Dosimetric risk factors for radiation esophagitis in patients with breast cancer following regional nodal radiation.

BACKGROUND: Radiation esophagitis (RE) is one of the most common clinical symptoms of regi-onal lymph node radiotherapy for breast cancer. However, there are fewer studies focusing on RE caused by hypofractionated radiotherapy (HFRT). AIM: To analyze the clinical and dosimetric factors that contribute to the development of RE in patients with breast cancer treated with HFRT of regional lymph nodes. METHODS: Between January and December 2022, we retrospectively analysed 64 patients with breast cancer who met our inclusion criteria underwent regional nodal intensity-modulated radiotherapy at a radiotherapy dose of 43.5 Gy/15F. RESULTS: Of the 64 patients in this study, 24 (37.5%) did not develop RE, 29 (45.3%) developed grade 1 RE (G1RE), 11 (17.2%) developed grade 2 RE (G2RE), and none developed grade 3 RE or higher. Our univariable logistic regression analysis found G2RE to be significantly correlated with the maximum dose, mean dose, relative volume 20-40, and absolute volume (AV) 20-40. Our stepwise linear regression analyses found AV30 and AV35 to be significantly associated with G2RE (P < 0.001). The optimal threshold for AV30 was 2.39 mL [area under the curve (AUC): 0.996; sensitivity: 90.9%; specificity: 91.1%]. The optimal threshold for AV35 was 0.71 mL (AUC: 0.932; sensitivity: 90.9%; specificity: 83.9%). CONCLUSION: AV30 and AV35 were significantly associated with G2RE. The thresholds for AV30 and AV35 should be limited to 2.39 mL and 0.71 mL, respectively.

A combined pre- and intra-operative nomogram in evaluation of degrees of liver cirrhosis predicts post-hepatectomy liver failure: a multicenter prospective study.

Background: Adequate evaluation of degrees of liver cirrhosis is essential in surgical treatment of hepatocellular carcinoma (HCC) patients. The impact of the degrees of cirrhosis on prediction of post-hepatectomy liver failure (PHLF) remains poorly defined. This study aimed to construct and validate a combined pre- and intra-operative nomogram based on the degrees of cirrhosis in predicting PHLF in HCC patients using prospective multi-center's data. Methods: Consecutive HCC patients who underwent hepatectomy between May 18, 2019 and Dec 19, 2020 were enrolled at five tertiary hospitals. Preoperative cirrhotic severity scoring (CSS) and intra-operative direct liver stiffness measurement (DSM) were performed to correlate with the Laennec histopathological grading system. The performances of the pre-operative nomogram and combined pre- and intra-operative nomogram in predicting PHLF were compared with conventional predictive models of PHLF. Results: For 327 patients in this study, histopathological studies showed the rates of HCC patients with no, mild, moderate, and severe cirrhosis were 41.9%, 29.1%, 22.9%, and 6.1%, respectively. Either CSS or DSM was closely correlated with histopathological stages of cirrhosis. Thirty-three (10.1%) patients developed PHLF. The 30- and 90-day mortality rates were 0.9%. Multivariate regression analysis showed four pre-operative variables [HBV-DNA level, ICG-R15, prothrombin time (PT), and CSS], and one intra-operative variable (DSM) to be independent risk factors of PHLF. The pre-operative nomogram was constructed based on these four pre-operative variables together with total bilirubin. The combined pre- and intra-operative nomogram was constructed by adding the intra-operative DSM. The pre-operative nomogram was better than the conventional models in predicting PHLF. The prediction was further improved with the combined pre- and intra-operative nomogram. Conclusions: The combined pre- and intra-operative nomogram further improved prediction of PHLF when compared with the pre-operative nomogram. Trial Registration: Clinicaltrials.gov Identifier: NCT04076631.

Trx4, a novel thioredoxin protein, is important for Toxoplasma gondii fitness.

BACKGROUND: To successfully replicate within the host cell, Toxoplasma gondii employs several mechanisms to overcome the host cell defenses and mitigate the harmful effects of the free radicals resulting from its own metabolic processes using effectors such as thioredoxin proteins. In this study, we characterize the location and functions of a newly identified thioredoxin in T. gondii, which was named Trx4. METHODS: We characterized the functional role of Trx4 in T. gondii Type I RH and Type II Pru strains by gene knockout and studied its subcellular localization by endogenous protein HA tagging using CRISPR-Cas9 gene editing. The enzyme-catalyzed proximity labeling technique, the TurboID system, was employed to identify the proteins in proximity to Trx4. RESULTS: Trx4 was identified as a dense granule protein of T. gondii predominantly expressed in the parasitophorous vacuole (PV) and was partially co-localized with GRA1 and GRA5. Functional analysis showed that deletion of trx4 markedly influenced the parasite lytic cycle, resulting in impaired host cell invasion capacity in both RH and Pru strains. Mutation of Trx domains in Trx4 in RH strain revealed that two Trx domains were important for the parasite invasion. By utilizing the TurboID system to biotinylate proteins in proximity to Trx4, we identified a substantial number of proteins, some of which are novel, and others are previously characterized, predominantly distributed in the dense granules. In addition, we uncovered three novel proteins co-localized with Trx4. Intriguingly, deletion of trx4 did not affect the localization of these three proteins. Finally, a virulence assay demonstrated that knockout of trx4 resulted in a significant attenuation of virulence and a significant reduction in brain cyst loads in mice. CONCLUSIONS: Trx4 plays an important role in T. gondii invasion and virulence in Type I RH strain and Type II Pru strain. Combining the TurboID system with CRISPR-Cas9 technique revealed many PV-localized proximity proteins associated with Trx4. These findings suggest a versatile role of Trx4 in mediating the processes that occur in this distinctive intracellular membrane-bound vacuolar compartment.

Immunization with Live-Attenuated RHΔhad2a Strain Confers Partial Protective Immunity against Acute and Chronic Infection of Toxoplasma gondii in Mice.

Toxoplasmosis caused by Toxoplasma gondii is an important zoonosis of human and animal health significance. Current chemical therapeutics have side effects, and no commercially available vaccine is licensed for the prevention of toxoplasmosis in humans and most animals. Developing a safe and effective vaccine with long-term protection against T. gondii infection is necessary to control toxoplasmosis. HAD2a is a key member of the haloacid dehalogenase (HAD) phosphatase family, which is essential for T. gondii daughter budding. However, the role of HAD2a in T. gondii virulence remains unknown. In this study, we successfully constructed the had2a gene knockout strain in the T. gondii-type I RH strain (RHΔhad2a) and determined its role in virulence and vaccination. These results demonstrate that HAD2a played an important role in parasite daughter budding and in vitro replication. Knockout of the had2a gene attenuated the virulence of the T. gondii-type I RH strain. Vaccination with RHΔhad2a tachyzoites induced a Th1-biased immune response, provided partial protection against acute T. gondii infection in mice by highly virulent tachyzoites of RH and PYS (ToxoDB#9, Chinese I) strains, and conferred strong protection against challenge infection by cysts and oocysts of the less virulent type II Pru strain. These results demonstrate that T. gondii had2a is important for its in vitro proliferation and virulence in mice and that RHΔhad2a may be used as a candidate strain to generate a multiple gene knockout live-attenuated strain or be collaboratively applied with other live-attenuated strains to confer more effective protection against T. gondii infection.

Electrocardiographic characteristics of bladder cancer patients receiving preoperative chemotherapy combined with immunotherapy.

OBJECTIVE: Patients treated with preoperative chemotherapy and immunotherapy for bladder cancer may be at increased risk of cardiotoxicity and electrophysiological abnormalities. This study aimed to analyze their electrocardiographic (ECG) alterations. METHODS: Patients with bladder cancer who were hospitalized and receiving tislelizumab plus nab-paclitaxel (TnP) were enrolled prospectively. ECG, cardiac biomarkers, and echocardiography were performed at baseline and the end of TnP. RESULTS: A total of 60 patients (76.7% males), including 30 muscle-invasive and 30 non-muscle-invasive bladder cancer, received three or four cycles of TnP, respectively. Hypertension was the commonest comorbidity (41.7%), and 25 patients (41.7%) were prescribed cardiovascular drugs. In comparison with baseline characteristics, cardiac troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were within normal ranges after TnP. However, echocardiographic parameter of left ventricular ejection fraction slightly decreased after TnP (62.81 ± 3.81% to 61.10 ± 4.37%, p = .011). The incidence of abnormal ECG increased from 65.0% at baseline to 76.7%, of which only a higher prevalence of fragmented QRS (fQRS) was observed (33.3% to 50.0%, p = .013; mainly in inferior leads). ECG parameters of QT dispersion (QTd) were prolonged significantly after the regimen (39.50 ± 11.37 to 44.20 ± 15.85 ms, p = .019). CONCLUSION: In bladder cancer patients receiving preoperative chemotherapy combined with immunotherapy, the main ECG abnormality was fQRS and QTd, with relatively normal cardiac biomarkers and echocardiographic parameters. Regular ECG screening should be carried out carefully to detect potential cardiotoxicity in the long-term follow-up.

A newly characterized dense granule protein (GRA76) is important for the growth and virulence of Toxoplasma gondii.

Pathogenicity of the zoonotic pathogen Toxoplasma gondii largely depends on the secretion of effector proteins into the extracellular milieu and host cell cytosol, including the dense granule proteins (GRAs). The protein-encoding gene TGME49_299780 was previously identified as a contributor to parasite fitness. However, its involvement in parasite growth, virulence and infectivity in vitro and in vivo remains unknown. Here, we comprehensively examined the role of this new protein, termed GRA76, in parasite pathogenicity. Subcellular localization revealed high expression of GRA76 in tachyzoites inside the parasitophorous vacuole (PV). However, its expression was significantly decreased in bradyzoites. A CRISPR-Cas9 approach was used to knock out the gra76 gene in the T. gondii type I RH strain and type II Pru strain. The in vitro plaque assays and intracellular replication showed the involvement of GRA76 in replication of RH and Pru strains. Deletion of the gra76 gene significantly decreased parasite virulence, and reduced the brain cyst burden in mice. Using RNA sequencing, we detected a significant increase in the expression of bradyzoite-associated genes such as BAG1 and LDH2 in the PruΔgra76 strain compared with the wild-type Pru strain. Using an in vitro bradyzoite differentiation assay, we showed that loss of GRA76 significantly increased the propensity for parasites to form bradyzoites. Immunization with PruΔgra76 conferred partial protection against acute and chronic infection in mice. These findings show the important role of GRA76 in the pathogenesis of T. gondii and highlight the potential of PruΔgra76 as a candidate for a live-attenuated vaccine.

Portal vein velocity predicts portal vein system thrombosis after splenectomy with esophagogastric devascularization.

BACKGROUND: Portal vein system thrombosis (PVST) is a potentially fatal complication after splenectomy with esophagogastric devascularization (SED) in cirrhotic patients with portal hypertension. However, the impact of portal vein velocity (PVV) on PVST after SED remains unclear. Therefore, this study aims to explore this issue. METHODS: Consecutive cirrhotic patients with portal hypertension who underwent SED at Tongji Hospital between January 2010 and June 2022 were enrolled. The patients were divided into two groups based on the presence or absence of PVST, which was assessed using ultrasound or computed tomography after the operation. PVV was measured by duplex Doppler ultrasound within one week before surgery. The independent risk factors for PVST were analyzed using univariate and multivariate logistic regression analysis. A nomogram based on these variables was developed and internally validated using 1000 bootstrap resamples. RESULTS: A total of 562 cirrhotic patients with portal hypertension who underwent SED were included, and PVST occurred in 185 patients (32.9%). Multivariate logistic regression analysis showed that PVV was the strongest independent risk factor for PVST. The incidence of PVST was significantly higher in patients with PVV ≤ 16.5 cm/s than in those with PVV > 16.5 cm/s (76.2% vs. 8.5%, p < 0.0001). The PVV-based nomogram was internally validated and showed good performance (optimism-corrected c-statistic = 0.907). Decision curve and clinical impact curve analyses indicated that the nomogram provided a high clinical benefit. CONCLUSION: A nomogram based on PVV provided an excellent preoperative prediction of PVST after splenectomy with esophagogastric devascularization.

Comparison of clinical outcomes following delivery of budesonide by both vibrating mesh nebulizer and jet nebulizer in premature infants with bronchopulmonary dysplasia.

Background: This study aimed to compare the efficacy of budesonide inhalation suspension administered via a vibrating mesh nebulizer vs. a jet nebulizer in the treatment of premature infants with bronchopulmonary dysplasia (BPD) undergoing high-frequency oscillatory ventilation (HFOV). Methods: Between July 2020 and July 2022, we retrospectively analyzed the medical records of 36 preterm infants diagnosed with BPD who underwent HFOV. Based on the nebulizer type used, infants were categorized into the vibrating mesh nebulizer group (VMN group) or the jet nebulizer group (JN group). Post-nebulization outcomes, such as the duration of mechanical ventilation, length of stay in the neonatal intensive care unit (NICU), ventilator-associated parameters, and arterial blood gas metrics, were compared between the two groups. Treatment-associated complications were also documented. Results: No significant differences were noted between the VMN and JN groups in terms of mechanical ventilation duration (p = 0.519), NICU length of stay (p = 0.112), ventilator-associated parameters, or complications (p = 0.700). However, after 2 weeks of treatment, the oxygenation index (p = 0.012) and arterial partial pressure of carbon dioxide (p = 0.006) were more favorable in the VMN group compared to the JN group. Conclusion: Among premature infants with BPD on HFOV, for administration of budesonide inhalation suspension resulted in an improved oxygenation index and reduced arterial partial pressure of carbon dioxide when compared to a jet nebulizer, indicating superior therapeutic efficacy.

The Toxoplasma protein phosphatase 6 catalytic subunit (TgPP6C) is essential for cell cycle progression and virulence.

Protein phosphatases are post-translational regulators of Toxoplasma gondii proliferation, tachyzoite-bradyzoite differentiation and pathogenesis. Here, we identify the putative protein phosphatase 6 (TgPP6) subunits of T. gondii and elucidate their role in the parasite lytic cycle. The putative catalytic subunit TgPP6C and regulatory subunit TgPP6R likely form a complex whereas the predicted structural subunit TgPP6S, with low homology to the human PP6 structural subunit, does not coassemble with TgPP6C and TgPP6R. Functional studies showed that TgPP6C and TgPP6R are essential for parasite growth and replication. The ablation of TgPP6C significantly reduced the synchronous division of the parasite's daughter cells during endodyogeny, resulting in disordered rosettes. Moreover, the six conserved motifs of TgPP6C were required for efficient endodyogeny. Phosphoproteomic analysis revealed that ablation of TgPP6C predominately altered the phosphorylation status of proteins involved in the regulation of the parasite cell cycle. Deletion of TgPP6C significantly attenuated the parasite virulence in mice. Immunization of mice with TgPP6C-deficient type I RH strain induced protective immunity against challenge with a lethal dose of RH or PYS tachyzoites and Pru cysts. Taken together, the results show that TgPP6C contributes to the cell division, replication and pathogenicity in T. gondii.

The role of m6A demethylase FTO in chemotherapy resistance mediating acute myeloid leukemia relapse.

Acute myeloid leukemia (AML) is the most common hematopoietic malignancies, and chemotherapy resistance is one of the main causes of relapse. Because of lower survival rate for patients with relapse, it is pivotal to identify etiological factors responsible for chemo-resistance. In this work, direct MeRIP-seq analysis of sequential samples at stage of complete remission (CR) and relapse identifies that dysregulated N6-methyladenosine (m6A) methylation is involved in this progression, and hypomethylated RNAs are related to cell differentiation. m6A demethylase FTO is overexpressed in relapse samples, which enhances the drug resistance of AML cells in vivo and in vitro. In addition, FTO knockdown cells exhibit stronger capacity of differentiation towards granules and myeloid lineages after cytosine arabinoside (Ara-C) treatment. Mechanistically, FOXO3 is identified as a downstream target of FTO, the hypomethylation of FOXO3 mRNA affects its RNA degradation and further reduces its own expression, which ultimately result in attenuated cell differentiation. Collectively, these results demonstrate that FTO-m6A-FOXO3 is the main regulatory axis to affect the chemotherapy resistance of AML cells and FTO is a potential therapeutic target of chemotherapy resistance in AML.

Correlation between immune-related adverse events and long-term outcomes in pembrolizumab-treated patients with unresectable hepatocellular carcinoma: A retrospective study.

BACKGROUND: Although immune checkpoint inhibitor (ICI) therapy has improved the prognosis of unresectable hepatocellular carcinoma (HCC), it has also resulted in unique immune-related adverse events (irAEs). The relationship between irAE and treatment outcomes in ICI-treated unresectable HCC patients remains unknown. AIM: To elucidate the correlation between immune-related toxic effects and prognosis in patients with unresectable HCC treated with pembrolizumab. METHODS: From March 2019 to February 2021, a total of 190 unresectable HCC (Barcelona Clinic Liver Cancer C) patients receiving pembrolizumab treatment were retrospectively reviewed. Overall survival (OS) was the primary endpoint, while objective response rate (ORR), disease control rate (DCR), and time to progression (TTP) were secondary evaluation indexes. We assessed demographics, irAEs, and outcomes by retrospective review. RESULTS: One hundred and forty-three males and 47 females were included in the study. The ORR and DCR were 12.1% (23/190) and 52.1% (99/190), respectively. The median OS was 376 d [95% confidence interval (CI): 340-411 d] and the median TTP was 98 d (95%CI: 75-124 d). The overall incidence of treatment-related adverse events was 72.6% (138/190) and 10.0% of them were severe irAEs (grade ≥ 3). Child-Pugh B class, portal vein tumor thrombus, extrahepatic metastasis, and hypothyroidism were the independent risk factors for survival. Patients with hypothyroidism showed a longer OS [517 d (95%CI: 423-562) vs 431 d (95%CI: 412-485), P = 0.011] and TTP [125 d (95%CI: 89-154) vs 87 d (95%CI: 61-98), P = 0.004] than those without irAEs. CONCLUSION: Pembrolizumab-treated patients with unresectable HCC who experienced hypothyroidism have promising ORR and durable response. Hypothyroidism, an irAE, may be used as a clinical evaluation parameter of response to ICIs in unresectable HCC.

A Prospective Study Using Propensity Score Matching to Compare Long-term Survival Outcomes After Robotic-assisted, Laparoscopic, or Open Liver Resection for Patients With BCLC Stage 0-A Hepatocellular Carcinoma.

OBJECTIVE: To compare the short- and long-term outcomes of robot-assisted (RALR), laparoscopic (LLR), or open liver resection (OLR) in the treatment of Barcelona Clinic Liver Cancer (BCLC) stage 0-A hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: Following the Balliol IDEAL classification, long-term oncological outcomes can be used to evaluate the value of minimally invasive techniques in the treatment of HCC, and to assess whether they should become a standard practice. METHODS: Data from prospective cohorts of patients with BCLC stage 0-A HCC who underwent curative liver resection using OLR, LLR, or RALR at Tongji Hospital were reviewed. The short-term and long-term oncological outcomes of these 3 different surgical approaches after adequate follow-up were compared using propensity score matching to reduce selection bias. RESULTS: Of 369 patients included in this study (71, RALR; 141, LLR; and 157, OLR), 56 patients in each of the 3 groups were chosen for further comparison, after propensity score matching. In the minimally invasive group (RALR+LLR), both the operative time and duration of Pringle's maneuver were significantly longer than those in the OLR group; however, the length of hospital stay was significantly shorter. There were no significant differences in the other intraoperative parameters and the incidence of postoperative complications among the 3 groups. HCC recurrence in the minimally invasive group when compared with the OLR group was characterized by a significantly higher proportion of single lesion or early-stage HCC. However, there were no significant differences in the 5-year disease-free survival (63.8%, 54.4%, and 50.6%) or overall survival rates (80.8%, 78.6%, and 75.7%, respectively) among the 3 groups. Clinically significant portal hypertension was the only risk factor that negatively affected the 5-year disease-free survival rate. Multivariate Cox regression analysis showed that clinically significant portal hypertension, serum alpha-fetoprotein level (≥400 ng/mL), and Edmondson-Steiner grading (III+IV) were independent risk factors for poor long-term survival. CONCLUSION: Both robotic and laparoscopic hepatectomies were safe and effective for patients with BCLC stage 0-A HCC when compared with open hepatectomy.

Occult pancreaticobiliary reflux is a pathogenic factor of some benign biliary diseases and gallbladder cancer.

BACKGROUND: Pancreaticobiliary maljunction (PBM) is a well-known high-risk factor for biliary malignant tumors because of constant pancreaticobiliary reflux (PBR). However, the impact of occult pancreaticobiliary reflux (OPR), which is characterized by high bile amylase levels in individuals with anatomically normal pancreaticobiliary junction, on biliary diseases remains unclear. The aim of this study was to assess the correlation between OPR and biliary diseases. METHODS: We enrolled 94 consecutive patients with normal pancreaticobiliary junction and primary biliary diseases confirmed by magnetic resonance cholangiopancreatography. We prospectively collected patients' bile samples and measured bile amylase levels. We investigated the incidence of OPR and the difference in bile amylase levels among these patients and assessed the correlation between high bile amylase levels (HBAL) and benign or malignant biliary diseases, as well as the OPR risk factors. RESULTS: The incidence of OPR was 36.6% in patients with benign biliary diseases, 26.7% in those with cholangiocarcinoma and 62.5% in those with gallbladder cancer. The median bile amylase level tended to be higher in patients with gallbladder cancer than in those with benign biliary diseases, but there was no significant difference (165.5 IU/L vs. 23.0 IU/L, P = 0.212). The prevalence of an HBAL with bile amylase levels of 1000-7500 IU/L was similar in patients with gallbladder cancer and benign biliary diseases. However, the incidence of HBAL with bile amylase levels greater than 7500 IU/L was significantly higher in patients with gallbladder cancer than in those with benign biliary diseases (37.5% vs. 4.2%, P = 0.012). Multivariate logistic regression analysis revealed that choledocholithiasis was an independent risk factor for OPR. CONCLUSIONS: OPR can occur in benign and malignant biliary diseases, and it may be a pathogenic factor for some benign biliary diseases and a high-risk factor for gallbladder cancer. There is a correlation between choledocholithiasis and OPR.

Functional Characterization of 15 Novel Dense Granule Proteins in Toxoplasma gondii Using the CRISPR-Cas9 System.

The analysis of the subcellular localization and function of dense granule proteins (GRAs) is of central importance for the understanding of host-parasite interaction and pathogenesis of Toxoplasma gondii infection. Here, we identified 15 novel GRAs and used C-terminal endogenous gene tagging to determine their localization at the intravacuolar network (IVN), parasitophorous vacuole (PV), or PV membrane (PVM) in the tachyzoites and at the periphery of the bradyzoites-containing cysts. The functions of the 15 gra genes were examined in type I RH strain and 5 of these gra genes were also evaluated in the cyst-forming type II Pru strain. The 15 novel gra genes were successfully disrupted by using CRISPR-Cas9 mediated homologous recombination and the results showed that 13 gra genes were not individually essential for T. gondii replication in vitro or virulence in mice during acute and chronic infection. Intriguingly, deletion of TGME49_266410 and TGME49_315910 in both RH and Pru strains decreased the parasite replication in vitro and attenuated its virulence, and also reduced the cyst-forming ability of the Pru strain in mice during chronic infection. Comparison of the transcriptomic profiles of the 15 gra genes suggests that they may play roles in other life cycle stages and genotypes of T. gondii. Taken together, our findings improve the understanding of T. gondii pathogenesis and demonstrate the involvement of two novel GRAs, TGME49_266410 and TGME49_315910, in the parasite replication and virulence. IMPORTANCE Dense granule proteins (GRAs) play important roles in Toxoplasma gondii pathogenicity. However, the functions of many putative GRAs have not been elucidated. Here, we found that 15 novel GRAs are secreted into intravacuolar network (IVN), parasitophorous vacuole (PV), or PV membrane (PVM) in tachyzoites and are located at the periphery of the bradyzoite-containing cysts. TGME49_266410 and TGME49_315910 were crucial to the growth of RH and Pru strains in vitro. Deletion of TGME49_266410 and TGME49_315910 attenuated the parasite virulence in mice. However, disruption of other 13 gra genes did not have a significant impact on the proliferation and pathogenicity of T. gondii in vitro or in vivo. The marked effects of the two novel GRAs (TGME49_266410 and TGME49_315910) on the in vitro growth and virulence of T. gondii are notable and warrant further elucidation of the temporal and spatial dynamics of translocation of these two novel GRAs and how do they interfere with host cell functions.

Prognostic value of T cell immunoglobulin and mucin-domain containing-3 expression in upper gastrointestinal tract tumors: A meta-analysis.

BACKGROUND: There is a lack of robust prognostic markers for upper gastrointestinal (GI) tract cancers, including esophageal, gastric, and esophagogastric junction cancers. T cell immunoglobulin and mucin-domain containing-3 (TIM3) plays a key immunomodulatory role and is linked to the prognosis of various cancers. However, the significance of TIM3 in upper GI tract tumors is still uncertain. AIM: To investigate the prognostic value of TIM3 expression in upper GI tract tumors. METHODS: A literature search was conducted on the PubMed, Embase, and Web of Science databases for relevant studies published until June 2023. After screening and quality assessment, studies that met the criteria were included in the meta-analysis. Statistical methods were used for the pooled analysis to assess the association of TIM3 expression in upper GI tract tumors with the prognosis and clinicopathological parameters. The results were reported with the hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Nine studies involving 2556 patients with upper GI tract cancer were included. High TIM3 expression was associated with a worse prognosis in upper GI tract cancer (HR: 1.17, 95%CI: 1.01-1.36). Positive expression of TIM3 in gastric cancer was correlated with the T and N stage, but the difference was not statistically significant. However, TIM3 overexpression was significantly correlated with the TNM stage (odds ratio: 1.21, 95%CI: 0.63-2.33; P < 0.05). TIM3 expression showed no association with the other clinicopathological parameters. CONCLUSION: High expression of TIM3 in the upper GI tract cancer is associated with a worse prognosis and advanced T or N stages, indicating its potential value as a prognostic biomarker. These findings may provide a basis for the personalized treatment of upper GI tract cancers.

Targeting glycolysis in non-small cell lung cancer: Promises and challenges.

Metabolic disturbance, particularly of glucose metabolism, is a hallmark of tumors such as non-small cell lung cancer (NSCLC). Cancer cells tend to reprogram a majority of glucose metabolism reactions into glycolysis, even in oxygen-rich environments. Although glycolysis is not an efficient means of ATP production compared to oxidative phosphorylation, the inhibition of tumor glycolysis directly impedes cell survival and growth. This review focuses on research advances in glycolysis in NSCLC and systematically provides an overview of the key enzymes, biomarkers, non-coding RNAs, and signaling pathways that modulate the glycolysis process and, consequently, tumor growth and metastasis in NSCLC. Current medications, therapeutic approaches, and natural products that affect glycolysis in NSCLC are also summarized. We found that the identification of appropriate targets and biomarkers in glycolysis, specifically for NSCLC treatment, is still a challenge at present. However, LDHB, PDK1, MCT2, GLUT1, and PFKM might be promising targets in the treatment of NSCLC or its specific subtypes, and DPPA4, NQO1, GAPDH/MT-CO1, PGC-1α, OTUB2, ISLR, Barx2, OTUB2, and RFP180 might be prognostic predictors of NSCLC. In addition, natural products may serve as promising therapeutic approaches targeting multiple steps in glycolysis metabolism, since natural products always present multi-target properties. The development of metabolic intervention that targets glycolysis, alone or in combination with current therapy, is a potential therapeutic approach in NSCLC treatment. The aim of this review is to describe research patterns and interests concerning the metabolic treatment of NSCLC.

Deep learning-based radiomics based on contrast-enhanced ultrasound predicts early recurrence and survival outcome in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. AIM: To predict early recurrence (ER) and overall survival (OS) in patients with HCC after radical resection using deep learning-based radiomics (DLR). METHODS: A total of 414 consecutive patients with HCC who underwent surgical resection with available preoperative grayscale and contrast-enhanced ultrasound images were enrolled. The clinical, DLR, and clinical + DLR models were then designed to predict ER and OS. RESULTS: The DLR model for predicting ER showed satisfactory clinical benefits [area under the curve (AUC)] = 0.819 and 0.568 in the training and testing cohorts, respectively), similar to the clinical model (AUC = 0.580 and 0.520 in the training and testing cohorts, respectively; P > 0.05). The C-index of the clinical + DLR model in the prediction of OS in the training and testing cohorts was 0.800 and 0.759, respectively. The clinical + DLR model and the DLR model outperformed the clinical model in the training and testing cohorts (P < 0.001 for all). We divided patients into four categories by dichotomizing predicted ER and OS. For patients in class 1 (high ER rate and low risk of OS), retreatment (microwave ablation) after recurrence was associated with improved survival (hazard ratio = 7.895, P = 0.005). CONCLUSION: Compared to the clinical model, the clinical + DLR model significantly improves the accuracy of predicting OS in HCC patients after radical resection.

Postoperative outcomes and recurrence patterns of intermediate-stage hepatocellular carcinoma dictated by the sum of tumor size and number.

BACKGROUND: The selection criteria for Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) patients who would truly benefit from liver resection (LR) remain undefined. AIM: To identify BCLC-B HCC patients more suitable for LR. METHODS: We included patients undergoing curative LR for BCLC stage A or B multi-nodular HCC (MNHCC) and stratified BCLC-B patients by the sum of tumor size and number (N + S). Overall survival (OS), recurrence-free survival (RFS), recur-rence-to-death survival (RTDS), recurrence patterns, and treatments after recurrence in BCLC-B patients in each subgroup were compared with those in BCLC-A patients. RESULTS: In total, 143 patients who underwent curative LR for MNHCC with BCLC-A (n = 25) or BCLC-B (n = 118) were retrospectively analyzed. According to the N + S, patients with BCLC-B HCC were divided into two subgroups: BCLC-B1 (N + S ≤ 10, n = 83) and BCLC-B2 (N + S > 10, n = 35). Compared with BCLC-B2 patients, those with BCLC-B1 had a better OS (5-year OS rate: 67.4% vs 33.6%; P < 0.001), which was comparable to that in BCLC-A patients (5-year OS rate: 67.4% vs 74.1%; P = 0.250), and a better RFS (median RFS: 19 mo vs 7 mo; P < 0.001), which was worse than that in BCLC-A patients (median RFS: 19 mo vs 48 mo; P = 0.022). Further analysis of patients who developed recurrence showed that both BCLC-B1 and BCLC-A patients had better RTDS (median RTDS: Not reached vs 49 mo; P = 0.599), while the RTDS in BCLC-B2 patients was worse (median RTDS: 16 mo vs not reached, P < 0.001; 16 mo vs 49 mo, P = 0.042). The recurrence patterns were similar between BCLC-B1 and BCLC-A patients, but BCLC-B2 patients had a shorter recurrence time and a higher proportion of patients had recurrence with macrovascular invasion and/or extrahepatic metastasis, both of which were independent risk factors for RTDS. CONCLUSION: BCLC-B HCC patients undergoing hepatectomy with N + S ≤ 10 had mild recurrence patterns and excellent OS similar to those in BCLC-A MNHCC patients, and LR should be considered in these patients.

Anatomical Resection Improved the Outcome of Intrahepatic Cholangiocarcinoma: A Propensity Score Matching Analysis of a Retrospective Cohort.

Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common liver malignancy after hepatocellular carcinoma (HCC), with a dismal prognosis and high heterogeneity. The oncological advantages of anatomical resection (AR) and nonanatomical resection (NAR) in HCC have been studied, but surgical strategies for ICC remain controversial with insufficient investigations. Materials and Methods: From Jan 2013 to Dec 2016, 3880 consecutive patients were retrospectively reviewed from a single center. Patients with ICC undergoing AR or NAR have been enrolled according to inclusion and exclusion criteria. Propensity score matching (PSM) analysis was performed between two groups with a 1 : 1 ratio. The primary endpoint was overall survival (OS), and the secondary endpoints included disease-free survival (DFS), intraoperative patterns, postoperative morbidity, mortality, complications and recurrence. A prognostic nomogram was developed by a multivariate Cox proportion hazard model. Results: After PSM, 99 paired cases were selected from 276 patients enrolled in this study. Patients in the AR group achieved better 1-, 3-, and 5-year OS (70%, 46%, and 34%, respectively) and DFS (61%, 21%, and 10%, respectively) than patients in the NAR group with statistical significance after PSM analysis. The postoperative complications and recurrence patterns were comparable between the two groups. Multivariate analysis identified NAR, tumor size >5 cm, multiple tumors, and poor differentiation as independent risk factors for OS (p < 0.05). Selected patients can benefit most from AR, according to subgroup analysis. A prognostic nomogram based on six independent risk factors for OS and factors with clinical significance was constructed to predict OS in ICC patients. Conclusion: AR improved the long-term survival of ICC with comparable postoperative complications and similar recurrence patterns. AR is suggested in ICC patients with sufficient remnant liver volume. In addition to surgery strategy, malignant characteristics of tumors are risk factors for ICC prognosis.

METTL3 regulates m6A methylation of PTCH1 and GLI2 in Sonic hedgehog signaling to promote tumor progression in SHH-medulloblastoma.

SHH subgroup medulloblastoma (SHH-MB) is one of the most common malignant pediatric tumors that arises in the cerebellum. Previously, we showed that RNA m6A methylation participates in regulation of cerebellar development. Here we investigate whether dysregulated m6A methylation contributes to tumorigenesis of SHH-MB. We show that high expression of m6A methyltransferase METTL3 associates with worse survival in the patients with SHH-MB. A large number of hypermethylated transcripts are identified in SHH-MB tumor cells by m6A-seq. We find that METTL3 promotes tumor progression via activating Sonic hedgehog signaling. Mechanistically, METTL3 methylates PTCH1 and GLI2 RNAs and further regulates their RNA stability and translation. Importantly, targeting METTL3 by depleting METTL3 expression or treatment with its catalytic inhibitor STM2457 restrains tumor progression. Collectively, this study shows a critical function for METTL3 and m6A methylation in SHH-MB, indicative of a potential role of METTL3 as therapeutic target in SHH-MB.