Early enforcement of cell identity by a functional component of the terminally differentiated state.

How progenitor cells can attain a distinct differentiated cell identity is a challenging problem given the fluctuating signaling environment in which cells exist and that critical transcription factors are often not unique to a differentiation process. Here, we test the hypothesis that a unique differentiated cell identity can result from a core component of the differentiated state doubling up as a signaling protein that also drives differentiation. Using live single-cell imaging in the adipocyte differentiation system, we show that progenitor fat cells (preadipocytes) can only commit to terminally differentiate after up-regulating FABP4, a lipid buffer that is highly enriched in mature adipocytes. Upon induction of adipogenesis in mouse preadipocyte cells, we show that after a long delay, cells first abruptly start to engage a positive feedback between CEBPA and PPARG before then engaging, after a second delay, a positive feedback between FABP4 and PPARG. These sequential positive feedbacks both need to engage in order to drive PPARG levels past the threshold for irreversible differentiation. In the last step before commitment, PPARG transcriptionally increases FABP4 expression while fatty acid-loaded FABP4 increases PPARG activity. Together, our study suggests a control principle for robust cell identity whereby a core component of the differentiated state also promotes differentiation from its own progenitor state.

The circadian clock mediates daily bursts of cell differentiation by periodically restricting cell-differentiation commitment.

Most mammalian cells have an intrinsic circadian clock that coordinates metabolic activity with the daily rest and wake cycle. The circadian clock is known to regulate cell differentiation, but how continuous daily oscillations of the internal clock can control a much longer, multiday differentiation process is not known. Here, we simultaneously monitor circadian clock and adipocyte-differentiation progression live in single cells. Strikingly, we find a bursting behavior in the cell population whereby individual preadipocytes commit to differentiate primarily during a 12-h window each day, corresponding to the time of rest. Daily gating occurs because cells irreversibly commit to differentiate within only a few hours, which is much faster than the rest phase and the overall multiday differentiation process. The daily bursts in differentiation commitment result from a differentiation-stimulus driven variable and slow increase in expression of PPARG, the master regulator of adipogenesis, overlaid with circadian boosts in PPARG expression driven by fast, clock-driven PPARG regulators such as CEBPA. Our finding of daily bursts in cell differentiation only during the circadian cycle phase corresponding to evening in humans is broadly relevant, given that most differentiating somatic cells are regulated by the circadian clock. Having a restricted time each day when differentiation occurs may open therapeutic strategies to use timed treatment relative to the clock to promote tissue regeneration.

The novel TERF2::PDGFRB fusion gene enhances tumorigenesis via PDGFRB/STAT5 signalling pathways and sensitivity to TKI in ph-like ALL.

Patients with Philadelphia chromosome-like acute lymphoblastic leukaemia (Ph-like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in this subgroup. Our study has unveiled a newfound fusion gene, TERF2::PDGFRB, and we have found that patients carrying this fusion gene exhibit sensitivity to dasatinib. Ba/F3 cells harbouring the TERF2::PDGFRB fusion display IL-3-independent cell proliferation through activation of the p-PDGFRB and p-STAT5 signalling pathways. These cells exhibit reduced apoptosis and demonstrate sensitivity to imatinib in vitro. When transfused into mice, Ba/F3 cells with the TERF2::PDGFRB fusion gene induce tumorigenesis and a shortened lifespan in cell-derived graft models, but this outcome can be improved with imatinib treatment. In summary, we have identified the novel TERF2::PDGFRB fusion gene, which exhibits oncogenic potential both in vitro and in vivo, making it a potential therapeutic target for tyrosine kinase inhibitors (TKIs).

A Predictive Model to Identify the Effects of Transcutaneous Sacral Nerve Stimulation With Pelvic Floor Exercises in Fecal Incontinence After Surgery for Anorectal Malformation.

INTRODUCTION: Although the combination of transcutaneous sacral nerve stimulation (tSNS) and pelvic floor exercises (PFEs) has shown significant effectiveness in treating fecal incontinence (FI) after surgery for congenital anorectal malformation (CARM), not all patients achieve satisfactory continence. Therefore, identifying which individuals will benefit from this method is crucial. METHODS: A prospective cohort study enrolled 92 children with FI. All patients underwent tSNS with PFE treatment, and an improved outcome was defined as a Wexner score ≤4. A predictive model to identify the effects of tSNS with PFEs in FI was developed based on the analysis of magnetic resonance imaging and high-resolution anorectal manometry with area under the receiver-operating characteristic curve to evaluate the predictive value of external anal sphincter (EAS) thickness index and anal squeezing pressure (ASP). RESULTS: tSNS with PFEs improved outcomes in 72 patients and led to poor outcomes in 20 (4 had their rectums deviate from the puborectalis muscle center or puborectal muscle ruptures while 16 lacked EAS with a lower ASP). The areas under the receiver-operating characteristic curve for EAS thickness index and ASP in predicting the effects of tSNS with PFEs were 0.915 (95% confidence interval 0.846-0.983, P = 0.000) and 0.886 (95% confidence interval 0.819-0.952, P = 0.000), respectively. By applying cutoff values of 0.076 for EAS thickness index and 21.95 mm Hg for ASP, tSNS with PFEs was found to be ineffective. DISCUSSION: tSNS with PFEs is effective for most patients with FI after CARM surgery, except when the rectum deviates from the puborectal muscle center, puborectal muscle rupture occurs, or EAS is absent with a low ASP.

Outcomes of Salvage Surgery Versus Non-Salvage Surgery for Initially Unresectable Hepatocellular Carcinoma After Conversion Therapy with Transcatheter Arterial Chemoembolization Combined with Lenvatinib Plus Anti-PD-1 Antibody: A Multicenter Retrospective Study.

BACKGROUND: Combination treatment with transcatheter arterial chemoembolization (TACE), lenvatinib, and anti-programmed death-1 (anti-PD-1) antibodies (triple therapy) has a high rate of tumor response and converted resection for initially unresectable hepatocellular carcinoma (uHCC) patients. This study aimed to assess the outcomes of salvage surgery in uHCC patients after conversion therapy with triple therapy. METHODS: uHCC patients who met the criteria for hepatectomy after receiving triple therapy as first-line treatment were eligible for inclusion in this study. The overall survival (OS) and progression-free survival (PFS) rates in patients who received salvage surgery (SR group) and those who did not (non-SR group) were compared. RESULTS: Of the 144 patients assessed, 91 patients underwent salvage surgery and 53 did not. The OS rates in the SR group were significantly better than those in the non-SR group. The 1- and 2-year OS rates in the SR group were 92.0% and 79.9%, respectively, whereas those in the non-SR group were 85.5% and 39.6 %, respectively (p = 0.007); however, there was no significant difference in the PFS rates. Upon further stratification, OS and PFS were significantly better in the SR group than in the non-SR group in patients who were assessed as partial responses (PR), while there was no significant difference in patients who were assessed as complete response (CR). CONCLUSIONS: Salvage surgery is recommended and is associated with a favorable prognosis for uHCC patients who were assessed as PR after conversion therapy, however it may not be necessary for uHCC if CR was achieved.

Robotic versus Laparoscopic Total Mesorectal Excision Surgery in Rectal Cancer: Analysis of Medium-Term Oncological Outcomes.

Background. Robotic systems can overcome some limitations of laparoscopic total mesorectal excision (L-TME), thus improving the quality of the surgery. So far, many studies have reported the technical feasibility and short-term oncological results of robotic total mesorectal excision (R-TME) in treating rectal cancer (RC); however, only a few evaluated the survival and long-term oncological outcomes. The following study compared the medium-term oncological data, 3-year overall survival (OS), and disease-free survival (DFS) of L-TME and R-TME in patients with rectal cancer. Methods. In this retrospective study, records of patients (patients with stage I-III rectal cancer) who underwent surgery (127 cases of L-TME and 148 cases of R-TME) at the Gansu Provincial Hospital between June 2016 and March 2018 were included in the analysis. Kaplan-Meier analysis evaluated the 3-year OS and DFS for all patients treated with curative intent. Results. The conversion rate was significantly higher, and the postoperative hospital stay was significantly longer in the L-TME group than in the R-TME group (all P<.05). Major complications were significantly lower in the robotic group (P<.05). The 3-year DFS rate (for all stages) was 74.8% for L-TME and 85.8% for R-TME (P = .021). For disease stage III, the 3-year DFS and OS were significantly higher in the R-TME group (P<.05). Conclusion. R-TME can achieve better oncological outcomes and is more beneficial for RC patients compared with L-TME, especially for those with stage III rectal cancers. Nevertheless, further randomized controlled trials and a longer follow-up period are needed to confirm these findings.

Impact of Bile Duct Tumor Thrombus on the Long-Term Surgical Outcomes of Hepatocellular Carcinoma Patients: A Propensity Score Matching Analysis.

BACKGROUND: Hepatectomy with tumor thrombectomy is the preferred treatment option for hepatocellular carcinoma (HCC) patients with bile duct tumor thrombus (BDTT); however, the impact of BDTT on their prognosis is unclear. OBJECTIVE: We aimed to investigate the long-term surgical outcomes of HCC patients with BDTT. METHODS: The data of HCC patients with and without BDTT who underwent hepatectomy were retrospectively reviewed and the long-term outcomes were compared. For propensity score matching (PSM) analysis, patients were matched in a 1:1 ratio. Subgroup analysis was conducted according to the American Joint Committee on Cancer (AJCC) staging system. RESULTS: Before PSM, HCC patients with BDTT had more advanced tumor stages and adverse clinicopathological features. Recurrence-free survival (RFS) and overall survival (OS) were significantly higher in the non-BDTT group before PSM (RFS, p < 0.001; OS, p < 0.001), while after PSM, the BDTT group had significantly poorer RFS (p = 0.025). There was no difference in OS between the groups (p = 0.588). Subgroup analysis showed that RFS and OS in AJCC stage I-II patients were significantly poorer in the BDTT group; no differences were found in the AJCC stage III group before or after PSM. When the presence of BDTT was recommended to increase the AJCC staging system by one stage in AJCC stage I-II patients, the predictive ability for RFS and OS was higher. CONCLUSIONS: BDTT was associated with significantly poorer long-term surgical outcomes in AJCC stage I-II patients. A modified AJCC staging system including BDTT status in stage I-II might have a better prognostic ability.

Human poliovirus receptor contributes to biliary atresia pathogenesis by exacerbating natural-killer-cell-mediated bile duct injury.

BACKGROUND AND AIMS: Natural killer (NK) cells play an important role in biliary atresia (BA) pathogenesis; human poliovirus receptor (PVR) is an important NK-cell modulator. Here, we explored the role of PVR in BA pathogenesis. METHODS: Poliovirus receptor expression and NK cell-associated genes were detected in human BA samples and a rotavirus-induced BA mouse model using quantitative PCR and immunofluorescence staining. Chemically modified small interfering RNA silenced PVR expression in the BA model, and its effects on the population and function of intrahepatic NK cells were investigated using flow cytometry (FCM). The effects of PVR overexpression and knockdown on proliferation, apoptosis and NK-cell-mediated lysis of cultured human cholangiocytes were analysed using FCM and cell viability assays. Serum PVR, high-mobility group box 1 (HMGB1), and interleukin-1beta (IL-1beta) levels were measured in a cohort of 50 patients using ELISA. RESULTS: Poliovirus receptor expression was upregulated in the biliary epithelium of BA patients and BA model and was positively correlated with the population and activation of intrahepatic NK cells. Silencing of PVR expression impaired the cytotoxicity of NK cells, reduced inflammation and protected mice from rotavirus-induced BA. Activation of the TLR3-IRF3 signalling pathway induced PVR expression in cultured cholangiocytes. PVR overexpression promoted proliferation and inhibited the apoptosis of cholangiocytes but exacerbated NK cell-mediated cholangiocyte lysis. Serum PVR levels were elevated in BA patients and were positively correlated with HMGB1 and IL-1beta levels. CONCLUSIONS: Poliovirus receptor contributes to BA pathogenesis by regulating NK cell-mediated bile duct injury; PVR has the value as a biomarker of BA.

Analysis of the therapeutic effect of artificial leather embedding combined with fascial sleeve flap transplantation on chronic wounds of lower limbs with bone and plate exposure.

BACKGROUND: After severe trauma of lower limbs, bone, tendon or plate graft exposure is common. The traditional repair method is to use a variety of skin flap transplantation to cover the exposed part, but the wound often can not heal after operation, or the wound is cracked, ulcer, sinus, bone and steel plate are exposed again after wound healing. The reason for this result is that when the flap is covered, the space around the bone plate is not well closed, forming a dead cavity, blood and exudate accumulation, hematoma formation or infection, and finally the wound ruptures again. In addition, due to the swelling and contracture of the flap after operation, the suture tension between the flap and the receiving area becomes larger, the skin becomes thinner and broken, and then the wound is formed. In order to solve the above problems, we carried out the study of artificial true skin embedding combined with fascial sleeve flap transplantation in the treatment of chronic bone plate exposed wounds of lower limbs. METHODS: In this paper, 11 cases of chronic wounds with bone exposure and skin necrosis after steel plate implantation were selected. First stage is the wound bed preparation including primary wound expansion, removal of necrotic tissue and incision of sinus wall, removal of deep necrotic bone and fibrotic scarred skin on the outer wall of steel plate to normal tissue on the outer edge of the wound, removal of precipitated peptone and purulent fur in the hole, periphery and bone space of the steel plate, and removal of tendon tissue with basal necrosis and disintegration of the wound. After vacuum sealing drainage (VSD) 1-2 weeks, the peritraumatic basal granulation tissue grew well and there was no necrotic tissue in the wound. In the second stage, the exposed bone was covered with artificial dermis, the steel plate hole or the periphery and the basal space were filled, and the exposed steel plate was completely embedded, and then the fascia sleeve flap was transplanted to cover the wound. The sural neurovascular flap was performed in nine cases and the lateral superior malleolar artery perforator flap in two case. RESULTS: The flap survived well in all 11 cases. During the follow-up of 6 months to the removal of the plate, there was no case of rupture, exposure and sinus formation. CONCLUSIONS: Artificial dermal covering combined with fascial sleeve flap transplantation can effectively avoid wound dehiscence or sinus formation caused by foreign body retention, infection and flap contracture. It has good effect in repairing chronic wounds with bone plate exposure after severe trauma of lower limbs.

Postoperative adjuvant transarterial chemoembolization improves outcomes of hepatocellular carcinoma associated with bile duct tumor thrombus: a propensity score matching analysis.

BACKGROUND: Surgical resection is the primary treatment for hepatocellular carcinoma (HCC) with bile duct tumor thrombus (BDTT). This study was conducted to investigate the efficacy of postoperative adjuvant TACE (PA-TACE) in patients with HCC and BDTT. METHODS: Data from patients who underwent surgery for HCC with BDTT at two medical centers were retrospectively analyzed. The survival outcomes of patients who were treated by hepatic resection followed by PA-TACE were compared with those of patients who underwent surgery alone. Propensity score matching (PSM) analysis was performed with a 1:1 ratio. RESULTS: Of the 308 consecutively enrolled HCC patients with BDTT who underwent surgical resection, 134 underwent PA-TACE whereas 174 underwent surgery alone. From the initial cohort, PSM matched 106 pairs of patients. The OS and DFS rates were significantly better for the PA-TACE group than the surgery alone group (for OS: before PSM, P = 0.026; after PSM, P = 0.039; for DFS: before PSM, P = 0.010; after PSM, P = 0.013). CONCLUSION: PA-TACE was associated with better survival outcomes than surgery alone for patients with HCC and BDTT. Prospective clinical trials are warranted to validate the beneficial effect of PA-TACE on HCC patients associated with BDTT.

Recurrence hazard rate in patients with hepatocellular carcinoma and bile duct tumor thrombus: a multicenter observational study.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) bile duct tumor thrombus (BDTT) have a high rate of postoperative recurrence. We aimed to describe the patterns and kinetics of recurrence in BDTT patients and provide management options accordingly. METHODS: This retrospective study included 311 HCC patients with BDTT who underwent surgery from 2009 to 2017 at five centers in China. The hazard rate of recurrence was calculated using the hazard function. RESULTS: The hazard rate of intrahepatic recurrence was higher than that of extrahepatic recurrence (0.0588 vs. 0.0301), and both showed a decreasing trend, and the intrahepatic recurrence and extrahepatic recurrence risk decreased to a lower level after 40 and 20 months, respectively. Patients who underwent anatomic resection had a consistently lower hazard rate of recurrence than patients who underwent nonanatomic resection, whereas patients who received postoperative adjuvant transarterial chemoembolization (TACE) mainly had a lower hazard rate of recurrence in the first year than patients who did not. CONCLUSION: The follow-up of BDTT patients should be at least 40 months because of its high rate of recurrence, in parallel with the need for vigilance for extrahepatic recurrence within 20 months. Anatomic hepatectomy and adjuvant TACE are recommended to improve BDTT patient outcomes.

[Evidence mapping of clinical research on 20 Chinese patent medicines for hypertension].

In this study, evidence mapping was employed to sort out and summarise the evidence from clinical studies of Chinese patent medicines for hypertension and to understand the evidence distribution in related studies. Chinese patent medicines for hypertension were searched from Medicine Catalogue for National Basic Medical Insurance, Employment Injury Insurance, and Maternity Insu-rance(2021) and Chinese Pharmacopoeia(2020). Relevant articles(published from January 1, 2016 to February 14, 2022) were retrieved from Cochrane Library, PubMed, Web of Science, CNKI, Wanfang, VIP, and SinoMed. Then, the evidence distribution was analysed based on description, tables, and bubble charts. A total of 31 Chinese patent medicines were identified and 20 were finally included, involving 111 articles. The basic information of the 20 Chinese patent medicines, the number of related articles, the hypertension staging and traditional Chinese medicine(TCM) syndrome types of the subjects, sample size, interventions, and outcome indicators were compared. The results showed Chinese patent medicines with the function of pacifying liver and eliminating wind were frequently studied, and most of them were single-center, small-sample, short-period randomized controlled trials. They failed to highlight the key and advantages of TCM. A wide variety of outcome indicators were involved, and in addition to blood pressure, surrogate outcome indicators and composite outcome indicators were emphasized. However, health economic indicators, quality of life, and damage to target organs such as blood vessels and heart, were rarely used.

[New advances in the diagnosis and treatment of biliary atresia]. / 胆道闭锁的诊断及治疗新进展.

The diagnosis of biliary atresia (BA) is mainly based on clinical manifestations, screening, and related biochemistry tests. In recent years, the development of blood biomarkers and the improvement in ultrasound examination have made it possible for BA to be diagnosed at a younger age. In particular, matrix metalloproteinase-7 shows high sensitivity and specificity and has a higher diagnostic efficiency than existing biochemical parameters, thereby holding a promise for clinical application. Sound touch elastography can increase the diagnostic efficiency for BA in terms of diagnosis and prognostic evaluation. Surgery is still the only method for the treatment of BA at present, with the preferred surgical treatment regimen of Kasai portoenterostomy combined with pharmacotherapies for alleviating infection and inflammation, and the patients who fail Kasai portoenterostomy or have liver dysfunction may require liver transplantation to save their lives. Therefore, the current research on BA should focus on the biomarkers for early diagnosis, specifically targeted drugs, and drugs for preventing progressive liver fibrosis. This article reviews the current diagnosis and treatment methods for BA and discusses the potential research directions.

Long-Term Outcomes of Anatomic Versus Nonanatomic Resection in Hepatocellular Carcinoma Patients with Bile Duct Tumor Thrombus: A Propensity Score Matching Analysis.

BACKGROUND: Anatomic resection (AR) of the liver is generally recommended in hepatocellular carcinoma (HCC) patients. However, the benefits of AR and nonanatomic resection (NAR) in HCC patients with bile duct tumor thrombus (BDTT) are unknown. This study aimed to compare long-term outcomes of AR and NAR in HCC patients with BDTT after curative resection. PATIENTS AND METHODS: A total of 175 consecutive HCC patients with BDTT after curative resection between April 2009 and December 2017 were included. One-to-one propensity score matching (PSM) was performed to minimize the influence of potential confounders. Recurrence-free survival (RFS) and overall survival (OS) were compared between the cohorts. RESULTS: After PSM, 120 patients were analyzed. The AR group had better RFS than the NAR group (P = 0.010). Even though there was no statistically significant difference in OS (P = 0.140, power = 0.33), the 3- and 5-year OS rates in the AR group (52.4% and 44.2%, respectively) were obviously higher than those in the NAR group (35.4% and 30.4%, respectively). When patients were further stratified according to tumor size, better RFS and OS were observed in patients with small (≤ 5 cm) tumors after AR (P < 0.001 and P = 0.004, respectively). Multivariate analysis identified AR (P = 0.024) as an independent favorable prognostic factor for RFS in HCC patients with BDTT. CONCLUSIONS: AR is recommended for HCC patients with BDTT, especially in patients with small (≤ 5 cm) tumors.

A nomogram based on combining systemic and hepatic inflammation markers for predicting microscopic bile duct tumour thrombus in hepatocellular carcinoma.

BACKGROUND: Bile duct invasion is a relatively rare event and is not well characterised in hepatocellular carcinoma (HCC). It remains very difficult to diagnose HCC with bile duct tumour thrombus (BDTT) before surgery. Increasing evidence has revealed that inflammation plays a critical role in tumorigenesis. This study aimed to develop nomograms based on systemic and hepatic inflammation markers to predict microscopic BDTT (micro-BDTT) before surgery in HCC. METHODS: A total of 723 HCC patients who underwent hepatectomy as initial therapy between January 2012 and June 2020 were included in the study. Logistic regression analysis was used to identify independent risk factors for micro-BDTT. The nomograms were constructed using significant predictors, including α-fetoprotein (AFP), alkaline phosphatase (ALP), direct bilirubin (DB), prognostic nutritional index (PNI), and γ-glutamyl transferase (γ-GT)/alanine aminotransferase (ALT). The prediction accuracies of the nomograms were evaluated using the area under the receiver operating characteristic (ROC) curve. RESULTS: AFP, ALP, DB, PNI, and γ-GT/ALT were independent risk factors for predicting micro-BDTT (P = 0.036, P = 0.004, P = 0.013, P = 0.012, and P = 0.006, respectively), which were assembled into the nomograms. The area under the ROC curve of the nomograms combining PNI and γ-GT/ALT for predicting micro-BDTT was 0.804 (95% confidence interval [CI]: 0.730-0.878). The sensitivity and specificity values when used in predicting micro-BDTT before surgery were 0.739 (95% CI: 0.612-0.866) and 0.781 (95% CI: 0.750-0.813), respectively. CONCLUSIONS: The nomogram based on combining systemic and hepatic inflammation markers is suitable for predicting micro-BDTT before surgery in HCC patients, leading to a rational therapeutic choice for HCC.

[Syndromic Hirschsprung′s disease and its mode of inheritance].

Hirschsprung′s disease (HSCR) is one of the major causes of chronic incomplete intestinal obstruction in children. HSCR is considered a type of neurocristopathy caused by no colonization of ganglion cells on some parts of the bowel wall due to abnormal termination of the migration of vagal neural cells during embryonic development. This disease can be classified into different types according to the length of the affected intestinal canal. Most HSCR patients present with single deformity, but some HSCR patients are affected by other deformities, which constitutes syndromic HSCR, such as congenital central hypoventilation syndrome, Fryns syndrome, and cartilage-hair hypoplasia syndrome. Most syndromes have abnormal genetic material. An adequate knowledge of syndromic HSCR is of vital importance for accurate diagnosis and prognostic evaluation. This article reviews the clinical manifestations, genetic basis, and genetic modes of different types of syndromic HSCR.

Comprehensive evaluation of antibiotics pollution the Yangtze River basin, China: Emission, multimedia fate and risk assessment.

Antibiotics have attracted global attention because of their potential ecological and health risks. The emission, multimedia fate and risk of 18 selected antibiotics in the entire Yangtze River basin were evaluated by using a level Ⅳ fugacity model. High antibiotic emissions were found in the middle and lower reaches of the Yangtze River basin. The total antibiotic emissions in the Yangtze River basin exceeded 1600 tons per year between 2013 and 2021. The spatial distribution of antibiotics concentration was the upper Yangtze River > middle Yangtze River > lower Yangtze River, which is positively correlated with animal husbandry size in the basin. Temperature and precipitation increases may decrease the antibiotic concentrations in the environment. Transfer fluxes showed that source emission inputs, advection processes, and degradation fluxes contributed more to the total input and output. High ecological risks in the water environment were found in 2018, 2019, 2020, and 2021. The comprehensive health risk assessment through drinking water and fish consumption routes showed that a small part of the Yangtze River basin is at medium risk, and children have a relatively high degree of health risk. This study provides a scientific basis for the pollution control of antibiotics at the basin scale.

The TAE score predicts prognosis of unresectable HCC patients treated with TACE plus lenvatinib with PD-1 inhibitors.

BACKGROUND AND AIMS: Transcatheter arterial chemoembolization combined with lenvatinib and PD-1 inhibitors (triple therapy) exhibits promising efficacy for unresectable hepatocellular carcinoma (uHCC). We aimed to evaluate the prognosis of patients with uHCC who received triple therapy and develop a prognostic scoring model to identify patients who benefit the most from triple therapy. METHODS: A total of 246 patients with uHCC who received triple therapy at eight centers were included and assigned to the training and validation cohorts. Prognosis was evaluated by the Kaplan-Meier curves. The prognostic model was developed by utilizing predictors of overall survival (OS), which were identified through the Cox proportional hazards model. RESULTS: In the training cohort, the 3-year OS was 52.0%, with a corresponding progression-free survival (PFS) of 30.6%. The median PFS was 13.2 months [95% confidence interval, 9.7-16.7]. Three variables (total bilirubin ≥ 17 µmol/L, alpha-fetoprotein ≥ 400 ng/mL, and extrahepatic metastasis) were predictors of poor survival and were used for developing a prognostic model (TAE score). The 2-year OS rates in the favorable (0 points), intermediate (1 point), and dismal groups (2-3 points) were 96.9%, 61.4%, and 11.4%, respectively (p < 0.001). The PFS was also stratified according to the TAE score. These findings were confirmed in an external validation cohort. CONCLUSIONS: Triple therapy showed encouraging clinical outcomes, and the TAE score aids in identifying patients who would benefit the most from triple therapy.