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Abstract This randomized, prospective, multicenter (12 centers in China) phase III trial (Chinese Clinical Trial Registry #ChiCTR2000041170) compared drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with apatinib and DEB-TACE monotherapy for patients with unresectable hepatocellular carcinoma (uHCC). Progression-free survival (PFS) was the primary endpoint. Overall survival (OS), mRECIST-based objective response rates (ORR) and disease control rates (DCR), and treatment-related adverse events (TRAEs) were secondary endpoints. Totally 243 cases were randomized, with 122 and 121 in the DEB-TACE + apatinib and DEB-TACE groups, respectively. Cases administered DEB-TACE + apatinib displayed markedly improved median PFS (7.1 months [95%CI 6.6–8.3] vs. 5.2 months [95%CI 5.0–5.9]) and OS (23.3 months [95%CI 20.7–29.6] vs. 18.9 months [95%CI 17.9–20.1] compared with those treated with DEB-TACE (both p

Abstract Background Refractoriness to surgical resection and chemotherapy makes intrahepatic cholangiocarcinoma (ICC) a fatal cancer of the digestive system with high mortality and poor prognosis. Important function invests circRNAs with tremendous potential in biomarkers and therapeutic targets. Nevertheless, it is still unknown how circRNAs contribute to the evolution of ICC. Methods CircRNAs in paired ICC and adjacent tissues were screened by circRNAs sequencing. To explore the impact of circRNAs on ICC development, experiments involving gain and loss of function were conducted. Various experimental techniques, including quantitative real-time PCR (qPCR), western blotting, RNA immunoprecipitation (RIP), luciferase reporter assays, RNA pull-down, chromatin immunoprecipitation (ChIP), ubiquitination assays and so on were employed to identify the molecular regulatory role of circRNAs. Results Herein, we reported a new circRNA, which originates from exon 9 to exon 15 of the SLCO1B3 gene (named circSLCO1B3), orchestrated ICC progression by promoting tumor proliferation, metastasis and immune evasion. We found that the circSLCO1B3 gene was highly overexpressed in ICC tissues and related to lymphatic metastasis, tumor sizes, and tumor differentiation. Mechanically, circSLCO1B3 not only promoted ICC proliferation and metastasis via miR-502-5p/HOXC8/SMAD3 axis, but also eradicated anti-tumor immunity via suppressing ubiquitin-proteasome-dependent degradation of PD-L1 by E3 ubiquitin ligase SPOP. We further found that methyltransferase like 3 (METTL3) mediated the m6A methylation of circSLCO1B3 and stabilizes its expression. Our findings indicate that circSLCO1B3 is a potential prognostic marker and therapeutic target in ICC patients. Conclusions Taken together, m6A-modified circSLCO1B3 was correlated with poor prognosis in ICC and promoted ICC progression not only by enhancing proliferation and metastasis via potentiating HOXC8 expression, but also by inducing immune evasion via antagonizing PD-L1 degradation. These results suggest that circSLCO1B3 is a potential prognostic marker and therapeutic target for ICC.

Abstract Objective To study the predictive factors of false negatives in the diagnosis of biliary stricture (BS) by percutaneous transluminal clamp biopsy (PTCB). Method From January 2016 to January 2021, 194 patients with a high suspicion of malignant tumors due to BS underwent PTCB during biliary drainage at our department. The final diagnosis was confirmed by postoperative pathology, other tissue or cell evidence, or medical imaging follow-up. Univariate and multivariate regression analyses were performed on the pathological results, summarizing the independent risk factors for false-negative value (FNV) to help further clinical diagnosis and treatment. Results Of the 194 cases, 176 and 18 cases were finally diagnosed as malignant and benign BS, respectively, compared to 144 and 50 cases by PTCB, including 32 false-negative cases. The sensitivity, specificity, false-positive value, and FNV of PTCB were 81.8%, 100%, 0%, and 18.2%, respectively. Multivariate analysis showed that non-cholangiocarcinoma BS was an independent risk factor for FNV of PTCB (odds ratio 7.5 (95% CI 1.74–32.6), p

ABSTRACT Budd-Chiari syndrome (B-CS) is a rare and lethal condition characterized by hepatic venous outflow tract blockage. Gut microbiota has been linked to numerous hepatic disorders, but its significance in B-CS pathogenesis is uncertain. First, we performed a case-control study (Ncase = 140, Ncontrol = 63) to compare the fecal microbiota of B-CS and healthy individuals by metagenomics sequencing. B-CS patients’ gut microbial composition and activity changed significantly, with a different metagenomic makeup, increased potentially pathogenic bacteria, including Prevotella, and disease-linked microbial function. Imbalanced cytokines in patients were demonstrated to be associated with gut dysbiosis, which led us to suspect that B-CS is associated with gut microbiota and immune dysregulation. Next, 16S ribosomal DNA sequencing on fecal microbiota transplantation (FMT) mice models examined the link between gut dysbiosis and B-CS. FMT models showed damaged liver tissues, posterior inferior vena cava, and increased Prevotella in the disturbed gut microbiota of FMT mice. Notably, B-CS-FMT impaired the morphological structure of colonic tissues and increased intestinal permeability. Furthermore, a significant increase of the same cytokines (IL-5, IL-6, IL-9, IL-10, IL-17A, IL-17F, and IL-13) and endotoxin levels in B-CS-FMT mice were observed. Our study suggested that gut microbial dysbiosis may cause B-CS through immunological dysregulation.IMPORTANCEThis study revealed that gut microbial dysbiosis may cause Budd-Chiari syndrome (B-CS). Gut dysbiosis enhanced intestinal permeability, and toxic metabolites and imbalanced cytokines activated the immune system. Consequently, the escalation of causative factors led to their concentration in the portal vein, thereby compromising both the liver parenchyma and outflow tract. Therefore, we proposed that gut microbial dysbiosis induced immune imbalance by chronic systemic inflammation, which contributed to the B-CS development. Furthermore, Prevotella may mediate inflammation development and immune imbalance, showing potential in B-CS pathogenesis.

Abstract Objectives To evaluate the safety and effectiveness of computed tomography (CT)-guided radioactive 125I seeds brachytherapy (RISB) for lung oligometastases (LO) from colorectal cancer (CRC). Methods Data for 144 LOs from 70 CRC patients who underwent CT-guided RISB were retrospectively analyzed. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoints were technical success, local control rate (LCR), and complications. Kaplan–Meier method was used for survival analysis. Cox model was used to identify the independent predictors of poor prognosis. Results The RISB procedures were successfully performed in all patients, and the success rate was 100%. The median follow-up was 27.8 months. The median PFS was 10.0 months (95% CI: 8.9–11.1) and the 1- and 2-year PFS rates were 32.9% and 5.9%, respectively. On multivariate analysis, serum carcinoembryonic antigen (CEA) ≤ 15 ng/ml (P = 0.048), middle-high differentiated pathological classification (P = 0.015), primary TNM stages I-III (P = 0.001), LO number ≤ 2 (P

Background: The most common loadable chemotherapeutic drugs in drug-eluting bead transarterial chemoembolization (DEB-TACE) include doxorubicin, epirubicin, etc. CalliSpheres ® beads have exhibited efficient loadability and eluting characteristics for raltitrexed as well as in vitro and animal experiments. However, the efficacy and safety of raltitrexed-loaded DEB-TACE in patients with intermediate-stage hepatocellular carcinoma (HCC) remain unclear. Objectives: To assess the efficacy and safety of raltitrexed-loaded DEB-TACE in patients with intermediate-stage HCC. Design: The study was conducted as a single-arm prospective study. Methods: This study was a prospective, single-arm trial conducted between June 2019 and June 2022. CalliSpheres ® beads loaded with raltitrexed were used in the DEB-TACE procedure. The follow-up lasted for at least 1 year or until death. The primary endpoint was overall survival (OS), and the secondary endpoints were time to progression (TTP), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs). Results: The 6-month ORR and disease control rates were 90.1% and 93.8%, respectively. The median OS was 33.0 months. The 1-, 2-, and 3-year survival rates were 95.1%, 82.1%, and 43.6%, respectively. Child–Pugh class and bilobar disease occurrence were identified as independent OS predictors. The median TTP and PFS were 22.7 and 19.8 months, respectively. Eleven (11.5%) patients experienced at least one grade 3 AE, and serious AEs were reported in five participants (5.2%). No patient experienced grade 4 or 5 AEs. Conclusion: Raltitrexed-loaded DEB-TACE is feasible, safe, and effective in patients with intermediate-stage HCC. Trial registration: This trial was registered at www.chictr.org.cn under the identifier: 1900024097 on 25 June 2019.

Abstract Purpose An assessment is being conducted to determine the safety and effectiveness of using Cone-beam computed tomography (CBCT)-guided transcatheter arterial chemoembolization (TACE) and microwave ablation (MWA) sequentially to treat small hepatocellular carcinomas (HCCs) located in the hepatic dome. Materials and methods Fifty-three patients with small HCCs in the hepatic dome who underwent TACE combined with simultaneous CBCT-guided MWA were studied. Inclusion criteria were a single HCCs ≤ 5.0 cm or a maximum of three. The safety and interventional-related complications were monitored, and local tumor progression (LTP), overall survival (OS), and prognostic factors for LTP/OS were evaluated. Results The procedures were successfully accomplished in all patients. According to Common Terminology Criteria for Adverse Events (CTCAE), adverse reactions and complications are mainly Grade 1 or 2 (mild symptoms, no or local/noninvasive intervention indicated). Liver and kidney function and alpha-fetoprotein (AFP) levels remained within a reasonable range after 4 weeks of treatment (both p

Abstract Background We aimed to evaluate the safety and efficacy of intraluminal iodine-125 seed strand brachytherapy and percutaneous nephrostomy in patients with ureteral carcinoma. Methods From January 2014 to January 2023, 48 patients with ureteral cancer not suitable for surgical resection were enrolled. Iodine-125 seed strand was inserted in 26 patients under c-arm CT and fluoroscopic guidance (Group A), and 22 patients underwent percutaneous nephrostomy without seed strand (Group B). The clinical outcomes (technical success rate, tumor sizes, hydronephrosis Girignon grade, complications, objective response rate (ORR), disease control rate (DCR), and survival time) were evaluated and compared. Results A total of 53 seed strands were successfully inserted and replaced in Group A, with a technical success rate of 100%. No procedure-related death or severe complications occurred in both group. Migration of seed strand or drainage tube was the most common complication. The Girignon grade of hydronephrosis was significantly improved 1, 3 and 6 months after procedure in both groups. DCR in Group A were 96.2%, 80.0%, and 70.0% at 1-, 3-, and 6-month follow up, respectively. At 1 and 6 months later, ORR in Group A were significantly higher than those in Group B (p

Abstract Background To evaluate the clinical efficacy of percutaneous biliary drainage (PBD) combined with 125I seed strand brachytherapy (ISSB) for the treatment of hilar cholangiocarcinoma (HCCA). Methods The clinical data of 64 patients with HCCA (median age 62.5, male 29, female 35) treated in our department from April 2017 to April 2021 were retrospectively analyzed. Thirty-four patients in the experimental group (EG) were treated with PBD combined with ISSB, while 30 patients in the control group (CG) were treated with PBD alone. The primary study endpoints were technical success, clinical success and the 2-month local tumor control (LTC) rate. Secondary endpoints were early/late complications, median progression-free survival (mPFS) and overall survival (mOS). Results The technical and clinical success in the EG and CG showed no significant differences (100 vs. 100%, 94.1 vs. 93.3%, P > 0.05). Both early and late complications showed no significant differences between the two groups (P > 0.05). The 2-month LTC rates were significantly better in the EG versus the CG (94.1% vs. 26.7%, 157.7 ± 115.3 vs. 478.1 ± 235.3 U/ml), respectively (P

AbstractObjective To compare the clinical efficacy of percutaneous vertebroplasty (PVP) alone and microwave ablation (MWA) combined with PVP for the treatment of painful spinal metastases from non-small cell lung cancer (NSCLC).Methods From October 2014 to October 2021, the data of 58 NSCLC patients with refractory painful spinal metastases (visual analog scale score ≥ 5) were retrospectively collected and analyzed. Patients in Group A (n = 30) and Group B (n = 28) received PVP alone and MWA combined with PVP, respectively. The primary endpoint was pain relief. The secondary endpoints were quality of life (QoL), local tumor progression (LTP), and complications.Results The technical success rate was 100% in both groups. Patients in both groups showed similar pain relief at 1–12 weeks, but patients in Group B still showed sustained pain relief at 24 weeks compared to those in Group A (p = 0.03). The assessment of QoL showed similar changes. LTP (33.00% vs. 7.14%, p = 0.02) and cement leakage rates (40.00% vs. 7.14%, p = 0.03) were lower in Group B. The multivariate analysis demonstrated spinal metastases with a maximum diameter ≤ 3.0 cm (p = 0.027) and MWA combined with PVP (p = 0.028) were two independent protective factors for LTP. For cement leakage, spinal metastases with vertebral body compression (p = 0.019) was an independent risk factor, while MWA combined with PVP (p = 0.042) was an independent protective factor.Conclusion MWA combined with PVP for painful spinal metastases from NSCLC performed more sustained pain relief (>6 months) and ultimately improved QoL with lower LTP and cement leakage rates, compared to PVP alone.

Residual tumor recurrence after surgical resection of hepatocellular carcinoma (HCC) remains a considerable challenge that imperils the prognosis of patients. Notably, intraoperative bleeding and postoperative infection are potential risk factors for tumor recurrence. However, the biomaterial strategy for the above problems has rarely been reported. Herein, a series of cryogels (coded as SQ-n) based on sodium alginate (SA) and quaternized chitosan (QC) were synthesized and selected for optimal ratios. The in vitro assays showed that SQ-50 possessed superior hemostasis, excellent antibacterial property, and great cytocompatibility. Subsequently, SQAP was constructed by loading black phosphorus nanosheets (BPNSs) and anlotinib hydrochloride (AL3818) based on SQ-50. Physicochemical experiments confirmed that near-infrared (NIR)-assisted SQAP could control the release of AL3818 in photothermal response, significantly inhibiting the proliferation and survival of HUVECs and H22 cells. Furthermore, in vivo studies indicated that the NIR-assisted SQAP prevented local recurrence of ectopic HCC after surgical resection, achieved through the synergistic effect of mPTT and molecular targeted therapy. Thus, the multifunctional SQAP provides a “one-stop” synergistic strategy for HCC postoperative recurrence, showing great potential for clinical application.

Purpose To analyze the clinical safety and efficacy of 3.0-T closed MR-guided microwave ablation (MWA) for the treatment of HCC located under the hepatic dome.Methods From May 2018 to October 2020, 49 patients with 74 HCCs located under the hepatic dome underwent MWA using 3.0-T closed MR guidance. The technical success rate, operative time, complete ablation (CA) rate, complications, local tumor progression (LTP), tumor-free survival (TFS) and overall survival (OS) were examined. Routine blood analysis, liver/kidney function and alpha fetoprotein (AFP) and protein induced by vitamin k absent or antagonist (PIVKA) levels were compared before and 2 months after MWA.Results All patients underwent MWA successfully, including 10 patients who underwent general anesthesia. The technical success rate was 100% without major complications. The CA rate was 95.9% (71/74) at the 2-month evaluation. The LTP rate was 2.7% during the median follow-up of 17.8 months (range: 4–43 months); the 6-, 12-, 18-month TFS rates were 97.8, 90.6, 68.1%, respectively, and the 6-, 12-, 18-month OS rates were 100, 97.6, 92.1%, respectively. There were no significant changes in routine blood tests and liver/kidney function (p > 0.05), while the AFP and PIVKA level decreased significantly at 2 months (p

Abstract Background Non-inflamed tumors, including immune-excluded and immune-desert tumors, are commonly resistant to anti-PD-1/PD-L1 (α-PD-1/PD-L1) therapy. Our previous study reported the potent antitumor activity of anti-TGF-β/PD-L1 bispecific antibody YM101 in immune-excluded tumors. However, YM101 had limited antitumor activity in immune-desert models. MSA-2 is a novel oral stimulator of interferon genes (STING) agonist, which activates the innate immune system and may synergize with YM101 in overcoming immunotherapy resistance. Methods The dose-dependent effect of MSA-2 on STING signaling was determined by interferon-β level. The maturation and function of dendritic cell (DC) were measured by flow cytometry, RNA-seq, one-way mixed lymphocyte reaction (MLR), OVA peptide pulse, and cytokine/chemokine detection. The synergistic effect between MSA-2 and YM101 was assessed by one-way MLR. The macrophage activation was measured by flow cytometry and cytokine/chemokine detection. The in vivo antitumor activity of MSA-2 combined with YM101 was explored in syngeneic murine tumor models. After treatments, the alterations in the tumor microenvironment (TME) were detected by flow cytometry, immunohistochemistry staining, immunofluorescence staining, RNA-seq, and single-cell RNA-seq (scRNA-seq). Results MSA-2 could promote the maturation and antigen presentation capability of murine DC. In the one-way MLR assay, MSA-2 synergized with YM101 in enhancing naive T cell activation. Moreover, MSA-2 stimulated the classical activation of macrophage, without significant influence on alternative activation. Further in vivo explorations showed that MSA-2 increased multiple proinflammatory cytokines and chemokines in the TME. MSA-2 combined with YM101 remarkedly retarded tumor growth in immune-excluded and immune-desert models, with superior antitumor activity to monotherapies. Flow cytometry, bulk RNA-seq, and scRNA-seq assays indicated that the combination therapy simultaneously boosted the innate and adaptive immunity, promoted antigen presentation, improved T cell migration and chemotaxis, and upregulated the numbers and activities of tumor-infiltrating lymphocytes. Conclusion Our results demonstrate that MSA-2 synergizes with YM101 in boosting antitumor immunity. This immune cocktail therapy effectively overcomes immunotherapy resistance in immune-excluded and immune-desert models.

Abstract Background Transcatheter arterial embolization (TAE) is one of the first-line treatments for advanced hepatocellular cancer. The pain caused by TAE is a stark complication, which remains to be prevented by biomedical engineering methods. Methods Herein, a commercial embolic agent CalliSpheres® bead (CB) was functionally modified with lidocaine (Lid) using an electrostatic self-assembly technique. The products were coded as CB/Lid-n (n = 0, 5, 10, corresponding to the relative content of Lid). The chemical compositions, morphology, drug-loading, and drug-releasing ability of CB/Lid-n were comprehensively investigated. The biocompatibility was determined by hemolysis assay, live/dead cell staining assay, CCK8 assay, immunofluorescence (IHC) staining assay and quantitative real-time PCR. The thermal withdrawal latency (TWL) and edema ratio (ER) were performed to evaluate the analgesia of CB/Lid-n using a plantar inflammation model. A series of histological staining, including immunohistochemistry (IL-6, IL-10, TGF-β and Navi1.7) and TUNEL were conducted to reveal the underlying mechanism of anti-tumor effect of CB/Lid-n on a VX2-tumor bearing model. Results Lid was successfully loaded onto the surface of CalliSpheres® bead, and the average diameter of CalliSpheres® bead increased along with the dosage of Lid. CB/Lid-n exhibited desirable drug-loading ratio, drug-embedding ratio, and sustained drug-release capability. CB/Lid-n had mild toxicity towards L929 cells, while triggered no obvious hemolysis. Furthermore, CB/Lid-n could improve the carrageenan-induced inflammation response micro-environment in vivo and in vitro. We found that CB/Lid-10 could selectively kill tumor by blocking blood supply, inhibiting cell proliferation, and promoting cell apoptosis. CB/Lid-10 could also release Lid to relieve post-operative pain, mainly by remodeling the harsh inflammation micro-environment (IME). Conclusions In summary, CB/Lid-10 has relatively good biocompatibility and bioactivity, and it can serve as a promising candidate for painless transcatheter arterial embolization.

Abstract To investigate the safety and effectiveness of trans-oral trans-sheath forceps biopsy (TTFB) for patients with severe esophageal obstruction under fluoroscopy. From November 2016 to November 2019, 35 patients with level III or IV dysphagia and a Karnofsky score of less than 60 were enrolled to undergo TTFB and esophageal nutrition tube insertion or stenting simultaneously. Data on diagnostic performance, early complications, and radiation dose were collected, and Karnofsky scores before and after the procedures were compared. The technical success of TTFB was 100%. The sensitivity, specificity and accuracy were 92.3% (24/26), 77.8% (7/9), and 88.6% (31/35), respectively. Complications occurred in two cases (5.7%). The mean procedure duration and irradiation dose were 23.2 min and 7.2 mSv, respectively. The Karnofsky scores significantly increased after 2–4 weeks (t = 11.22, P

Malignant central airway obstruction (MCAO) resulting from tumor metastasis and compression severely impairs respiration, posing life-threatening risks. To address this, we employed a synergistic modification strategy, combining cisplatin (CIS) and silver nanoparticles (AgNPs). Polycaprolactone (PCL) served as a drug carrier, enabling the preparation of a functional CIS@AgNPs@PCL fiber membrane-covered airway stent via electrospinning. This approach aimed to enhance the patency rate of MCAO. Characterization via ATR-FTIR, scanning electron microscope-energy-dispersive spectroscopy, and transmission electron microscope confirmed successful immobilization of CIS and AgNPs onto the stent surface. CIS@AgNPs@PCL substantially suppressed non-small cell lung cancer cells (A549), causing DNA damage, ultrastructural disruption, and over 50% apoptosis in 48 h. It also displayed potent antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans biofilms. A mouse subcutaneous tumor recurrence model assessed anti-cancer efficacy. CIS@AgNPs@PCL fiber-covered stents significantly inhibited lung cancer tissue and enhanced anti-cancer effects by up-regulating caspase-3 and Bax, while down-regulating Bcl-2. This study's functional airway stent provides a proof-of-concept for an integrated anti-cancer and antibacterial strategy. It promptly restores the lumen, inhibits biofilm formation, prevents tumor progression, and improves postoperative MCAO patency.

Abstract This study was performed to evaluate the outcome of endovascular intervention therapy for Budd-Chiari syndrome (BCS) and compare recanalization, transjugular intrahepatic portosystemic shunt (TIPS)/direct intrahepatic portosystemic shunt (DIPS), and combined procedure treatment. For the meta-analysis, 71 studies were identified by searching four databases. The individual studies’ samples were used to calculate a confidence interval (CI 95%), and data were pooled using a fixed-effect model and random effect model. The pooled measure and an equal-weighted average rate were calculated in all participant studies. Heterogeneity between the studies was assessed with I2, and T2 tests, and publication bias was estimated using Egger’s regression test. A total of 4,407 BCS patients had undergone an endovascular intervention procedure. The pooled results were 98.9% (95% CI 97.8‒98.9%) for a technical success operation, and 96.9% (95% CI 94.9‒98.9%) for a clinical success operation. The re-intervention rate after the initial intervention procedure was 18.9% (95% CI 14.7‒22.9%), and the survival rates at 1 and 5 years after the initial intervention procedure were 98.9% (95% CI 96.8‒98.9%) and 94.9% (95% CI 92.9‒96.9%), respectively. Patients receiving recanalization treatment (98%) had a better prognosis than those with a combined procedure (95.6%) and TIPS/DIPS treatment (94.5%). The systematic review and meta-analysis further solidify the role of endovascular intervention treatment in BCS as safe and effective. It maintains high technical and clinical success and long-term survival rates. The recanalization treatment had a better prognosis and outcome than the combined procedures and TIPS/DIPS treatment.

Abstract Characterized by the expression of the critical transcription factor forkhead box protein P3, regulatory T (Treg) cells are an essential part of the immune system, with a dual effect on the pathogenesis of autoimmune diseases and cancer. Targeting Tregs to reestablish the proinflammatory and immunogenic tumor microenvironment (TME) is an increasingly attractive strategy for cancer treatment and has been emphasized in recent years. However, attempts have been significantly hindered by the subsequent autoimmunity after Treg ablation owing to systemic loss of their suppressive capacity. Cellular metabolic reprogramming is acknowledged as a hallmark of cancer, and emerging evidence suggests that elucidating the underlying mechanisms of how intratumoral Tregs acquire metabolic fitness and superior immunosuppression in the TME may contribute to clinical benefits. In this review, we discuss the common and distinct metabolic profiles of Tregs in peripheral tissues and the TME, as well as the differences between Tregs and other conventional T cells in their metabolic preferences. By focusing on the critical roles of different metabolic programs, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, fatty acid synthesis, and amino acid metabolism, as well as their essential regulators in modulating Treg proliferation, migration, and function, we hope to provide new insights into Treg cell-targeted antitumor immunotherapies.

Abstract Objective To analyze the usefulness of temporary sheath-assisted tracheal intubation during tracheal stenting (TS) under fluoroscopy. Methods A total of 261 patients with airway stenosis due to malignant tumors underwent TS from May 2017 to January 2021, and 21 patients required tracheal intubation (TI) after air stenting because of viscous sputum blockage, endotracheal bleeding, and other conditions. The technique of temporary sheath-assisted TI was used. The vital signs (such as SpO2, blood pressure, heart rate, and respiratory), technical success, clinical success, and complications were analyzed. Results Temporary sheath-assisted TI was successful in all patients, and the mean procedure time was 0.7 min, with a technical success rate of 100%. Hypoxia resolved in all patients, and sputum blockage or endotracheal bleeding could be treated easily through the TI channel under fluoroscopy. All the vital signs significantly increased after TI (P

Abstract To investigate the feasibility and effectiveness of 3.0 T wide-bore magnetic resonance (MR)-guided microwave ablation (MA) of liver metastases (LM). From October 2018 to May 2020, 39 patients with 63 LM were treated with 3.0 T wide-bore MR-guided 2450-MHz MA therapy. The procedure parameters, technical success, complications, biochemical index changes, local tumor response, local tumor progression (LTP), 12-month disease-free survival (DFS) and 12-month overall survival (OS) were recorded and analyzed. The mean tumor maximum diameter and total procedure time were 3.0 cm and 55.2 min, respectively. Technical success was 100%, but 5 cases (12.8%) had grade-1 complications. Alanine transaminase, aspartate transaminase and total bilirubin showed a slight transient increase on day 3 (P 0.05). The complete ablation rates for ≤ 2.5 and > 2.5 cm lesions were 100% and 92.5%, respectively. During the median follow-up of 12.0 months, the LTP rate was 4.8% (3/63), and the 12-month DFS and OS rates were 61.3% and 92.2%, respectively. 3.0 T wide-bore MR-guided MA for LM is a safe and effective approach, especially for small LM.

Abstract Background Drug-eluting bead transarterial chemoembolization (DEB-TACE) with Callispheres® beads (CB) is currently used in the treatment of hepatocellular carcinoma. However, clinical data regarding DEB-TACE using raltitrexed-eluting CB for gastrointestinal adenocarcinoma liver metastases (GALM) treatment is limited. We aimed to report the preliminary outcomes of DEB-TACE using CB in unresectable GALM patients. Methods This retrospective study enrolled unresectable GALM patients who were treated with DEB-TACE using raltitrexed-eluting CB from October 2018 to October 2021. Totally, 25 patients, 18 males and 7 females, mean age 66.8±9.5 years, were continuously enrolled. Postoperative treatment response, survival rates, and complication were calculated during the procedure and follow-up. Results Twenty-four patients were technically successful, with a technical success rate of 96.0%. The 3-month overall response rate and disease control rate were 21.7% and 73.9%, and 6-month overall response rate and disease control rate were 30.0% and 65.0%. The median survival time from diagnosis of GALM was 31.3 months. The median survival time and median PFS from first DEB-TACE was 21.3 months (95% confidence interval 9.1–33.5) and 10.7 months (3.7–17.7), respectively. Main adverse events included abdominal pain (36.0%), fever (12.0%), and nausea/vomiting (28.0%) after DEB-TACE. No treatment-related deaths and grade 3 or grade 4 adverse events were observed. Conclusions DEB-TACE using raltitrexed eluting CB was demonstrated as a safe and efficient alternative choice for GALM.

Abstract Objective To evaluate the clinical results of the vacuum sealing drainage (VSD) combined with a naso-intestinal nutritional tube (NIT) and a gastric decompression tube (GDT) for the treatment of esophagogastrostomy neck fistula (ENF). Methods From January 2018 to October 2020, twenty patients (13 men and 7 women, ages 46–72) with ENF secondary to esophagogastrostomy were treated with VSD combined with NIT and GDT. Technical and clinical success rates, the incidence of early/late complications, the time of fistula closure (TFC) and therapy-related indicators were analyzed. The Karnofsky score and Eastern Cooperative Oncology Group (ECOG) score were compared before and after triple treatment. Results Technical and clinical success rates were 100% and 85%, respectively. Early complications occurred in 5/20 (25%) patients, and late complications occurred in 8/20 (40%) patients. The median TFC was 18 days (range 10–23). All therapy-related indicators were normalized posttreatment. The Karnofsky score and ECOG score after treatment were significantly different compared with pretreatment scores (p

Abstract Cancer is a top-ranked life-threatening disease with intratumor heterogeneity. Tumor heterogeneity is associated with metastasis, relapse, and therapy resistance. These factors contribute to treatment failure and an unfavorable prognosis. Personalized tumor models faithfully capturing the tumor heterogeneity of individual patients are urgently needed for precision medicine. Advances in stem cell culture have given rise to powerful organoid technology for the generation of in vitro three-dimensional tissues that have been shown to more accurately recapitulate the structures, specific functions, molecular characteristics, genomic alterations, expression profiles, and tumor microenvironment of primary tumors. Tumoroids in vitro serve as an important component of the pipeline for the discovery of potential therapeutic targets and the identification of novel compounds. In this review, we will summarize recent advances in tumoroid cultures as an excellent tool for accurate cancer modeling. Additionally, vascularization and immune microenvironment modeling based on organoid technology will also be described. Furthermore, we will summarize the great potential of tumor organoids in predicting the therapeutic response, investigating resistance-related mechanisms, optimizing treatment strategies, and exploring potential therapies. In addition, the bottlenecks and challenges of current tumoroids will also be discussed in this review.

Anti-inflammatory and antihyperplasia activities are essential requirements for the successful use of airway stents. In this work, silver nanoparticles (AgNPs) and cisplatin (DDP) were combined in a synergistic modification strategy to improve the surface function of airway stents. Using polycaprolactone (PCL) as a drug carrier, a dual-functional PCL-AgNPs-DDP fiber film-coated airway stent was fabricated by electrospinning. The physicochemical and biological properties of the obtained fiber films were examined. The ATR-FTIR, XPS, SEM-EDS and TEM results suggested that AgNPs and DDP could be successfully immobilized onto the airway stent surface. The drug release and surface degradation results revealed that AgNPs and DDP can undergo sustained release from films for 30 d, and the weight loss was approximately 50% after 35 d. In addition, the dual-functional fiber film suppressed human embryonic lung fibroblast growth and exhibited excellent antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa and Candida albicans. Furthermore, the effectiveness of the dual-functional fiber film-coated airway stent was evaluated by application to the trachea of New Zealand rabbits. The in vivo results indicated that PCL-AgNPs-DDP fiber film-coated airway stent can significantly inhibit granulation tissue formation and collagen deposition, reduced the expression of IL-8, TNF-α, IL-1α, PCNA, α-SMA and CD68, and ultimately achieved anti-inflammatory and antihyperplasia effects. Hence, this study provides a dual-functional surface-coated airway stent to address the clinical complications associated with respiratory tract inflammation and granulation tissue hyperplasia, thus inhibiting tracheal stenosis.

ObjectiveOur aim is to evaluate the safety and efficacy of iodine-125 seed strand for intraluminal brachytherapy on ureteral carcinoma.MethodsFrom November 2014 to November 2021, 22 patients with ureteral cancer not suitable for surgical resection were enrolled. Iodine-125 seed strand was inserted under c-arm CT and fluoroscopic guidance. The technical success rate, complications, disease control rate, and survival time were evaluated. Hydronephrosis Girignon grade and ureteral cancer sizes before and after treatment were compared.ResultsA total of 46 seed strands were successfully inserted and replaced, with a technical success rate of 100% and median procedure time of 62 min. No procedure-related death, ureteral perforation, infection, or severe bleeding occurred. Minor complications were observed in eight (36.4%) patients, and migration of seed strand was the most common complication. Six months after seed strand brachytherapy, one complete response, three partial responses, and five stable diseases were evaluated, and the disease control rate was 64.3%. The Girignon grade of hydronephrosis was significantly improved 1 to 3 months after seed strand insertion. Disease control rates were 94.4, 62.5, and 64.3% at 1-, 3-, and 6-month follow-up. Twenty patients were successfully followed up, with a mean follow-up of 18.0 ± 14.5 months. The median overall survival and progress-free survival were 24.7 and 13.0 months, respectively.ConclusionIodine-125 seed strand is safe and effective for intraluminal brachytherapy and can be used as an alternative to patients with ureteral carcinoma who are not suitable for surgical resection or systemic combined therapy.

PURPOSEWe aimed to evaluate the clinical benefit of 125I seed brachytherapy under DynaCT guidance for palliative local treatment of bone metastases.METHODSFrom December 2014 to September 2017, 82 patients with painful bone metastases, who experienced treatment failure using standard strategies or rejected treatment were enrolled in this retrospective study. All patients underwent 125I seed brachytherapy under DynaCT guidance. Technical success, visual analogue scale (VAS), numerical rating scale (NRS), verbal rating scale (VRS), Karnofsky performance status (KPS) and complications were analyzed.RESULTSThe success rate of 125I seed implantation was 100%. The VAS and NRS scores for the most severe pain were 7.0 (5.0–9.0) and 8.0 (6.0–9.0) before brachytherapy. The pain scores assessed every 2 hours gradually decreased within 12 hours (p < 0.001). A comparison of KPS scores showed that patients had significantly better quality of life on weeks 1, 4, and 8 than on week 0 (p < 0.001). The associated complications were mild subcutaneous hemorrhage 25.6% (21/82), fever 7.3% (6/82), minor displacement of radioactive seeds 5.0% (4/82), pathologic fracture 2.4% (2/82), and local skin reaction 2.4% (2/82). After symptomatic treatment, all complications were relieved. Minor displacement of radioactive seeds did not cause damage to adjacent tissues. No serious life-threatening complications occurred in the study group.CONCLUSIONDynaCT-guided 125I seed implantation is a safe and effective method for palliation of painful bone metastases from cancer after failure or rejection of conventional treatments.

Abstract Background A large number of patients with stage II/III colorectal cancer (CRC) have a high recurrence rate after radical resection. We aimed to develop a novel tool to stratify patients with different recurrence-risk for optimizing decision-making in post-operative surveillance and therapeutic regimens. Methods We retrospectively enrolled four independent cohorts from the Gene Expression Omnibus and 66 CRC tissues from our hospital. The initial signature discovery was conducted in GSE143985 (n = 91). This was followed by independent validation of this signature in GSE17536 (n = 111), GSE29621 (n = 40), and GSE92921 (n = 59). Further experimental validation using qRT-PCR assays (n = 66) was performed to ensure the robustness and clinical feasible of this signature. Results We developed a novel recurrence-related signature consisting of six genes. This signature was validated to be significantly associated with dismal recurrence-free survival in five cohorts GSE143985 (HR: 4.296 [2.612–7.065], P

ObjectiveWe reported the long-term outcomes of transcatheter chemoembolization (TACE) for patients with late-stage or recurrent oral carcinoma.MethodsThis retrospective study enrolled 18 patients with late-stage or recurrent oral carcinoma between December 2015 and April 2021. The tumor-feeding artery was catheterized, and cisplatin/oxaliplatin and 5-FU/raltitrexed were infused with embolization using polyvinyl alcohol or gelatin sponge. Computed tomography was performed at about 1, 3, and 6 months after the procedure, and every 6 months after that. During the procedure and follow-up, procedure outcomes, complications, treatment efficacy, and overall survival were analyzed.ResultsA total of 31 sessions of TACE were performed, with a technical success rate of 100%. Of 12 patients combined with oral hemorrhage, two patients showed rebleeding 35 and 37 days later, with a clinical efficiency of hemostasis of 88.9%. Mild complications were observed in 11 patients (61.1%). Severe complications or procedure-related deaths were not observed during or after the procedure. The objective response rate and disease control rate were 20.0% and 86.7%, 38.5% and 61.5%, and 25.0% and 50.0% at 1, 3, and 6 months later, respectively. Seventeen patients (94.4%) were followed up, with a median duration of 37.8 months (IQR 22.3–56.8). Nine patients died of tumor progression, one died of massive rebleeding, and one died of severe lung infection. The median overall survival was 23.8 months.ConclusionTACE is a safe and effective procedure with minimal invasiveness for treating late-stage or recurrent oral carcinoma. TACE can be recommended as a palliative treatment, particularly for patients with oral hemorrhage.

BackgroundMost patients with advanced pancreatic cancer do not have the chance to undergo surgery or chemotherapy because of their poor conditions. Biliary drainage is a palliative treatment to restore liver function and alleviate jaundice, but most patients still face the risk of biliary obstruction in the short term after operation. The purpose of this study is to evaluate the efficacy and safety of brachytherapy drainage catheter (BDC)-combined chemotherapy in the treatment of pancreatic cancer complicated with obstructive jaundice.Patients and MethodsFrom November 2017 and May 2019, 48 patients underwent the BDC or conventional drainage catheter (CDC) intervention with chemotherapy. The outcomes/endpoints analyzed were technical and clinical success, early complications, stent patency period, and survival.ResultsThe technical and clinical success rates in both groups were 100%, and the early complication rates were not significantly different (P = 0.43). The median stent patency in the BDC group was significantly longer than that in the CDC group (7.8 ± 1.5 vs. 5.7 ± 0.7 months, P = 0.001), and the median overall survival period in the BDC group was prone to significant difference than that in the CDC group (9.4 ± 4.0 vs. 8.2 ± 0.3 months, P = 0.089).ConclusionThe findings of this study show that BDC with chemotherapy was associated with better stent patency and survival. However, since the sample size was very small, large randomized controlled multicenter studies are needed to further evaluate the long-term survival effects of BDC in patients with advanced pancreatic carcinoma combined with obstructive jaundice.

Abstract Background Percutaneous magnetic resonance-guided (MR-guided) MWA procedures have traditionally been performed under local anesthesia (LA) and sedation. However, pain control is often difficult to manage, especially in some cases when the tumor is large or in a specific location, such as near the abdominal wall or close to the hepatic dome. This study retrospectively compared the results of general anesthesia (GA) and local anesthesia (LA) for MR-guided microwave ablation (MWA) in patients with hepatocellular carcinoma (HCC ≤ 5.0 cm) to investigate whether different anesthesia methods lead to different clinical outcomes. Methods The results of the analysis include procedure-related complications, imaging response, and the time to complete two sets of procedures. According to the type of anesthesia, the Kaplan-Meier method was used to compare the local tumor progression (LTP) of the two groups who underwent MR-guided MWA. Results All patients achieved technical success. The mean ablation duration of each patient in the GA group and LA group was remarkably different (P = 0.012). Both groups had no difference in complications or LTP (both P > 0.05). Notably, the tumor location (challenging locations) and the number of lesions (2–3 lesions) could be the main factors affecting LTP (p = 0.000, p = 0.015). Univariate Cox proportional hazard regression indicated that using different anesthesia methods (GA and LA) was not associated with longer LTP (P = 0.237), while tumor location (challenging locations) and the number of lesions (2–3 lesions) were both related to shorter LTP (P = 0.000, P = 0.020, respectively). Additionally, multivariate Cox regression further revealed that the tumor location (regular locations) and the number of lesions (single) could independently predict better LTP (P = 0.000, P = 0.005, respectively). Conclusions No correlation was observed between GA and LA for LTP after MR-guided MWA. However, tumors in challenging locations and the number of lesions (2–3 lesions) appear to be the main factors affecting LTP.

Abstract Background Given their widespread availability and relatively low cost, percutaneous thermal ablation is commonly performed under the guidance of computed tomography (CT) or ultrasound (US). However, such imaging modalities may be restricted due to insufficient image contrast and limited tumor visibility, which results in imperfect intraoperative treatment or an increased risk of damage to critical anatomical structures. Currently, magnetic resonance (MR) guidance has been proven to be a possible solution to overcome the above shortcomings, as it provides more reliable visualization of the target tumor and allows for multiplanar capabilities, making it the modality of choice. Unfortunately, MR-guided ablation is limited to specialized centers, and the cost is relatively high. Is ablation therapy under MR guidance better than that under CT guidance? This study retrospectively compared the efficacy of CT-guided and MR-guided microwave ablation (MWA) for the treatment of hepatocellular carcinoma (HCC ≤ 5.0 cm). Methods In this retrospective study, 47 patients and 54 patients received MWA under the guidance of CT and MR, respectively. The inclusion criteria were a single HCC ≤ 5.0 cm or a maximum of three. The local tumor progression (LTP), overall survival (OS), prognostic factors for local progression, and safety of this technique were assessed. Results All procedures were technically successful. The complication rates of the two groups were remarkably different with respect to incidences of liver abscess and pleural effusion (P

PURPOSEWe aimed to assess the effectiveness of percutaneous radiofrequency ablation (PRFA) combined with iodine-125 (125I) seed strand brachytherapy (125I-BT) for treatment of occluded biliary stents.METHODSFrom November 2015 to September 2017, 13 consecutive patients with occluded biliary metal stents, implanted for malignant obstruction, underwent PRFA combined with 125I-BT to reopen the bile duct. Data included clinical and technical success, stent patency, complications, and overall survival.RESULTSThe clinical and technical success rates were both 100%. One month after treatment, the total serum bilirubin level had decreased significantly (P < 0.001). Early complications of cholangitis or hemobilia were experienced by one patient each. Three patients (23.1%) had late complications, including two cases of cholangitis and one case of cholecystitis. During the mean follow-up of 233±82.9 days (range, 88–365 days), the stent patency time was 239±26.5 days (95% CI, 187–291 days), and the 6-month stent patency rate was 68.4%. Five patents died; the mean survival time was 298±30.1 days (95% CI, 239–358 days). The 6-month survival rate was 83%.CONCLUSIONPRFA therapy combined with 125I-BT is feasible and safe for patients with occluded metal stents placed for malignant biliary obstruction. Nevertheless, randomized controlled trails are needed to confirm the effectiveness of this new approach.

Abstract Background The tumor immunological microenvironment (TIME) has a prominent impact on prognosis and immunotherapy. However, the heterogeneous TIME and the mechanisms by which TIME affects immunotherapy have not been elucidated in hepatocellular carcinoma (HCC). Methods A total of 2195 eligible HCC patients from TCGA and GEO database were collected. We comprehensively explored the different heterogeneous TIME phenotypes and its clinical significance. The potential immune escape mechanisms and what genomic alterations may drive the formation of different phenotypes were further investigated. Results We identified three phenotypes in HCC: TIME-1, the “immune-deficiency” phenotype, with immune cell depletion and proliferation; TIME-2, the “immune-suppressed” phenotype, with enrichment of immunosuppressive cells; TIME-3, the “immune-activated phenotype”, with abundant leukocytes infiltration and immune activation. The prognosis and sensitivity to both sorafenib and immunotherapy differed among the three phenotypes. We also underlined the potential immune escape mechanisms: lack of leukocytes and defective tumor antigen presentation capacity in TIME-1, increased immunosuppressive cells in TIME-2, and rich in immunoinhibitory molecules in TIME-3. The different phenotypes also demonstrated specific genomic events: TIME-1 characterized by TP53, CDKN2A, CTNNB1, AXIN1 and FOXD4 alterations; TIME-2 characterized by significant alteration patterns in the PI3K pathway; TIME-3 characterized by ARID1A mutation. Besides, the TIME index (TI) was proposed to quantify TIME infiltration pattern, and it was a superior prognostic and immunotherapy predictor. A pipeline was developed to classify single patient into one of these three subtypes and calculated the TI. Conclusions We identified three TIME phenotypes with different clinical outcomes, immune escape mechanisms and genomic alterations in HCC, which could present strategies for improving the efficacy of immunotherapy. TI as a novel prognostic and immunotherapeutic signature that could guide personalized immunotherapy and clinical management of HCC.

Objective To evaluate the feasibility and safety of using cone-beam CT (CBCT) to measure changes in parenchymal blood volume (PBV) of patients with hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE) and to guide microwave ablation (MWA) for residual tumors. Methods A retrospective study was performed on 42 patients with HCC who completed TACE and received CBCT-guided perfusion imaging. The residual active lesions after TACE were supplemented with MWA to complete the treatment process according to the residual PBV. The outcomes were analyzed, including PBV changes, interventional-related complications, local tumor progression (LTP) and overall survival (OS). Results Technical success was achieved in all lesions. Correlation analysis revealed that greater volume of residual PBV after MWA is negatively correlated with LTP. (p = .000); and the decrease of PBV was positively correlated with LTP (p = .000). All adverse events and complications were CTCAE Grade 1/2. After combination treatment, the 1-, 3-, and 5-year LTP-free survival were 97.6%, 69.0% and 15.1%, respectively, with a median LTP of 49.0 months (95% CI:43.129,54.871). Multivariate Cox regression revealed that the residual PBV > 13 ml/1000 was an independent factor predicting a shorter OS and LTP (Both p

Abstract Purpose To evaluate the method and effectiveness of transcatheter arterial chemoembolization (TACE) combined with simultaneous DynaCT-guided Microwave ablation (MWA) for the treatment of small hepatocellular carcinoma (SHCC). Materials and methods From June 2015 to May 2017, a total of 28 consecutive patients with SHCC received single treatment of TACE and 23 subjects received a combination treatment of TACE with simultaneous DynaCT-guided MWA. Following 1 month of treatment, the tumor response was assessed using the mRECIST criteria and the outcomes were analyzed including intervention-associated complications, changes in liver function, imaging response, and progression-free survival (PFS). Results The technical success rate was 100%. The rates of CR (65%) in the combined TACE and MWA group were higher than those of the TACE group (46%). The rate of common adverse events, such as liver abscess, spontaneous bacterial peritonitis and liver dysfunction, in the combined TACE and MWA group (56%) was comparable to the corresponding rate of the TACE group (P > 0.411). The median and mean PFS of the TACE group were significantly lower than those of the combined TACE and MWA group (19.00 months vs. 29.00 months, 21.076 months vs. 24.693 months, p = 0.019, log-rank test). Conclusion Stereotactic DynaCT-guided MWA is a safe and effective method for the treatment of SHCC, which usually provides an effective tumor puncture path, notably for lesions that cannot be detected following TACE. Overall, the data suggested that this treatment method could improve the clinical outcome of patients with SHCC.

The immune checkpoint pathway consisting of the cell membrane-bound molecule programmed death protein 1 (PD-1) and its ligand PD-L1 has been found to mediate negative regulatory signals that effectively inhibit T-cell proliferation and function and impair antitumor immune responses. Considerable evidence suggests that the PD-1/PD-L1 pathway is responsible for tumor immune tolerance and immune escape. Blockage of this pathway has been found to reverse T lymphocyte depletion and restore antitumor immunity. Antagonists targeting this pathway have shown significant clinical activity in specific cancer types. Although originally identified as membrane-type molecules, several other forms of PD-1/PD-L1 have been detected in the blood of cancer patients, including soluble PD-1/PD-L1 (sPD-1/sPD-L1) and exosomal PD-L1 (exoPD-L1), increasing the composition and functional complications of the PD-1/PD-L1 signaling pathway. For example, sPD-1 has been shown to block the PD-1/PD-L immunosuppressive pathway by binding to PD-L1 and PD-L2, whereas the role of sPD-L1 and its mechanism of action in cancer remain unclear. In addition, many studies have investigated the roles of exoPD-L1 in immunosuppression, as a biomarker for tumor progression and as a predictive biomarker for response to immunotherapy. This review describes the molecular mechanisms underlying the generation of sPD-1/sPD-L1 and exoPD-L1, along with their biological activities and methods of detection. In addition, this review discusses the clinical importance of sPD-1/sPD-L1 and exoPD-L1 in cancer, including their predictive and prognostic roles and the effects of treatments that target these molecules.

Objectives. Although raltitrexed shows therapeutic effects in many types of malignant tumors, the therapeutic effects and safety of drug-eluting bead transarterial chemoembolization (DEB-TACE) loaded with raltitrexed for the treatment of hepatocellular carcinoma (HCC) are rare. This study aimed to investigate the safety and efficacy of DEB-TACE with raltitrexed-loaded CalliSpheres beads (CB) in patients with unresectable or recurrent HCC. Methods. Between May 2018 and October 2021, 41 patients with unresectable or recurrent HCC treated by DEB-TACE loaded with raltitrexed were retrospectively enrolled. The primary end points were overall survival and progression-free survival. The response evaluation criteria in solid tumors (RECIST) criteria and modified RECIST criteria (mRECIST) were used to assess the tumor response after the DEB-TACE procedure. Results. A total of 79 DEB-TACE procedures were successfully performed, and the technical success rate was 100%. The overall response rate and disease control rate assessed by mRECIST criteria were 76.9% and 88.5%, 62.5% and 70.8%, and 35.3% and 47.1%, respectively, at 1, 3, and 6 months postprocedure. The mean progression-free survival and overall survival were 21.6 ± 3.6 and 43.7 ± 5.8 months, respectively. The 6-, 24-, and 36-month overall survival rates were 86.8%, 62.7%, and 57.1%, respectively. Minor complications were observed in 21 patients (51.2%), with no treatment-related mortality or severe adverse events. The most common treatment-related complications were abdominal pain (48.8%) and nausea (29.3%). Conclusion. DEB-TACE with raltitrexed-loaded CB suggests a feasible, safe, and efficacious palliative regimen in unresectable or recurrent HCC patients.

Radioisotopes have long been leveraged for internal radiotherapy-mediated cancer treatment. However, such therapeutic approaches are associated with serious side effects, and their efficacy is limited by intratumoral hypoxia. Herein, we prepared a folic acid-decorated palladium decahedral platform capable of enhancing the radiotherapeutic efficacy of iodine-125 (125I) seed treatment. This decahedral nanoenzyme was able to target tumor regions and catalyze the conversion of intracellular H2O2 to O2, thereby alleviating hypoxia within the tumor microenvironment. In addition, palladium was hypoxia can be alleviated, on the other hand, palladium was able to enhance the radiotherapeutic energy deposition within tumor tissues. The results of this analysis indicated that synthesized decahedral constructs can efficiently target and modify the hypoxic tumor microenvironment while simultaneously enhancing radiation energy deposition therein. Relative to palladium nanodots, the prolonged in vivo circulation of these decahedral constructs better enabled them to facilitate sustained radiosensitization. Overall, the results of this study highlight a novel approach to improving the therapeutic utility of 125I seed interstitial implantation, thus underscoring an important direction for future clinical research.

We investigated the effects of gut microbiota and serum metabolite levels in patients with Budd-Chiari syndrome (B-CS) and their importance for guiding clinical management strategies. In total, 214 B-CS patients (93 untreated and 121 treated) and 41 healthy controls were enrolled. Gut microbiota and serum metabolome were analysed using shotgun metagenomics and liquid chromatography-mass spectrometry. The gut microbiota of the patients showed abundance of Campylobacter and low levels of Saccharomyces, Deinococcus, and Thiomonas (P < 0.05). Thirty metabolites, including taurocholate and (R)-3-hydroxybutyric acid, were identified in the patients (VIP > 1, P < 0.05 and FC > 1.2 or FC < 0.83). Random forest (RF) models showed that serum metabolome could effectively identify B-CS from healthy controls and RF-metabolomics exhibited perfect discrimination (AUC = 100%, 95% CI: 100% – 100%), which was significantly higher than that achieved by RF-metagenomics (AUC = 58.48%, 95% CI: 38.46% – 78.5%). Campylobacter concisus and taurocholate showed significant positive correlation in patients with clinical manifestations (P < 0.05). Actinobacteria levels were significantly higher in untreated patients than in treated patients (P < 0.05). Campylobacter and Veillonella levels were significantly higher in treated patients than in healthy controls (P < 0.05). We identified major alterations in the gut microbiota and serum metabolome of patients with B-CS. Faecal metagenomics- and serum metabolomics-guided management strategies are required for patients with B-CS.

BackgroundA considerable number of patients with stage II/III colorectal cancer (CRC) will relapse within 5 years after surgery, which is a leading cause of death in early-stage CRC. The current TNM stage system is limited due to the heterogeneous clinical outcomes displayed in patients of same stage. Therefore, searching for a novel tool to identify patients at high recurrence-risk for improving post-operative individual management is an urgent need.MethodsUsing four independent public cohorts and qRT-PCR data from 66 tissues, we developed and validated a recurrence-associated immune signature (RAIS) based on global immune genes. The clinical and molecular features, tumor immune microenvironment landscape, and immune checkpoints profiles of RAIS were also investigated.ResultsIn five independent cohorts, this novel scoring system was proven to be an independent recurrent factor and displayed excellent discrimination and calibration in predicting the recurrence-risk at 1~5 years. Further analysis revealed that the high-risk group displayed high mutation rate of TP53, while the low-risk group had more abundance of activated CD4+/CD8+ T cells and high expression of PD-1/PD-L1.ConclusionsThe RAIS model is highly predictive of recurrence in patients with stage II/III CRC, which might serve as a powerful tool to further optimize decision-making in adjuvant chemotherapy and immunotherapy, as well as tailor surveillance protocol for individual patients.

Abstract Immune checkpoint inhibitor (ICI) activates host’s anti-tumor immune response by blocking negative regulatory immune signals. A series of clinical trials showed that ICI could effectively induce tumor regression in a subset of advanced cancer patients. In clinical practice, a main concerning for choosing ICI is the low response rate. Even though multiple predictive biomarkers such as PD-L1 expression, mismatch-repair deficiency, and status of tumor infiltrating lymphocytes have been adopted for patient selection, frequent resistance to ICI monotherapy has not been completely resolved. However, some recent studies indicated that ICI resistance could be alleviated by combination therapy with anti-angiogenesis treatment. Actually, anti-angiogenesis therapy not only prunes blood vessel which is essential to cancer growth and metastasis, but also reprograms the tumor immune microenvironment. Preclinical studies demonstrated that the efficacy of combination therapy of ICI and anti-angiogenesis was superior to monotherapy. In mice model, combination therapy could effectively increase the ratio of anti-tumor/pro-tumor immune cell and decrease the expression of multiple immune checkpoints more than PD-1. Based on exciting results from preclinical studies, many clinical trials were deployed to investigate the synergistic effect of the combination therapy and acquired promising outcome. This review summarized the latest understanding of ICI combined anti-angiogenesis therapy and highlighted the advances of relevant clinical trials.

Background: Esophageal adenocarcinoma (EAC) remains a leading cause of cancer-related deaths worldwide and demonstrates a predominant rising incidence in Western countries. Recently, immunotherapy has dramatically changed the landscape of treatment for many advanced cancers, with the benefit in EAC thus far been limited to a small fraction of patients.Methods: Using somatic mutation data of The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium, we delineated the somatic mutation landscape of EAC patients from US and England. Based on the expression data of TCGA cohort, multiple bioinformatics algorithms were utilized to perform function annotation, immune cell infiltration analysis, and immunotherapy response assessment.Results: We found that RYR2 was a common frequently mutated gene in both cohorts, and patients with RYR2 mutation suggested higher tumor mutation burden (TMB), better prognosis, and superior expression of immune checkpoints. Moreover, RYR2 mutation upregulated the signaling pathways implicated in immune response and enhanced antitumor immunity in EAC. Multiple bioinformatics algorithms for assessing immunotherapy response demonstrated that patients with RYR2 mutation might benefit more from immunotherapy. In order to provide additional reference for antitumor therapy of different RYR2 status, we identified nine latent antitumor drugs associated with RYR2 status in EAC.Conclusion: This study reveals a novel gene whose mutation could be served as a potential biomarker for prognosis, TMB, and immunotherapy of EAC patients.

Genomic alterations constitute crucial elements of colorectal cancer (CRC). However, a comprehensive understanding of CRC genomic alterations from a global perspective is lacking. In this study, a total of 2,778 patients in 15 public datasets were enrolled. Tissues and clinical information of 30 patients were also collected. We successfully identified two distinct mutation signature clusters (MSC) featured by massive mutations and dominant somatic copy number alterations (SCNA), respectively. MSC-1 was associated with defective DNA mismatch repair, exhibiting more frequent mutations such as ATM, BRAF, and SMAD4. The mutational co-occurrences of BRAF-HMCN and DNAH17-MDN1 as well as the methylation silence event of MLH-1 were only found in MSC-1. MSC-2 was linked to the carcinogenic process of age and tobacco chewing habit, exhibiting dominant SCNA such as MYC (8q24.21) and PTEN (10q23.31) deletion as well as CCND3 (6p21.1) and ERBB2 (17q12) amplification. MSC-1 displayed higher immunogenicity and immune infiltration. MSC-2 had better prognosis and significant stromal activation. Based on the two subtypes, we identified and validated the expression relationship of FAM83A and IDO1 as a robust biomarker for prognosis and distant metastasis of CRC in 15 independent cohorts and qRT-PCR data from 30 samples. These results advance precise treatment and clinical management in CRC.

BackgroundFerroptosis is essential for tumorigenesis and progression of hepatocellular carcinoma (HCC). The heterogeneity of ferroptosis and its relationship with tumor microenvironment (TME) have still remain elusive.MethodsBased on 74 ferroptosis related genes (FRGs) and 3,933 HCC samples from 32 datasets, we comprehensively explored the heterogenous ferroptosis subtypes. The clinical significance, functional status, immune infiltration, immune escape mechanisms, and genomic alterations of different subtypes were further investigated.ResultsWe identified and validated two heterogeneous ferroptosis subtypes: C1 was metabolismlowimmunityhigh subtype and C2 was metabolismhighimmunitylow subtype. Compared to C2, C1 owned worse prognosis, and C1 tended to occur in the patients with clinical characteristics such as younger, female, advanced stage, higher grade, vascular invasion. C1 and C2 were more sensitive to immunotherapy and sorafenib, respectively. The immune escape mechanisms of C1 might be accumulating more immunosuppressive cells, inhibitory cytokines, and immune checkpoints, while C2 was mainly associated with inferior immunogenicity, defecting in antigen presentation, and lacking leukocytes. In addition, C1 was characterized by BAP1 mutation, MYC amplification, and SCD1 methylation, while C2 was characterized by the significant alterations in cell cycle and chromatin remodeling processes. We also constructed and validated a robust and promising signature termed ferroptosis related risk score (FRRS) for assessing prognosis and immunotherapy.ConclusionWe identified and validated two heterogeneous ferroptosis subtypes and a reliable risk signature which used to assess prognosis and immunotherapy. Our results facilitated the understood of ferroptosis as well as clinical management and precise therapy of HCC.

Purpose. The goal of this study was to assess the clinical efficacy and safety of the arsenic trioxide (ATO)/lipiodol emulsion in the transcatheter arterial chemoembolization (TACE) combined with apatinib in the treatment of advanced hepatocellular carcinoma (HCC). Methods. From December 2015 to February 2017, a total of 87 patients were consecutively enrolled and underwent ATO-TACE (aTACE) combined with apatinib in the treatment of advanced HCC. The treatment response and adverse events were assessed at the first month and third month after aTACE therapy. Progression-free survival (PFS), overall survival (OS), and treatment-related adverse events were also analyzed. Results. 87 patients (57 men; 30 women) were enrolled in the present study. Compared to that at the pre-aTACE examination, the levels of AST and ALT were elevated at the first week after procedure (65.84 U/L ± 22.93 U/L vs. 54.15 U/L ± 19.60 U/L, p=0.032; 63.44 U/L ± 22.50 U/L vs. 51.60 U/L ± 13.89 U/L, p=0.027, respectively). Most of the adverse events were grade 1 or 2 according to National Cancer Institute Common Terminology Criteria for Adverse Event (CTCAE). Of the exception, 4 persons (2%) did have grade 3 hand-foot skin reactions, 1 (1%) had grade 3 diarrhea, 1 (1%) had grade 3 hypertension, and 3 (3%) had grade 3 proteinuria and forced to reduce the dose of apatinib by half. The survival analysis of the combination with aTACE and apatinib therapy found that the median PFS was 10.2 months (95% CI: 8.543–11.857), and the median OS was 23.300 months (95% CI: 20.833–25.767). Additionally, both univariate and multivariate Cox regression revealed that the tumor burden (≤50%) and the patients without portal vein tumor thrombus (PVTT) significantly impacted the patient’s PFS and OS and were related to better survival. Conclusion. aTACE combined with apatinib is a safe and promising treatment approach for patients with advanced HCC. Additionally, tumor burden (≤50%) and the patients without PVTT are associated with better PFS and OS.

Background. Hepatocellular carcinoma (HCC) remains an important cause of cancer death. The molecular mechanism of hepatocarcinogenesis and prognostic factors of HCC have not been completely uncovered. Methods. In this study, we screened out differentially expressed lncRNAs (DE lncRNAs), miRNAs (DE miRNAs), and mRNAs (DE mRNAs) by comparing the gene expression of HCC and normal tissue in The Cancer Genome Atlas (TCGA) database. DE mRNAs were used to perform Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Then, the miRNA and lncRNA/mRNA modules that were most closely related to the survival time of patients with HCC were screened to construct a competitive endogenous RNA (ceRNA) network by weighted gene coexpression network analysis (WGCNA). Moreover, univariable Cox regression and Kaplan-Meier curve analyses of DE lncRNAs and DE mRNAs were conducted. Finally, the lasso-penalized Cox regression analysis and nomogram model were used to establish a new risk scoring system and predict the prognosis of patients with liver cancer. The expression of survival-related DE lncRNAs was verified by qRT-PCR. Results. A total of 1896 DEmRNAs, 330 DElncRNAs, and 76 DEmiRNAs were identified in HCC and normal tissue samples. Then, the turquoise miRNA and turquoise lncRNA/mRNA modules that were most closely related to the survival time of patients with HCC were screened to construct a ceRNA network by WGCNA. In this ceRNA network, there were 566 lncRNA-miRNA-mRNA regulatory pairs, including 30 upregulated lncRNAs, 16 downregulated miRNAs, and 75 upregulated mRNAs. Moreover, we screened out 19 lncRNAs and 14 hub mRNAs related to prognosis from this ceRNA network by univariable Cox regression and Kaplan-Meier curve analyses. Finally, a new risk scoring system was established by selecting the optimal risk lncRNAs from the 19 prognosis-related lncRNAs through lasso-penalized Cox regression analysis. In addition, we established a nomogram model consisting of independent prognostic factors to predict the survival rate of HCC patients. Finally, the correlation between the risk score and immune cell infiltration and gene set enrichment analysis were determined. Conclusions. In conclusion, the results may provide potential biomarkers or therapeutic targets for HCC and the establishment of the new risk scoring system and nomogram model provides the new perspective for predicting the prognosis of HCC.

Purpose: The purpose of this study was to evaluate the efficacy of brachytherapy combined with or without hormone therapy in patients with localized prostate cancer.Methods and Materials: We systemically searched the Medline, Web of Science, Cochrane Library and Embase databases for studies published between the databases' dates of inception and February 2019. The primary endpoints were the 5-year overall survival (OS) rates, 5-year biochemical progression-free survival (bPFS) rates and 10-year bPFS rates. The results were expressed as the relative risk (RR) and 95% confidence interval (CI). Based on the heterogeneity evaluated with the I2 statistic, a meta-analysis was performed using either a random- or fixed-effects model.Results: A total of 16 cohort studies including 9,359 patients met all the criteria for inclusion in the analysis. Our data showed that brachytherapy (BT) combined with hormone therapy (HT) increased the patients' 5-year bPFS rates (RR = 1.04, 95% CI: 1.01–1.08, P = 0.005) and 10-year bPFS rates (RR = 1.12, 95% CI: 1.02–1.23, P = 0.001) compared with BT monotherapy. However, BT combined with HT did not increase the patients' 5-year OS rates (RR = 1.02, 95% CI: 0.99–1.095, P = 0.1) compared with BT monotherapy.Conclusions: BT combined with HT can increase the bPFS rates of patients with localized prostate cancer, but it does not improve patients' OS rates.