The clinical significance of sarcopenia in patients with hepatocellular carcinoma treated with lenvatinib and PD-1 inhibitors.

Background and aim: Sarcopenia has gained considerable attention in the context of hepatocellular carcinoma, as it has been correlated with a poorer prognosis among patients undergoing sorafenib or lenvatinib treatment for hepatocellular carcinoma (HCC). The clinical significance of sarcopenia in first-line advanced HCC patients treated with lenvatinib and programmed death-1 (PD-1) inhibitors needs to be clarified. Methods: Sarcopenia was diagnosed using CT (Computed tomography) or MRI (Magnetic Resonance Imaging), with the psoas muscle index (PMI) as the surrogate marker. Patients were grouped based on sarcopenia presences, and a comparative analysis examined characteristics, adverse events, and prognosis. The Cox regression analysis was applied to identify independent prognostic factors for survival, while nomograms were constructed to predict 1-year survival. Results: Among 180 patients, 46 had sarcopenia. Patients with baseline sarcopenia demonstrated significantly inferior median progression-free survival (mPFS) (3.0 vs. 8.3 months) and median overall survival (mOS) (7.3 vs. 21.6 months). The same results for mPFS (3.3 vs. 9.2 months) and mOS (9.4 vs. 24.2 months) were observed in patients who developed sarcopenia after treatment. Furthermore, significantly higher grade 3 or higher adverse events (AEs) (73.91% vs 41.79%, p<0.001) were recorded in the sarcopenia group compared to the non-sarcopenia group. In the multivariate analysis, distant metastasis, elevated PLR and CRP levels, and low PMI remained independent predictive factors for poor OS. Additionally, skeletal muscle loss remained a significant independent risk factor for PFS. We developed a nomogram incorporating these four indicators, which predicted 12-month survival with a C-index of 0.853 (95% CI, 0.791 - 0.915), aligning well with actual observations. Conclusion: The prognosis of patients with HCC and sarcopenia is significantly worse when treated with lenvatinib and PD-1 inhibitors. The combination regimen of lenvatinib plus PD-1 inhibitors should be cautiously recommended due to the inferior prognosis and higher AEs.

Activation of ductal progenitor-like cells from adult human pancreas requires extracellular matrix protein signaling.

Ductal progenitor-like cells are a sub-population of ductal cells in the adult human pancreas that have the potential to contribute to regenerative medicine. However, the microenvironmental cues that regulate their activation are poorly understood. Here, we establish a 3-dimensional suspension culture system containing six defined soluble factors in which primary human ductal progenitor-like and ductal non-progenitor cells survive but do not proliferate. Expansion and polarization occur when suspension cells are provided with a low concentration (5% v/v) of Matrigel, a sarcoma cell product enriched in many extracellular matrix (ECM) proteins. Screening of ECM proteins identified that collagen IV can partially recapitulate the effects of Matrigel. Inhibition of integrin α1ß1, a major collagen IV receptor, negates collagen IV- and Matrigel-stimulated effects. These results demonstrate that collagen IV is a key ECM protein that stimulates the expansion and polarization of human ductal progenitor-like and ductal non-progenitor cells via integrin α1ß1 receptor signaling.

[Effects of α1-antitrypsin on motor function in mice with immature brain white matter injury]. / α1-æŠ—èƒ°è›‹ç™½é ¶å¯¹æœªæˆç†Ÿè„‘ç™½è´¨æŸä¼¤å°é¼ è¿åŠ¨åŠŸèƒ½çš„å½±å“.

OBJECTIVES: To investigate the effects of α1-antitrypsin (AAT) on motor function in adult mice with immature brain white matter injury. METHODS: Five-day-old C57BL/6J mice were randomly assigned to the sham surgery group (n=27), hypoxia-ischemia (HI) + saline group (n=27), and HI+AAT group (n=27). The HI white matter injury mouse model was established using HI methods. The HI+AAT group received intraperitoneal injections of AAT (50 mg/kg) 24 hours before HI, immediately after HI, and 72 hours after HI; the HI+saline group received intraperitoneal injections of the same volume of saline at the corresponding time points. Brain T2-weighted magnetic resonance imaging scans were performed at 7 and 55 days after modeling. At 2 months of age, adult mice were evaluated for static, dynamic, and coordination parameters using the Catwalk gait analysis system. RESULTS: Compared to the sham surgery group, mice with HI injury showed high signal intensity on brain T2-weighted magnetic resonance imaging at 7 days after modeling, indicating significant white matter injury. The white matter injury persisted at 55 days after modeling. In comparison to the sham surgery group, the HI+saline group exhibited decreased paw print area, maximum contact area, average pressure, maximum pressure, paw print width, average velocity, body velocity, stride length, swing speed, percentage of gait pattern AA, and percentage of inter-limb coordination (left hind paw → left front paw) (P<0.05). The HI+saline group showed increased inter-paw distance, percentage of gait pattern AB, and percentage of phase lag (left front paw → left hind paw) compared to the sham surgery group (P<0.05). In comparison to the HI+saline group, the HI+AAT group showed increased average velocity, body velocity, stride length, and swing speed (right front paw) (P<0.05). CONCLUSIONS: The mice with immature brain white matter injury may exhibit significant motor dysfunction in adulthood, while the use of AAT can improve some aspects of their motor function.

Lenvatinib combined with sintilimab plus transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma.

BACKGROUND: Recently, combination therapy has shown a better trend towards improved tumour response and survival outcomes than monotherapy in patients with hepatocellular carcinoma (HCC). However, research on triple therapy [lenvatinib + sintilimab + transarterial chemoembolization (TACE)] as a first-line treatment for advanced HCC is limited. AIM: To evaluate the safety and efficacy of triple therapy as a first-line treatment for advanced HCC. METHODS: HCC patients with Barcelona Clinic Liver Cancer stage C treated with triple therapy were enrolled. All patients were treated with lenvatinib every day and sintilimab once every 3 wk. Moreover, TACE was performed every 4-6 wk if necessary. The primary outcome of the study was overall survival (OS). The secondary outcomes were the objective response rate (ORR), disease control rate (DCR), and incidence of adverse events. RESULTS: Forty HCC patients who underwent triple therapy were retrospectively analysed from January 2019 to January 2022. With a median follow-up of 8.5 months, the 3-, 6-, and 12-mo OS rates were 100%, 88.5%, and 22.5%, respectively. The ORR and DCR were 45% and 90%, respectively. The median progressive free survival and median OS were not reached. Common complications were observed in 76% of the patients (grade 3, 15%; grade 4, 2.5%). CONCLUSION: Combination therapy comprising lenvatinib, sintilimab and TACE achieved promising outcomes in advanced HCC patients and had manageable effects.

Rare, Tightly-Bound, Multi-Cellular Clusters in the Pancreatic Ducts of Adult Mice Function Like Progenitor Cells and Survive and Proliferate After Acinar Cell Injury.

Pancreatic ductal progenitor cells have been proposed to contribute to adult tissue maintenance and regeneration after injury, but the identity of such ductal cells remains elusive. Here, from adult mice, we identify a near homogenous population of ductal progenitor-like clusters, with an average of 8 cells per cluster. They are a rare subpopulation, about 0.1% of the total pancreatic cells, and can be sorted using a fluorescence-activated cell sorter with the CD133highCD71lowFSCmid-high phenotype. They exhibit properties in self-renewal and tri-lineage differentiation (including endocrine-like cells) in a unique 3-dimensional colony assay system. An in vitro lineage tracing experiment, using a novel HprtDsRed/+ mouse model, demonstrates that a single cell from a cluster clonally gives rise to a colony. Droplet RNAseq analysis demonstrates that these ductal clusters express embryonic multipotent progenitor cell markers Sox9, Pdx1, and Nkx6-1, and genes involved in actin cytoskeleton regulation, inflammation responses, organ development, and cancer. Surprisingly, these ductal clusters resist prolonged trypsin digestion in vitro, preferentially survive in vivo after a severe acinar cell injury and become proliferative within 14 days post-injury. Thus, the ductal clusters are the fundamental units of progenitor-like cells in the adult murine pancreas with implications in diabetes treatment and tumorigenicity.

Inhibition of USP7 upregulates USP22 and activates its downstream cancer-related signaling pathways in human cancer cells.

Deubiquitinases (DUBs) play important roles in various human cancers and targeting DUBs is considered as a novel anticancer therapeutic strategy. Overexpression of ubiquitin specific protease 7 and 22 (USP7 and USP22) are associated with malignancy, therapy resistance, and poor prognosis in many cancers. Although both DUBs are involved in the regulation of similar genes and signaling pathways, such as histone H2B monoubiquitination (H2Bub1), c-Myc, FOXP3, and p53, the interdependence of USP22 and USP7 expression has never been described. In the study, we found that targeting USP7 via either siRNA-mediated knockdown or pharmaceutical inhibitors dramatically upregulates USP22 in cancer cells. Mechanistically, the elevated USP22 occurs through a transcriptional pathway, possibly due to desuppression of the transcriptional activity of SP1 via promoting its degradation upon USP7 inhibition. Importantly, increased USP22 expression leads to significant activation of downstream signal pathways including H2Bub1 and c-Myc, which may potentially enhance cancer malignancy and counteract the anticancer efficacy of USP7 inhibition. Importantly, targeting USP7 further suppresses the in vitro proliferation of USP22-knockout (USP22-Ko) A549 and H1299 lung cancer cells and induces a stronger activation of p53 tumor suppressor signaling pathway. In addition, USP22-Ko cancer cells are more sensitive to a combination of cisplatin and USP7 inhibitor. USP7 inhibitor treatment further suppresses in vivo angiogenesis and tumor growth and induced more apoptosis in USP22-Ko cancer xenografts. Taken together, our findings demonstrate that USP7 inhibition can dramatically upregulate USP22 in cancer cells; and targeting USP7 and USP22 may represent a more effective approach for targeted cancer therapy, which warrants further study. Video Abstract.

Physician-Modified Endografts for the Treatment of Thoracic Aortic Pathologies Involving the Aortic Arch.

OBJECTIVE: This study aimed to evaluate the outcomes of physician-modified endografts (PMEGs) for the treatment of thoracic aortic pathologies involving the aortic arch. METHODS: A retrospective single-center study was performed on consecutive patients with thoracic aortic pathologies treated by PMEGs between February 2018 and May 2022. Data on baseline characteristics, operative procedure, and follow-up information were collected. The endpoints included technical success, complications, mortality, overall survival, re-intervention, and target vessel instability. RESULTS: This study comprised 173 patients (mean age=58±13, range=28-83, 148 men) with thoracic aortic pathologies, including 44 thoracic aortic aneurysms, 113 aortic dissections (9 type A, 4 residual type A, 75 type B, 32 non-A non-B), 3 aortic intramural hematomas, and 13 penetrating aortic ulcers. Thirty-five of the patients had PMEGs with 3 fenestrations, 32 had 2 fenestrations, and 106 had 1 single fenestration. Technical success was 98% (170/173), and the 30-day mortality was 2% (3/173). Perioperative complications included stroke (n=3, 2%), retrograde type A dissection (RTAD; n=3, 2%) and renal injury (n=3, 2%). Seven deaths (4%) were noted during a median follow-up of 11 (range=1-52) months. Eleven cases of re-intervention were stent-related. There were 5 type Ia endoleaks (3%), 2 type III endoleaks (1%) from the innominate artery (IA), and 3 type Ic endoleaks (2%) from the left subclavian arteries. One case of IA stent-graft (SG) stenosis was noted because of mural thrombus. Estimate rates of overall survival, freedom from secondary intervention, and freedom from target vessel instability at 2 years were 93.4% (95% confidence interval [CI]=88.7%-98.1%), 80.7% (95% CI=73.3%-88.1%), and 89.0% (95% CI=80.4%-97.6%), respectively. CONCLUSIONS: Physician-modified endografts showed promising immediate therapeutic results in the treatment of thoracic aortic pathologies involving the aortic arch. Our study demonstrates that the technique is feasible and produces acceptable results. Long-term outcomes are required for further refinement of this technical approach to confirm technical success and durability over time as a valuable option for endovascular aortic arch repair in specialized centers. CLINICAL IMPACT: Our short- and mid-term outcomes of physician-modified endografts in 173 patients showed promising results compared to other branched/fenestrated techniques and backed up the endovascular repair of the aortic arch. Meanwhile, the technical expertise pointed out in our manuscript, including preloaded guidewire, diameter-reducing wire and inner mini-cuffs, provided reference and technical guidance for our peers. Most importantly, it demonstrated that the PMEG, as a device whose components were all commercially available, might be a better option for emergency surgery and for centers who had no access to custom-made devices.

TRPM8 as a Potential Biomarker and Therapeutic Target for Gastric Cancer Identified by a Combination of Text Mining and RNA Sequencing.

INTRODUCTION: Gastric cancer is a well-known malignant tumor that causes millions of deaths worldwide every year. Due to the lack of a specific biomarker for gastric cancer, most patients are diagnosed at an advanced stage of the disease which results in a poor prognosis and a higher death rate. Therefore, novel biomarkers are urgently needed for early diagnosis and to improve the survival rate. METHODS: In this study, we conducted RNA sequencing of tumor samples from 21 patients with gastric cancer. A total of 3192 differentially expressed genes (1589 up-regulated and 1603 down-regulated) were identified. Subsequently, we applied a text-mining algorithm for further analysis of these data and selected 30 representative genes to investigate as candidates for novel biomarkers in gastric cancer. RESULTS: Among these genes, we confirmed transient receptor potential melastatin 8 channels (TRPM8) as a novel biomarker based on Western blot and immunochemistry validation performed on 134 samples. Compared to normal gastric tissue, the tumor tissues exhibited a significantly higher expression level of TRPM8. CONCLUSION: This study provides insights into the underlying role of TRPM8 in cell proliferation. In addition, TRPM8 may be used as a potential therapeutic target for patients with gastric cancer.

A multicenter prospective study of TACE combined with lenvatinib and camrelizumab for hepatocellular carcinoma with portal vein tumor thrombus.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) predicts a poor prognosis. The aim of the present study was to evaluate the efficacy and safety of using lenvatinib and camrelizumab combined with transarterial chemoembolization (TACE) to treat HCC with PVTT. METHODS: This was a single-arm, open-label, multicenter, and prospective study. Eligible patients with advanced HCC accompanied by PVTT were enrolled to receive TACE combined with lenvatinib and camrelizumab. The primary endpoint was progression-free survival (PFS), while the secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: Between April 2020 and April 2022, 69 patients were successfully enrolled. With a median follow-up time of 17.3 months, the median age of the patient cohort was 57 years (range: 49-64 years). According to modified Response Evaluation Criteria in Solid Tumors, the ORR was 26.1% (18 partial responses [PRs]) and the DCR was 78.3% (18 PRs, 36 stable diseases [SDs]). The median PFS (mPFS) and median OS (mOS) were 9.3 and 18.2 months, respectively. And tumor number >3 was identified as an adverse risk factor for both PFS and OS. The most common adverse events across all grades included fatigue (50.7%), hypertension (46.4%), and diarrhea (43.5%). Twenty-four patients (34.8%) experienced Grade 3 toxicity that was relieved by dose adjustment and symptomatic treatment. No treatment-related deaths occurred. CONCLUSIONS: TACE combined with lenvatinib and camrelizumab is a well-tolerated modality treatment with promising efficacy for advanced HCC with PVTT.

The controlling nutritional status score predicts postoperative mortality in patients with ruptured abdominal aortic aneurysm: a retrospective study.

Background: Ruptured abdominal aortic aneurysms (rAAAs) are challenging for vascular surgeons because they have a high mortality rate. In many diseases, nutritional status is closely associated with prognosis. The Controlling Nutritional Status (CONUT) screening tool score is a prognostic factor in some malignant and chronic diseases; however, the impact of nutritional status on rAAA has not yet been reported. In this study, we explored the relationship between the CONUT score and the postoperative prognosis of patients with rAAA. Methods: This was a retrospective review of 39 patients with rAAA who underwent surgical treatment from March 2018 to September 2021 at one center. Patient characteristics, nutritional status (CONUT score), and postoperative status were recorded. The patients were divided into groups A and B based on the CONUT score. The baseline characteristics of the two groups were compared, and Cox proportional hazards and logistic regression analyses were used to determine independent predictors of mid-term mortality and complications, respectively. Results: The overall mid-term mortality rate was 28.21% (11/39). Compared with group A, group B had higher intraoperative (P = 0.047) and mid-term mortality (P = 0.033) rates. The univariate analysis showed that age [hazard ratio (HR), 1.098; 95% confidence interval (CI), 1.019-1.182; P = 0.014], CONUT score (HR, 1.316; 95% CI, 1.027-1.686; P = 0.03), and surgical procedure (HR, 0.127; 95% CI, 0.016-0.992; P = 0.049) were associated with mid-term mortality, whereas the multivariate analysis showed that the CONUT score (HR, 1.313; 95% CI, 1.009-1.710; P = 0.043) was an independent predictor of mid-term mortality. The multivariate logistic regression analysis did not reveal any associations with complications. The Kaplan-Meier curves showed that group B had a lower mid-term survival rate (log-rank P = 0.024). Conclusion: Malnutrition is closely associated with the prognosis of patients with rAAA, and the CONUT score can be used to predict mid-term mortality.

A Newly Identified Spike Protein Targeted Linear B-Cell Epitope Based Dissolvable Microneedle Array Successfully Eliciting Neutralizing Activities against SARS-CoV-2 Wild-Type Strain in Mice.

Vaccination is a cost-effective medical intervention. Inactivated whole virusor large protein fragments-based severe acute respiratory syndrome coronavirus (SARS-CoV-2) vaccines have high unnecessary antigenic load to induce allergenicity and/orreactogenicity, which can be avoided by peptide vaccines of short peptide fragments that may induce highly targeted immune response. However, epitope identification and peptide delivery remain the major obstacles in developing peptide vaccines. Here, a multi-source data integrated linear B-cell epitope screening strategy is presented and a linear B-cell epitope enriched hotspot region is identified in Spike protein, from which a monomeric peptide vaccine (Epitope25) is developed and applied to subcutaneously immunize wildtype BALB/c mice. Indirect ELISA assay reveals specific and dose-dependent binding between Epitope25 and serum IgG antibodies from immunized mice. The neutralizing activity of sera from vaccinated mice is validated by pseudo and live SARS-CoV-2 wild-type strain neutralization assays. Then a dissolvable microneedle array (DMNA) is developed to pain-freely deliver Epitope25. Compared with intramuscular injection, DMNA and subcutaneous injection elicit neutralizing activities against SARS-CoV-2 wild-type strain as demonstrated by live SARS-CoV-2 virus neutralization assay. No obvious damages are found in major organs of immunized mice. This study may lay the foundation for developing linear B-cell epitope-based vaccines against SARS-CoV-2.

Update on the genetic diversity and population structure of Echinococcus granulosus in Gansu Province, Tibet Autonomous Region, and Xinjiang Uygur Autonomous Region, Western China, inferred from mitochondrial cox1, nad1, and nad5 sequences.

The identification of additional Echinococcus granulosus sensu lato (s.l.) complex species/genotypes in recent years raises the possibility that there might be more variation among this species in China than is currently understood. The aim of this study was to explore intra- and inter-species variation and population structure of Echinococcus species isolated from sheep in three areas of Western China. Of the isolates, 317, 322, and 326 were successfully amplified and sequenced for cox1, nad1, and nad5 genes, respectively. BLAST analysis revealed that the majority of the isolates were E. granulosus s.s., and using the cox1, nad1, and nad5 genes, respectively, 17, 14, and 11 isolates corresponded to Elodea canadensis (genotype G6/G7). In the three study areas, G1 genotypes were the most prevalent. There were 233 mutation sites along with 129 parsimony informative sites. A transition/transversion ratio of 7.5, 8, and 3.25, respectively, for cox1, nad1, and nad5 genes was obtained. Every mitochondrial gene had intraspecific variations, which were represented in a star-like network with a major haplotype with observable mutations from other distant and minor haplotypes. The Tajima's D value was significantly negative in all populations, indicating a substantial divergence from neutrality and supporting the demographic expansion of E. granulosus s.s. in the study areas. The phylogeny inferred by the maximum likelihood (ML) method using nucleotide sequences of cox1-nad1-nad5 further confirmed their identity. The nodes assigned to the G1, G3, and G6 clades as well as the reference sequences utilized had maximal posterior probability values (1.00). In conclusion, our study confirms the existence of a significant major haplotype of E. granulosus s.s. where G1 is the predominant genotype causing of CE in both livestock and humans in China.

Three-Dimensional Printing to Guide Fenestrated/Branched TEVAR in Triple Aortic Arch Branch Reconstruction With a Curative Effect Analysis.

PURPOSE: To summarize experience with and the efficacy of fenestrated/branched thoracic endovascular repair (F/B-TEVAR) using physician-modified stent-grafts (PMSGs) under 3D printing guidance in triple aortic arch branch reconstruction. MATERIALS AND METHODS: From February 2018 to April 2022, 14 cases of aortic arch aneurysms and 30 cases of aortic arch dissection (22 acute aortic arch dissection and 8 long-term aortic arch dissection)were treated by F/B-TEVAR in our department, including 34 males and 10 females, with an average age of 59.84 ± 11.72 years. Three aortic arch branches were affected in all patients. A 3D-printed model was made according to computed tomography angiography images and used to guide the fabrication of PMSGs. All patients were followed up. RESULTS: A total of 132 branches were successfully reconstructed with no case of conversion to open surgery. The average operation time was 4.97 ± 1.40 hours, including a mean 44.05 ± 7.72 minutes for stent-graft customization, the mean postoperative hospitalization duration was 9.91 ± 4.47 days, the average intraoperative blood loss was 480.91 mL (100-2810 mL), and the mean postoperative intensive care unit monitoring duration was 1.02 days (0-5 days). No deaths occurred within 30 days of surgery. Postoperative neurological complications occurred in 1 case (2.3%), and retrograde type A dissection occurred in 1 case (2.3%). CONCLUSION: Compared with conventional surgery, triple aortic arch branch reconstruction under the guidance of 3D printing is a minimally invasive treatment method with the advantages of accurate positioning, rapid postoperative recovery, few complications, and reliable short- to mid-term effects. CLINICAL IMPACT: At present the PMSG usually depend on imaging data and software calculation. With the guidance of 3D printing technology, image data could be transformed into 3D model, which has improved the accuracy of the positioning of the fenestrations. The diameter reduction technique and the internal mini cuff technique have made a complement to the slimed-down fenestration selection process and the low rate of endoleak. As reproducible study, our results may provide reference for TEVAR in different cases.

3D Printing-guided endovascular repair of enormous twisted thoracoabdominal aortic aneurysm with branch stenosis and occlusion.

A 67-year-old male patient was admitted with an enormous twisted thoracoabdominal aortic aneurysm (TAAA) with multiple branch arteries stenosis and occlusion. Three-dimensional (3D) printing technology combined with mechanics was used for developing a transparent model of lesion to simulate the segment of diseased aorta. A stent graft was deployed in the 3D model to make a physician-modified stent graft (PMSGs) on table. The locations of the opening of branches were marked twice during operation. The PMSG was successfully deployed during the surgery and repaired the TAAA, with no endoleak and all the branched arteries patency in follow-up. This technique could offer precision individualized therapy and could simplify the procedure process greatly.

Transarterial chemoembolization combined with radiofrequency ablation in the treatment of large hepatocellular carcinoma with stage C.

BACKGROUND: The combination therapy of transarterial chemoembolization and radiofrequency ablation (TACE-RFA) shows promising efficacy in large hepatocellular carcinoma (HCC). Data on the clinical efficacy and safety of TACE-RFA for large HCC with barcelona clinic liver cancer (BCLC) stage C are lacking in China. AIM: To determine the safety and efficacy of TACE-RFA for large, advanced HCC. METHODS: Patients of HCC with BCLC stage C who were treated with TACE-RFA or TACE alone at our institute from August 2008 to January 2017 were retrospectively reviewed. The complications were observed. The associations between overall survival (OS) and treatment method were analysed. RESULTS: Data were collected from 102 HCC patients. Among them, 64 underwent TACE-RFA and 38 underwent TACE. The combination of TACE and RFA was safe. All complications were controllable. The median OS in the TACE-RFA group was significantly longer than that in the TACE group (8.0 mo vs 4.0 mo, P = 0.000). The 6-, 12- and 24-mo survival rates of the combination group were 68.8%, 34.4%, and 10.9%, respectively, while those of the TACE group were 36.8%, 7.9%, and 0% (P < 0.05). CONCLUSION: TACE-RFA has an advantage over TACE alone in improving OS in large HCC patients with BCLC stage C.

Sintilimab-Induced Diabetic Ketoacidosis in a Patient with Radiation and Multichemorefractory Penile Cancer: A Case Report and Literature Review.

Penile squamous cell carcinoma (PSCC) is a rare disease. The treatment options for advanced penile cancer are often limited, and the prognosis remains poor. We reported a 52-year-old male recurrent and metastatic PSCC patient with high PD-L1 expression (90%) and TMB (14.4 muts/Mb). He had undergone penectomy, bilateral inguinal lymph node dissection, and excision of the abdominal wall mass. Despite cisplatin-based concurrent chemoradiotherapy and sequential chemotherapy with docetaxel plus cisplatin then being carried out, the carcinoma still progressed. The patient then obtained progression-free survival with continuous sintilimab, although he experienced the new onset of ICI-induced diabetes after 24 cycles of sintilimab and required sustained insulin treatment. He had negative type 1 diabetes-associated autoantibodies and the susceptible HLA genotype DR3-DQ2 haplotype. This is the first patient with radiation and multichemorefractory PSCC who has obtained the remarkable anti-tumor effect of partial regression exceeding 32 months during continuous sintilimab and anlotinib treatment.

CT-guided percutaneous chemical ablation combined with radiofrequency ablation for hepatocellular carcinomas in high-risk locations: lobaplatin vs. ethanol.

To retrospectively compare the clinical efficacy and safety of CT-guided percutaneous injection of lobaplatin vs. ethanol for chemical ablation combined with radiofrequency ablation (RFA) in patients with hepatocellular carcinomas (HCCs) in high-risk locations. From January 2017 to June 2018, a total of 41 patients with HCCs in high-risk locations were enrolled and divided into two groups: percutaneous lobaplatin injection (PLI+RFA) group and percutaneous ethanol injection (PEI+RFA) group. The mixture of lobaplatin or ethanol was accurately injected into the high-risk part of the tumors, while RFA ablated the non-high-risk part. The efficacy and safety were compared between the two groups. 41 patients had 51 lesions in high-risk locations, including 24 cases with 30 lesions in PLI+RFA group and 17 cases with 21 lesions in PEI+RFA group. The complete ablation rate was 93.3% (28/30) in PLI+RFA group and 90.5% (19/21) in PEI+RFA group (P=1.000). The 2-year local tumor progression rate of PLI+RFA group and PEI+RFA group was 20.0% (6/30) and 19.0% (4/21), respectively (P=1.000). No significant differences were found in time to progression and overall survival between the two groups (P=0.501 and P=0.424, respectively). The incidence and severity of adverse events between the two groups were similar (P > 0.05). No severe complications were observed in both groups. Percutaneous lobaplatin injection combined with RFA in the treatment of HCC in high-risk locations may achieve the complete ablation rate similar to percutaneous ethanol injection combined with RFA, but further research is needed to confirm.

Case report: Remedial surgical treatment of aorto-duodenal fistula with infected aneurysm after endovascular aortic repair.

Aorto-duodenal fistula (ADF) is a rare cause of upper gastrointestinal bleeding, but it is associated with high mortality. It usually occurs in patients with prior aortic surgery or who have undergone aortic graft placement. Abdominal aortic aneurysm (AAA) might be a cause of primary ADF, which could develop into sudden shock. Because ADF is difficult to diagnose, surgery to correct it has a poor outcome. We here report the successful treatment of an ADF complicated with infected AAA after endovascular repair of a ruptured aneurysm of the iliac artery.

Transcription factor AP2 enhances malignancy of non-small cell lung cancer through upregulation of USP22 gene expression.

BACKGROUND: Ubiquitin-specific protease 22 (USP22), a putative cancer stem cell marker, is frequently upregulated in cancers, and USP22 overexpression is associated with aggressive growth, metastasis, and therapy resistance in various human cancers including lung cancer. However, USP22 gene amplification seldom occurs, and the mechanism underlying USP22 upregulation in human cancers remains largely unknown. METHODS: A luciferase reporter driven by a promoter region of USP22 gene was selectively constructed to screen against a customized siRNA library targeting 89 selected transcription factors to identify potential transcription factors (TFs) that regulate USP22 expression in human non-small cell lung cancers (NSCLC). Association of identified TFs with USP22 and potential role of the TFs were validated and explored in NSCLC by biological assays and immunohistochemistry analysis. RESULTS: Luciferase reporter assays revealed that SP1 and activating transcription factor 3 (ATF3) inhibit USP22 transcription, while transcription factor AP-2 Alpha/Beta (TFAP2A/2B) and c-Myc promote USP22 transcription. Binding site-directed mutagenesis and chromosome immunoprecipitation (ChIP) assays validated AP2α and AP2ß are novel TFs of USP22. Furthermore, overexpression of AP2A and AP2B significantly upregulates USP22 expression, and its target: Cyclin D1, concurrently enhances the proliferation, migration, and invasion of NSCLC A549 and H1299 cells in a partially USP22-dependent manner. Moreover, AP2 protein level correlated with USP22 protein in human NSCLC tissues. CONCLUSION: Our findings indicate AP2α and AP2ß are important transcription factors driving USP22 gene expression to promote the progression of NSCLC, and further support USP22 as a potential biomarker and therapeutic target for lung cancer. Video Abstract.

Sintilimab Combined with Lenvatinib for Advanced Intrahepatic Cholangiocarcinoma in Second-Line Setting-A Multi-Center Observational Study.

Background: Patients with advanced intrahepatic cholangiocarcinoma (iCCA) have a poor prognosis and a substantial unmet clinical need. The study was aimed to investigate the efficacy and safety of sintilimab combined with lenvatinib for advanced iCCA in second-line setting. Methods: The patients at multiple centers, who progressed after the first-line chemotherapy or could not tolerate chemotherapy, were treated with the combination of sintilimab plus lenvatinib. The primary endpoint was time to progression (TTP), and the secondary endpoints included tumor objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Prognostic factors were analyzed using Cox regression analysis. Results: A total of 41 patients with advanced iCCA were enrolled for this multi-center observational study. Under a median follow-up of 12.1 months, the median age was 59 years (range, 33-75 years). Sixteen patients died of disease progression, with a median TTP of 6.6 months (95% CI, 4.9-8.3). ORR and DCR were 46.3% and 70.3%, respectively. The patients with PD-L1 TPS ≥10% reported a significantly higher ORR compared to those with PD-L1 TPS <10%, 93.8% (15/16) vs. 16.0% (4/25), p<0.001. The median TTP was significantly improved in patients with PD-L1 TPS ≥10%, 16.9 months (95% CI, 7.5-26.3) vs. 4.1 months (95% CI, 1.8-6.4), p=0.001. Attaining treatment response predicts favorable TTP in a multivariate Cox model. Treatment-emergent adverse events occurred with 70.3% probability, and no treatment-related death had been reported. Conclusion: The combination of sintilimab plus lenvatinib is effective and well tolerated for advanced iCCA in the second-line setting. PD-L1 TPS expression may predict the efficacy of the combination therapy. Further investigation is warranted to investigate this combination regimen in advanced iCCA.