Ex vivo liver resection combined with autologous liver transplantation offers the opportunity to treat otherwise unresectable hepatobiliary malignancies and has been applied in clinic. The implementation of enhanced recovery after surgery (ERAS) program improves the outcome of surgical procedures. This is a retrospective single-center study including 11 cases of patients with liver cancer that underwent autologous liver transplantation and received ERAS: cholangiocarcinoma of the hilar region (n = 5), intrahepatic cholangiocarcinoma (n = 3), gallbladder cancer (n = 1), liver metastasis from colorectal cancer (n = 1), and liver metastasis from gastrointestinal mesenchymal tumor (n = 1). There were no deaths within 30 days and major complications occurred in two patients, and four patients were readmitted upon the first month after the surgery. Median hospital stay was 20 days (range 13-44) and median open diet was Day 4 (range 2-9) after surgery and median early post-operative activity was Day 5 (range 2-9) after surgery. In conclusion, autologous liver transplantation is feasible in the treatment of otherwise unresectable hepatobiliary malignancies, and our study showed favorable results with autologous liver transplantation in ERAS modality. ERAS modality provides a good option for some patients whose tumors cannot be resected in situ and offers a chance for rapid recovery.

ABSTRACT Antibiotics are widely used to treat bacterial infection and reduce the mortality rate, while antibiotic overuse can cause gut microbiota dysbiosis. The impact of antibiotics on gut microbiota is not fully understood. In our study, four commonly used antibiotics (ceftazidime, cefoperazone-sulbactam, imipenem-cilastatin, and moxifloxacin) were given subcutaneously to mice, and their impacts on the gut microbiota composition and serum cytokine levels were evaluated through 16S rRNA analysis and a multiplex immunoassay. Antibiotic treatment markedly reduced gut microbiota diversity and changed gut microbiota composition. Antibiotic treatment significantly increased and decreased the abundance of Firmicutes and Bacteroidota, respectively. The antibiotic treatments increased the abundance of opportunistic pathogens such as Enterococcus and decreased that of Lachnospiraceae and Muribaculaceae . For moxifloxacin, the significantly high abundance of Enterococcus and Klebsiella was observed after 14 and 21 days of treatment. However, a relatively low abundance of opportunistic pathogens was found after 14 days of imipenem-cilastatin treatment. Additionally, the serum levels of various pro-inflammatory cytokines, such as IL-1β, IL-12 (p70), and IL-17, significantly increased after 21 days of antibiotic treatments. Overall, these results provide a guide for rational use of antibiotics in clinical settings: short-term use of moxifloxacin is recommended with regard to gut microbiota health, and the 14-day use of imipenem-cilastatin may have a less severe impact than other antibiotics. IMPORTANCE Antibiotic treatments are directly associated with changes in gut microbiota and are effective against both pathogens and beneficial bacteria. Gut microbiota dysbiosis induced by antibiotic treatment could increase the risk of some diseases. Therefore, an adequate understanding of gut microbiota changes after antibiotic use is crucial. In this study, we investigated the effects of continuous treatment with antibiotics on gut microbiota, serum cytokines, and intestinal inflammatory response. Our results suggest that short-term use of moxifloxacin is recommended, and the 14-day use of imipenem-cilastatin may have a less severe effect on gut microbiota health than cefoperazone-sulbactam. These results provide useful guidance on the rational use of antibiotics with regard to gut microbiota health.

OBJECTIVES:To establish a cell line stably expressing the transient receptor potential melastatin 2 (TRPM2) channel for screening TRPM2 inhibitors based on PiggyBac transposition system. METHODS:A plasmid PiggyBac-human TRPM2 (pPB-hTRPM2) eukaryotic expression vector was constructed using PiggyBac transposition system. The plasmid and a helper plasmid were co-transfected into HEK293T cells to express TRPM2, which was identified by fluorescence and patch-clamp assays. The high throughput screening performance was assessed with the Z ´ factor. Calcium imaging and patch clamp techniques were employed to assess the initial activity of eleven compound molecules, confirming the inhibitory effects of the primary molecules on TRPM2. The protective effect of the screened compounds on damaged cells was validated using the oxygen-glucose deprivation/reperfusion (OGD/R) injury model and CCK-8 kit. The level of cellular reactive oxygen species (ROS) was detected by flow cytometry. The neuroprotective effects of the compounds were evaluated using a transient middle cerebral artery occlusion (tMCAO) mouse model. RESULTS:The HEK293T cells transfected with pPB-hTRPM2-EGFP showed high TRPM2 expression. Puromycin-resistant cells, selected through screening, exhibited robust fluorescence. Whole-cell patch results revealed that induced cells displayed classical TRPM2 current characteristics comparable to the control group, showing no significant differences (P>0.05). With a Z ´ factor of 0.5416 in calcium imaging, the model demonstrated suitability for high-throughput screening of TRPM2 inhibitors. Calcium imaging and electrophysiological experiments indicated that compound 6 significantly inhibited the TRPM2 channel. Further experiments showed that 1.0 μmol/L of compound 6 enhanced cell viability (P<0.05) and reduced the level of ROS (P<0.05) of SH-SY5Y under OGD/R injury. 0.3 and 1.0 mg/kg of compound 6 reduced the cerebral infarction volume in tMCAO mice (both P<0.05). CONCLUSIONS:A stable TRPM2 gene expressing cell line has been successfully established using PiggyBac gene editing in this study. TRPM2 channel inhibitors were screened through calcium imaging and patch clamp techniques, and an inhibitor compound 6 was identified. This compound can alleviate cell damage after OGD/R by reducing cellular ROS levels and has a protective effect against cerebral ischemia-reperfusion injury in mice.

Rationale:Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is a rare malignant primary hepatic lymphoma. The sensible choice of treatment for patients with primary lymphoma combined with atrial fibrillation (AF) is controversial and challenging.Patient concerns:The patient presented with both primary hepatic MALT lymphoma and AF, which was difficult to manage.Diagnoses:Pathological and immunohistochemical examination are helpful for definitive diagnosis.Interventions:Surgical resection and subsequent anticoagulant therapy are main treatment methods, and adjuvant therapy depends on the situation.Outcomes:Primary hepatic MALT lymphoma is easy to misdiagnosis due to a lack of typical symptoms and imaging signs.Lessons:This case highlights for patients with primary hepatic MALT lymphoma combined with AF, toxicity caused by adjuvant chemotherapy should be fully considered, and careful selection should be made based on the general conditions and complications of patients.

Colorectal cancer (CRC) is one of the most prevalent types of malignant tumors. It's vital to explore new biomarkers and potential therapeutic targets in CRC lung metastasis through adopting integrated bioinformatics tools. Multiple cohort datasets and databases were integrated to clarify and verify potential key candidate biomarkers and signal transduction pathways in CRC lung metastasis. DAVID, STRING, UALCAN, GEPIA, TIMER, cBioPortal, THE HUMAN PROTEIN ATLAS, GSEA 4.3.2, FUNRICH 3.1.3, and R 4.2.3 were utilized in this study. The enriched biological processes and pathways modulated by the differentially expressed genes (DEGs) were determined with Gene Ontology, Kyoto Encyclopedia of Genes and Genomes. The search tool Retrieval of Interacting Genes and Cytoscape were used to construct a protein-protein interaction network among DEGs. Four hundred fifty-nine colorectal primary cancer and lung metastatic gene expression profiles were screened from 3 gene expression profiles (GSE41258, GSE68468, and GSE41568). Forty-one upregulated genes and 8 downregulated genes were identified from these 3 gene expression profiles and verified by the transcriptional levels of hub genes in other GEO datasets and The Cancer Genome Atlas database. Two pathways (immune responses and chemokine receptors bind chemokines), 13 key DEGs, 6 hub genes (MMP3, SFTPD, ABCA3, CLU, APOE, and SPP1), and 2 biomarkers (APOE, SPP1) with significantly prognostic values were screened. Forty-nine DEGs were identified as potential candidate diagnostic biomarkers for patients with CRC lung metastasis in present study. Enrichment analysis indicated that immune responses and chemokine receptors bind chemokines may play a leading role in lung metastasis of CRC, and further studies are needed to validate these findings.

Objective To compare the efficacy of laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) in a medium-volume medical center. Methods Data for patients who underwent OPD or LPD for carcinoma of the ampulla of Vater (VPC) between January 2017 and June 2022 were acquired retrospectively. Propensity score-matching (PSM) analysis was performed to balance the baseline characteristics between the groups. The primary outcome was disease-free survival (DFS). Cox regression analysis was used to explore the independent risk factors for DFS. Results A total of 124 patients with pathologically diagnosed VPC were included. After 1:1 matching, there were 23 cases each in the OPD and LPD groups. Kaplan–Meier survival analyses showed that the median DFS in the OPD and LPD groups was identical (16.0 months vs 16.0 months, respectively). Multivariate Cox regression analysis showed that low levels of alkaline phosphatase and γ-glutamyl transpeptidase, positive surgical margin, and lymph node enlargement were independent risk factors for DFS. Conclusion LPD in medium-volume centers with acceptable technical conditions may approach or even achieve the efficacy of LPD in large-volume centers.

Colorectal cancer is the second largest cause of cancer-related death in the world, and ranks as the third most common malignant tumor in the world. Approximately 25% of patients present with colorectal liver metastases(CRLM) at first diagnosis, and surgical treatment is often considered necessary for the potential long-term survival of patients with CRLM. The median overall survival (OS) of patients who achieved R0 resection in CRLM was 42 months, and the 5-year survival rate was 35%~40%. The initial resectable rate is less than 20%. Therefore, surgical resection of initial unresectable CRLM after conversion therapy will significantly improve the prognosis of patients with CRLM. In this review, we introduce the latest literature on initial unresectable CRLM conversion therapy,and discuss the advances in diagnosis, treatment methods and therapeutic effects, so as to guide clinical practice.

Background Gallbladder carcinoma (GBC) is highly malignant, and its early diagnosis remains difficult. This study aimed to develop a deep learning model based on contrast-enhanced computed tomography (CT) images to assist radiologists in identifying GBC. Methods We retrospectively enrolled 278 patients with gallbladder lesions (> 10 mm) who underwent contrast-enhanced CT and cholecystectomy and divided them into the training (n = 194) and validation (n = 84) datasets. The deep learning model was developed based on ResNet50 network. Radiomics and clinical models were built based on support vector machine (SVM) method. We comprehensively compared the performance of deep learning, radiomics, clinical models, and three radiologists. Results Three radiomics features including LoG_3.0 gray-level size zone matrix zone variance, HHL first-order kurtosis, and LHL gray-level co-occurrence matrix dependence variance were significantly different between benign gallbladder lesions and GBC, and were selected for developing radiomics model. Multivariate regression analysis revealed that age >= 65 years [odds ratios (OR) = 4.4, 95% confidence interval (CI): 2.1-9.1, P < 0.001], lesion size (OR = 2.6, 95% CI: 1.6-4.1, P < 0.001), and CA-19-9 > 37 U/mL (OR = 4.0, 95% CI: 1.6-10.0, P = 0.003) were significant clinical risk factors of GBC. The deep learning model achieved the area under the receiver operating characteristic curve (AUC) values of 0.864 (95% CI: 0.814-0.915) and 0.857 (95% CI: 0.773-0.942) in the training and validation datasets, which were comparable with radiomics, clinical models and three radiologists. The sensitivity of deep learning model was the highest both in the training [90% (95% CI: 82%-96%)] and validation [85% (95% CI: 68%-95%)] datasets. Conclusions The deep learning model may be a useful tool for radiologists to distinguish between GBC and benign gallbladder lesions.(c) 2023 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.

Objective Malignant biliary obstruction (MBO) is a rare disease with a poor prognosis. Recent studies have shown that endoscopic radiofrequency ablation (ERFA) may improve survival. We conducted a systematic review and meta-analysis of the efficacy of ERFA in combination with biliary stent placement for the treatment of MBO. Methods The study was registered in INPLASY (number 202340096). The PubMed, Cochrane Library, Web of Science, and Embase databases were searched from inception to April 2023. We selected studies comparing the efficacy of ERFA plus stent placement with stent placement alone. The primary outcomes were pooled hazard ratios (HRs) for overall survival and stent patency; the secondary outcomes were the odds ratios (ORs) for adverse events. Results Eleven studies (four randomized controlled trials and seven observational studies) were included in the meta-analysis. Pooled analysis showed a difference in survival time between the two groups (HR 0.65, 95% confidence interval [CI] 0.58–0.73, I 2 = 40%). However, there were no differences in the duration of stent patency or the incidence of adverse events (HR 1.04, 95% CI 0.84–1.29, I 2 = 46%; OR 1.41, 95% CI 1.02–1.96, I 2 = 29%). Conclusions ERFA has a significant survival benefit for MBO, but does not increase the risk of adverse events.

Around 80% of pancreatic ductal adenocarcinoma (PDAC) patients experience recurrence after curative resection. We aimed to develop a deep-learning model based on preoperative CT images to predict early recurrence (recurrence within 12 months) in PDAC patients. The retrospective study included 435 patients with PDAC from two independent centers. A modified 3D-ResNet18 network was used for a deep learning model construction. A nomogram was constructed by incorporating deep learning model outputs and independent preoperative radiological predictors. The deep learning model provided the area under the receiver operating curve (AUC) values of 0.836, 0.736, and 0.720 in the development, internal, and external validation datasets for early recurrence prediction, respectively. Multivariate logistic analysis revealed that higher deep learning model outputs (odds ratio [OR]: 1.675; 95% CI: 1.467, 1.950; p < 0.001), cN1/2 stage (OR: 1.964; 95% CI: 1.036, 3.774; p = 0.040), and arterial involvement (OR: 2.207; 95% CI: 1.043, 4.873; p = 0.043) were independent risk factors associated with early recurrence and were used to build an integrated nomogram. The nomogram yielded AUC values of 0.855, 0.752, and 0.741 in the development, internal, and external validation datasets. In conclusion, the proposed nomogram may help predict early recurrence in PDAC patients.

Different dopaminergic (DA) neuronal subgroups exhibit distinct vulnerability to stress, while the underlying mechanisms are elusive. Here we report that the transient receptor potential melastatin 2 (TRPM2) channel is preferentially expressed in vulnerable DA neuronal subgroups, which correlates positively with aging in Parkinson's Disease (PD) patients. Overexpression of human TRPM2 in the DA neurons of C. elegans resulted in selective death of ADE but not CEP neurons in aged worms. Mechanistically, TRPM2 activation mediates FZO-1/CED-9-dependent mitochondrial hyperfusion and mitochondrial permeability transition (MPT), leading to ADE death. In mice, TRPM2 knockout reduced vulnerable substantia nigra pars compacta (SNc) DA neuronal death induced by stress. Moreover, the TRPM2-mediated vulnerable DA neuronal death pathway is conserved from C. elegans to toxin-treated mice model and PD patient iPSC-derived DA neurons. The vulnerable SNc DA neuronal loss is the major symptom and cause of PD, and therefore the TRPM2-mediated pathway serves as a promising therapeutic target against PD.

OBJECTIVES:Gallbladder carcinoma (GBC) is the most common and aggressive biliary tract malignancy with high postoperative recurrence rates. This single-center study aimed to develop and validate a radiomics signature to estimate GBC recurrence-free survival (RFS).METHODS:This study retrospectively included 204 consecutive patients with pathologically diagnosed GBC and were randomly divided into development (n = 142) and validation (n = 62) cohorts (7:3). The radiomics features of tumor were extracted from preoperative contrast-enhanced CT imaging for each patient. In the development cohort, the least absolute shrinkage and selection operator (LASSO) Cox regression was employed to develop a radiomics signature for RFS prediction. The patients were stratified into high-score or low-score groups according to their median value of radiomics score. A nomogram was established using multivariable Cox regression by incorporating significant pathological predictors and radiomics signatures.RESULTS:The radiomics signature based on 12 features could discriminate high-risk patients with poor RFS. Multivariate Cox analysis revealed that pT3/4 stage (hazard ratio, [HR] = 2.691), pN2 stage (HR = 3.60), poor differentiation grade (HR = 2.651), and high radiomics score (HR = 1.482) were independent risk variables associated with worse RFS and were incorporated to construct a nomogram. The nomogram displayed good prediction performance in estimating RFS with AUC values of 0.895, 0.935, and 0.907 at 1, 3, and 5 years, respectively.CONCLUSIONS:The radiomics signature and combined nomogram may assist in predicting RFS in GBC patients.KEY POINTS:• A radiomics signature extracted from preoperative contrast-enhanced CT can be a useful tool to preoperatively predict RFS of GBC. • T3/T4 stage, N2, poor tumor differentiation, and high radiomics score were positively associated with postoperative recurrence.

Mitophagy is a selective autophagic process that removes damaged mitochondria. PINK1-Parkin axis is primarily responsible for initiating mitophagy via feedforward mechanism, in which PINK1 phosphorylates ubiquitin and Parkin, and Parkin gains E3 ligase activity at the mitochondrial outer membrane. However, the phosphatase of pParkin is unknown, and the braking mechanism of mitophagy is incomplete. Here we report that protein phosphatase 2A (PP2A) catalyzes the dephosphorylation of Parkin and ubiquitin, with Cα, Aα, and B55α, the catalytic scaffolding and regulatory subunits, respectively. Up- or down-regulation of PP2A protein level in cells by over-expression or transfection of specific siRNA decreases or increases Parkin and ubiquitin phosphorylation levels, respectively. Consequently, PP2A phosphatase activity negatively modulates mitochondrial translocation of Parkin and forestalls mitophagy. Our finding thus places PP2A, an enzyme already known for its involvement in the pathogenesis of neurodegenerative diseases, further intertwined with the PINK1-Parkin signaling pathway.

Drugs targeting N-methyl-D-aspartate receptors (NMDARs) have been approved to treat major depressive disorder (MDD); however, the presence of undesirable psychotomimetic and cognitive side effects may limit their utility. In this study, we show that the phosphorylation levels of the GluN2B subunit at tyrosine (Y) 1070 increase in mice after both acute and chronic restraint stress (CRS) exposure. Preventing GluN2B-Y1070 phosphorylation via Y1070F mutation knockin produces effects similar to those of antidepressants but does not affect cognitive or anxiety-related behaviors in subject mice. Mechanistically, the Y1070F mutation selectively reduces non-synaptic NMDAR currents and increases the number of excitatory synapses in the layer 5 pyramidal neurons of medial prefrontal cortex (mPFC) but not in the hippocampus. Altogether, our study identifies phosphorylation levels of GluN2B-Y1070 in the mPFC as a dynamic, master switch guarding depressive behaviors, suggesting that disrupting the Y1070 phosphorylation of GluN2B subunit has the potential for developing new antidepressants.

:To investigate the effect of transient receptor potential melastatin 2 （TRPM2） inhibitor A10 on oxygen glucose deprivation/reperfusion （OGD/R） injury in SH-SY5Y cells．:Human neuroblastoma SH-SY5Y cells were subject to OGD/R injury，and then were divided into blank control group，model control group and A10 group randomly. The cell survival rate was detected by cell counting kit 8 （CCK-8）; the level of cellular reactive oxygen species （ROS） was detected by reactive oxygen detection kit; the mitochondrial membrane potential was detected by tetramethylrhodamine （TMRM） method; the number of apoptotic cells was detected by TUNEL apoptosis assay kit; the protein expression level of cleaved caspase 3 was detected by Western blot．:Compared with 3，20，30，50， has lower cytotoxicity and better inhibition effect on channel activity. Compared with the model control group，ROS level was reduced，the mitochondrial membrane potential was improved，the number of apoptosis cells was reduced ，and the expression of cleaved caspase 3 was significantly reduced in the A10 group（all <0.05）. : A10 can alleviate cell damage after OGD/R by inhibiting TRPM2 channel function，reducing extracellular calcium influx，reducing cell ROS levels，stabilizing mitochondrial membrane potential levels，and reducing apoptosis.

ObjectivesThe aim of the current study was to develop and validate a nomogram based on CT radiomics features and clinical variables for predicting lymph node metastasis (LNM) in gallbladder cancer (GBC).MethodsA total of 353 GBC patients from two hospitals were enrolled in this study. A Radscore was developed using least absolute shrinkage and selection operator (LASSO) logistic model based on the radiomics features extracted from the portal venous-phase computed tomography (CT). Four prediction models were constructed based on the training cohort and were validated using internal and external validation cohorts. The most effective model was then selected to build a nomogram.ResultsThe clinical-radiomics nomogram, which comprised Radscore and three clinical variables, showed the best diagnostic efficiency in the training cohort (AUC = 0.851), internal validation cohort (AUC = 0.819), and external validation cohort (AUC = 0.824). Calibration curves showed good discrimination ability of the nomogram using the validation cohorts. Decision curve analysis (DCA) showed that the nomogram had a high clinical utility.ConclusionThe findings showed that the clinical-radiomics nomogram based on radiomics features and clinical parameters is a promising tool for preoperative prediction of LN status in patients with GBC.

Objective To compare the long-term prognosis effects of non-esophagectomy and esophagectomy on patients with T1 stage esophageal cancer. Methods All esophageal cancer patients in the study were included from the National Surveillance Epidemiology and End Results (SEER) database between 2005-2015. These patients were classified into non-esophagectomy group and esophagectomy group according to therapy methods and were compared in terms of esophagus cancer specific survival (ECSS) and overall survival (OS) rates. Results A total of 591 patients with T1 stage esophageal cancer were enrolled in this study, including 212 non-esophagectomy patients and 111 esophagectomy patients in the T1a subgroup and 37 non-esophagectomy patients and 140 esophagectomy patients in the T1b subgroup. In all T1 stage esophageal cancer patients, there was no difference in the effect of non-esophagectomy and esophagectomy on postoperative OS, but postoperative ECSS in patients treated with non-esophagectomy was significantly better than those treated with esophagectomy. Cox proportional hazards regression model analysis showed that the risk factors affecting ECSS included race, primary site, tumor size, grade, and AJCC stage but factors affecting OS only include tumor size, grade, and AJCC stage in T1 stage patients. In the subgroup analysis, there was no difference in either ECSS or OS between the non-esophagectomy group and the esophagectomy group in T1a patients. However, in T1b patients, the OS after esophagectomy was considerably better than that of non-esophagectomy. Conclusions Non-esophagectomy, including a variety of non-invasive procedures, is a safe and available option for patients with T1a stage esophageal cancer. For some T1b esophageal cancer patients, esophagectomy cannot be replaced at present due to its diagnostic and therapeutic effect on lymph node metastasis.

Background Microvascular invasion (MVI) has been shown to be closely associated with postoperative recurrence and metastasis in patients with intrahepatic cholangiocarcinoma (ICC). We aimed to develop a radiomics prediction model based on contrast-enhanced CT (CECT) to distinguish MVI in patients with mass-forming ICC. Methods 157 patients were included and randomly divided into training (n=110) and test (n=47) datasets. Radiomic signatures were built based on the recursive feature elimination support vector machine (Rfe-SVM) algorithm. Significant clinical-radiologic factors were screened, and a clinical model was built by multivariate logistic regression. A nomogram was developed by integrating radiomics signature and the significant clinical risk factors. Results The portal phase image radiomics signature with 6 features was constructed and provided an area under the receiver operating characteristic curve (AUC) of 0.804 in the training and 0.769 in the test datasets. Three significant predictors, including satellite nodules (odds ratio [OR]=13.73), arterial hypo-enhancement (OR=4.31), and tumor contour (OR=4.99), were identified by multivariate analysis. The clinical model using these predictors exhibited an AUC of 0.822 in the training and 0.756 in the test datasets. The nomogram combining significant clinical factors and radiomics signature achieved satisfactory prediction efficacy, showing an AUC of 0.886 in the training and 0.80 in the test datasets. Conclusions Both CECT radiomics analysis and radiologic factors have the potential for MVI prediction in mass-forming ICC patients. The nomogram can further improve the prediction efficacy.

Cerebral ischemia-reperfusion (I-R) transiently increased autophagy by producing excessively reactive oxygen species (ROS); on the other hand, activated autophagy would remove ROS-damaged mitochondria and proteins, which led to cell survival. However, the regulation mechanism of autophagy activity during cerebral I-R is still unclear. In this study, we found that deficiency of the TRPM2 channel which is a ROS sensor significantly decreased I-R-induced neuronal damage. I-R transiently increased autophagy activity both in vitro and in vivo. More importantly, TRPM2 deficiency decreased I-R-induced neurological deficit score and infarct volume. Interestingly, our results indicated that TRPM2 deficiency could further activate AMPK rather than Beclin1 activity, suggesting that TRPM2 inhibits autophagy by regulating the AMPK/mTOR pathway in I-R. In conclusion, our study reveals that ROS-activated TRPM2 inhibits autophagy by downregulating the AMPK/mTOR pathway, which results in neuronal death induced by cerebral I-R, further supporting that TRPM2 might be a potential drug target for cerebral ischemic injury therapy.

ObjectiveWe investigated lenvatinib plus programmed cell death-1 (PD-1) inhibitors as a first-line treatment for initially unresectable biliary tract cancer (BTC).MethodsIn this Phase II study, adults with initially unresectable BTC received lenvatinib (body weight ≥60 kg, 12 mg; <60 kg, 8 mg) daily and PD-1 inhibitors (pembrolizumab/tislelizumab/sintilimab/camrelizumab 200 mg or toripalimab 240 mg) every 3 weeks. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included surgical conversion rate, disease control rate (DCR), event-free survival (EFS), overall survival (OS) and tumor biomarkers.ResultsAmong 38 enrolled patients, the ORR was 42.1% and the DCR was 76.3%. Thirteen (34.2%) patients achieved downstaging and underwent surgery, six of whom (46.2%) achieved a major pathologic response (n=2) or partial pathologic response (n=4) in the primary tumor. In total, 84.2% of patients experienced ≥1 treatment-related adverse event (TRAE), 34.2% experienced a Grade ≥3 TRAE and no treatment-related deaths occurred. After a median follow-up of 13.7 months the median EFS was 8.0 months (95% CI: 4.6–11.4) and the median OS was 17.7 months (95% CI: not estimable).ConclusionsLenvatinib plus PD-1 inhibitors showed promising anti-tumor efficacy in patients with initially unresectable BTC and was generally well tolerated.Clinical Trial Registrationwww.chictr.org.cn, ChiCTR2100044476.