-stage liver diseases. As the artificial liver support system (ALSS) has been applied in liver failure, whether ALSS could benefit HBV-derived HRS remains uncertain. We retrospectively enlisted eligible HRS patients and compared the baseline characteristics and prognosis between HBV-derived HRS and non-HBV-derived HRS. Furthermore, propensity score matching (PSM) and Cox regression analyses were used to assess the beneficial effect of ALSS on HBV-derived HRS. In addition, a stratified analysis was carried out according to the degree of acute kidney injury (AKI) and the number of organ failures to observe in which populations ALSS can obtain the most excellent therapeutic effect. 669 patients were diagnosed as HRS, including 298 HBV negative and 371 HBV positive. Baseline characteristics were different between patients with HBV positive and HBV negative. HBV-derived HRS has higher 28-day mortality, though without a statistical difference. After PSM, 50 patients treated with ALSS and 150 patients treated with standard medical treatment (SMT) constituted a new cohort for the following analysis. We found that ALSS could significantly benefit HRS patients ( P = 0.025 ). Moreover, the median survival time of patients treated with ALSS was longer than those treated with SMT. INR, neutrophil percentage, and treatment with ALSS were independent predictive factors for short-term mortality in HBV-derived HRS. The stratified analysis showed that ALSS could reduce the 28-day mortality of patients with HBV-derived HRS, especially those in AKI stage 3 and with organ failure ≥ 2 . Additionally, serum bilirubin was significantly lower after ALSS, and the alteration of INR and creatinine were independent predictive elements for the mortality of HBV-derived HRS. HBV-derived HRS is more severe than non-HBV-derived HRS and has a worse prognosis. ALSS could reduce the short-term mortality of patients with HBV-derived HRS, especially those in AKI stage 3 and with organ failure ≥ 2 . INR and the change of creatinine and INR could predict the prognosis of HBV-derived HRS. ChiCTR2200060123.
Background Limertinib (ASK120067) is a newly developed third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both sensitizing EGFR and EGFR T790M mutations. This study aimed to evaluate the efficacy and safety of limertinib in patients with locally advanced or metastatic EGFR T790M mutated non-small cell lung cancer (NSCLC). Methods This is a single-arm, open-label, phase 2b study conducted at 62 hospitals across China. Patients with locally advanced or metastatic NSCLC with centrally confirmed EGFR T790M mutations in tumor tissue or blood plasma who progressed after first or second-generation EGFR-TKIs or with primary EGFR T790M mutations were enrolled. Patients received limertinib 160mg orally twice daily, until disease progression, or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by Independent Review Committee (IRC) per the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. Safety was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Results From June 24, 2019 to Feb 25, 2021, a total of 301 patients were enrolled and received the treatment of limertinib. All patients entered the full analysis set (FAS) and safety set (SS). By the data cutoff date on Sept 9, 2021, 76 (25.2%) remained on treatment. The median follow-up time was 10.4 months (range 0.3-26.3). Based on FAS, the IRC-assessed ORR was 68.8% (95%CI 63.2%-74.0%) and DCR was 92.4% (95%CI 88.8%-95.1%). The median PFS was 11.0 months (95%CI 9.7-12.4), median DoR was 11.1 months (95%CI 9.6-13.8), and median OS was not reached (NR) (95%CI 19.7 months-NR). Objective responses were achieved across all pre-specified subgroups. For 99 (32.9%) patients with central nervous system (CNS) metastases, the ORR was 64.6% (95%CI 54.4%-74.0%), median PFS was 9.7 months (95%CI 5.9-11.6), and median DoR was 9.6 months (95%CI 8.1-15.2). For 41 patients who had evaluable CNS lesion, the confirmed CNS-ORR was 56.1% (95%CI 39.7%-71.5%) and median CNS-PFS was 10.6 months (95%CI 5.6-NE). In SS, 289 (96.0%) patients experienced at least one treatment related adverse event (TRAE), with the most common being diarrhea (81.7%), anemia (32.6%), rash (29.9%) and appetite decrease (28.2%). Grade ≥3 TRAEs occurred in 104 (34.6%) patients, with the most common including diarrhea (13.0%), hypokalemia (4.3%), anemia (4.0%) and rash (3.3%). TRAEs leading to dose interruption and dose discontinuation occurred in 24.6% and 2% of patients, respectively. No TRAE leading to death occurred. Conclusion Limertinib (ASK120067) demonstrated promising efficacy and an acceptable safety profile for the treatment of patients with locally advanced or metastatic EGFR T790M mutated NSCLC. Clinical Trial information: NCT03502850.
e13575 Background: Homologous recombination deficiency (HRD) can be resulted from dysfunction of BRCA and is associated with sensitivity to platinum, PARP inhibitor and other DNA-damaging drugs. The results from a neoadjuvant trial showed that pathological complete response (pCR) was not significantly higher with cisplatin than with doxorubicin-cyclophosphamide in BRCA1/2-mutated breast cancers (BC). It suggests that BC with HRD might benefit from anthracycline-containing regiment. There are many commercial HRD detection assays, including the FoundationFocus CDx BRCA LOH and myChoice CDx, but there is still no uniform standard in China. Methods: A total of 96 in-house BC samples and 6 HRD positive standard cells (Cat No. CBP90023) were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ̃1X WGS. We constructed a new algorithm for HRD score based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. The sensitivity and specificity were compared between our algorithm and the ShallowHRD. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-containing neoadjuvant treatment outcomes. Results: A 100kb-window was defined as the optimal size by using 41 in-house cases and the TCGA dataset. The threshold of HRD was determined as the number of 10 LCNAs by using 55 in-house BCs with BRCA mutation, with the goal of achieving 95% sensitivity. The sensitivity and specificity of our algorithm were both 100%, while those of the ShallowHRD were 40% and 100%, respectively, by testing standard samples with positive HRD. Meanwhile, similar results were also observed that the sensitivity of our algorithm was far superior to ShallowHRD (87% vs 13%) in the clinical cohort. The association between HRD status and BRCA mutations was compared between our algorithm and the ShallowHRD by 120 BC WGS samples (20 cases carrying BRCA mutation) from the TCGA database. The results showed that BRCA status was significantly associated with HRD status by our algorithm and ShallowHRD (P = 0.00838 and P = 0.00284, respectively). However, our algorithm had a higher positive concordance rate than the ShallowHRD algorithm (70% vs 60%). In the clinical cohort of neoadjuvant treatment, HRD group was more likely to respond to anthracycline-containing chemotherapy than non-HRD group, with outcomes of pCR (OR = 9.5, 95% CI: 1.11–81.5, p = 0.04) and residual cancer burden score of 0 or 1 (RCB0/1) (OR = 10.29, 95% CI: 2.02–52.36, p = 0.005). Among 35 patients lacking BRCA mutations, HRD group tended to have RCB0/1 responses compared to non-HRD group (OR = 6.0, 95% CI: 1.00–35.91, p = 0.05). Conclusions: Here, we developed a new stable algorithm for HRD score. It’s a promising assay for clinical application to predict sensitivity of DNA-damaging drugs.
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83 members
Ming Chen
  • Department of Radiation Oncology
Jia-Jie Xu
  • Head and Neck surgical oncology
Fangzheng Wang
  • Department of Radiation Oncology
Meiyu Fang
  • Department of Medical Oncology
Hangzhou, China