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Xiheng Hu,1 Mingfeng Chen,1 Yangle Li,1 Yin Wang,2 Sailan Wen,2 Fu Jun3 1Department of Urology, Xiangya Hospital, Central South University, Changsha, Human 410008, P.R. China; 2Department of Pathology, Xiangya Hospital, Central South University, Changsha, Human 410008, P.R. China; 3Laboratory of Oncology Research, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Human 410008, P.R. China Objective: A greater knowledge of the mechanisms of the pathogenesis of penile cancers may assist in the development of more tailored targeted therapy. Herein, we aimed to evaluate the expression of CEACAM19 in penile cancer and to explore its regulatory mechanisms.Material and methods: This retrospective study enrolled 64 penile cancer patients who underwent penectomy between 2011 and 2015. CEACAM19 expression in tissues was detected by immunohistochemistry, which was analyzed in association with clinicopathological parameters. Kaplan–Meier analysis was performed to evaluate the relationship between CEACAM19 expression and prognosis of patients with penile cancer. Cell Counting Kit-8 assay and clonogenic assay were used to evaluate the cell viability and tumorigenic potential of penile cancer cell line, respectively; wound healing assay and transwell invasion assay were conducted to evaluate the effect of CEACAM19 depletion on cell migration and invasion in penile cancer cells; CEACAM19 protein expression was analyzed by Western blotting. Culture supranatant matrix metalloproteinase 2/9 (MMP2/9) was detected by ELISA.Results: CEACAM19 was differentially expressed in non-cancerous and penile cancer tissues. Over-expression of CEACAM19 was significantly associated with nodal and distant metastasis, and predicted unfavorable cancer-specific survival in penile cancer. Depletion of CEACAM19 expression suppressed cell proliferation, reduced colony formation, and attenuated cell migration and invasion in Penl1 cells. Furthermore, knockdown of CEACAM19 expression attenuated the levels of p-Smad2/3 and reduced secretion of MMP2/9 in Penl1 cells. The effects of CEACAM19 might result from its function in regulating the Smad2/3 activation, as inhibition on Smad2/3 activation suppressed cell migration and invasion and reduced MMP2/9 secretion in Penl1 cells.Conclusion: Over-expression of CEACAM19 might serve as a potential prognostic biomarker for clinical management of penile cancer. Strategies targeting CEACAM19-regulated signaling pathways may have a therapeutic benefit in penile cancer. Keywords: penile cancer, CEACAM19, prognosis, metastasis

Abstract Immunotherapy targeting programmed cell death-1 (PD-1) and PD-L1 immune checkpoints has reshaped treatment paradigms across several cancers, including breast cancer. Combining PD-1/PD-L1 immune checkpoint blockade (ICB) with chemotherapy has shown promising efficacy in both early and metastatic triple-negative breast cancer, although only a subset of patients experiences durable responses. Identifying responders and optimizing immune drug selection are therefore critical. The effectiveness of PD-1/PD-L1 immunotherapy depends on both tumor-intrinsic factors and the extrinsic cell-cell interactions within the tumor microenvironment (TME). This review systematically summarizes the key findings from clinical trials of ICBs in breast cancer and examines the mechanisms underlying PD-L1 expression regulation. We also highlight recent advances in identifying potential biomarkers for PD-1/PD-L1 therapy and emerging evidence of TME alterations following treatment. Among these, the quantity, immunophenotype, and spatial distribution of tumor-infiltrating lymphocytes stand out as promising biomarkers. Additionally, we explore strategies to enhance the effectiveness of ICBs in breast cancer, aiming to support the development of personalized treatment approaches tailored to the unique characteristics of each patient’s tumor.

Background Liver metastasis is highly aggressive and immune tolerant, and lacks effective treatment strategies. This study aimed to develop a neoantigen hydrogel vaccine (NPT-gels) with high clinical feasibility and further investigate its efficacy and antitumor molecular mechanisms in combination with immune checkpoint inhibitors (ICIs) for the treatment of liver metastases.Methods The effects of liver metastasis on survival and intratumor T-cell subpopulation infiltration in patients with advanced tumors were investigated using the Surveillance, Epidemiology, and End Results Program (SEER) database and immunofluorescence staining, respectively. NPT-gels were prepared using hyaluronic acid, screened neoantigen peptides, and dual clinical adjuvants [Poly(I:C) and thymosin α-1]. Then, the efficacy and corresponding antitumor molecular mechanisms of NPT-gels combined with programmed death receptor 1 and cytotoxic T-lymphocyte-associated protein 4 double blockade (PCDB) for the treatment of liver metastases were investigated using various preclinical liver metastasis models.Results Liver metastases are associated with poorer 5-year overall survival, characterized by low infiltration of cytotoxic CD8+ T cells and high infiltration of regulatory T cells (Tregs). NPT-gels overcame the challenges faced by conventional neoantigen peptide vaccines by sustaining a durable, high-intensity immune response with a single injection and significantly improving the infiltration of neoantigen-specific T-cell subpopulations in different mice subcutaneous tumor models. Importantly, NPT-gels further combined with PCDB could enhance neoantigen-specific T-cell infiltration and effectively unlock the immunosuppressive microenvironment of liver metastases, showing superior antitumor efficacy and inducing long-term immune memory in various preclinical liver metastasis models without obvious toxicity. Mechanistically, the combined strategy can inhibit Tregs, induce the production and infiltration of neoantigen-specific CD8+CD69+ T cells to enhance the immune response, and potentially elicit antigen-presenting effects in Naïve B_Ighd+ cells and M1-type macrophages.Conclusions This study demonstrated that NPT-gels combined with PCDB could exert a durable and powerful antitumor immunity by enhancing the recruitment and activation of CD8+CD69+ T cells, which supports the rationale and clinical translation of this combination strategy and provides important evidence for further improving the immunotherapy efficacy of liver metastases in the future.

Objective: Understanding the differences of suprasellar papillary and adamantinomatous craniopharyngiomas (PCPs/ACPs) is pivotal for target therapy, surgical strategy or postoperative management. Here, the clinical features, surgical nuances and postoperative hypothalamic outcomes of PCPs were systematically recapitulated. Methods: 24 PCPs and 52 ACPs underwent initial surgery were retrospectively reviewed. Clinical data, quantified third ventricle (3rd V) occupation and optic chiasm distortion were compared, as well as intra-operative findings, operating notes and prognosis. Moreover, analysis of tumor/3rd V relationship and hypothalamic outcomes were also performed. Results: Tumors were more likely to occupies the 3rd V cavity in PCPs. Chiasm distortion of “compressed forward” was the most common pattern (45.8 %) in PCPs, whereas “stretched forward” pattern accounted the highest (42.5 %) in ACPs. Besides, round-shaped with less calcification, duct-like recess, solid consistency, rare subdiaphragmatic invasion, visible lower stalk and improved postoperative visual outcome were more frequently observed in PCPs. The basal membranes of the tumor epithelium and the reactive gliosis were separated by a layer of collagen fibers in most PCPs, which differs from ACPs in the morphological examination of tumor/3rd V floor interface. In daytime sleepiness and memory difficulty, the PCPs showed significantly better outcomes than the ACPs groups, and PCPs suffered less postoperative weight gain (p < 0.05) than ACPs among adult-onset cases. Conclusion: PCPs are different from ACPs regards the clinical features, operative techniques and outcomes. If necessary, PCPs are suggested more amenable to total removal since its less invasiveness to the 3rd V floor and better hypothalamic outcomes.

Abstract Background NUAK family kinase 2 (NUAK2) has been identified as an important mediator for tumor progression in multiple malignancies. Nevertheless, its role in lung adenocarcinoma (LUAD) remains unclear. Methods Bioinformatic analysis was performed to assess the expression and prognosis of NUAK2 in patients with LUAD. The NUAK2 expression was measured in multiple LUAD cell lines, and the loss-of-function experiment was conducted. Cell proliferation ability was assessed using CCK-8 and colony formation assays. Spheroid formation, alkaline phosphatase (AP) staining, tube formation and SA-β-gal staining assays were performed to examine stemness, angiogenesis and senescence. Lipid peroxidase was assessed by TBARS production and lipid ROS. Western blot was used to detect critical proteins. In addition, A549 cells were treated with ferroptosis inhibitor ferrostatin-1 (Fer-1) for a rescue assay. Finally, A549 cells were subcutaneously injected into the right flank of mice to establish LUAD-bearing mouse model, and the tumor weight and size were detected. Results NUAK2 was upregulated in patients with LUAD and LUAD cell lines. NUAK2 depletion inhibited cell viability, colonies, tumor spheres and decreased Oct4 and Nanog expression, confirming NUAK2 depletion inhibited proliferation and stemness of A549 cells. Meanwhile, NUAK2 depletion blocked angiogenesis via reducing formed tubes and VEGFR1/2 expression, and promoted senescence of A549 cells by elevating SA-β-gal-positive cells and p16, p21 and p53 expression. Moreover, NUAK2 depletion elevated lipid ROS, TBARS production and Fe2+ level, demonstrating that NUAK2 depletion could trigger ferroptosis in A549 cells. Furthermore, the rescue experiments revealed that the impacts of NUAK2 depletion on malignant behaviors in A549 cells were partly weakened by additional Fer-1 treatment. Finally, in vivo experiments demonstrated that NUAK2 knockdown greatly inhibited tumor growth in LUAD-bearing mice. Conclusion In summary, NUAK2 depletion impeded oncogenic phenotypes of A549 cells partly via triggering ferroptosis, suggesting NUAK2 as a novel target for treating LUAD.

Chemokines play a crucial role in the pathogenesis of patients with hepatocellular carcinoma (HCC). The expression levels of interferon-γ-induced protein-10 (CXCL10) and macrophage inflammatory protein-3α (MIP-3a) were investigated to clarify their clinical significance in HCC.The protein levels of CXCL10 and MIP-3a in the serum of 105 HBV-associated HCC patients, 50 patients with liver cirrhosis (LC), 50 patients with chronic hepatitis B (CHB) and 50 healthy donors (HC) were detected by liquid chip technology (Luminex) or ELISA. In addition, their mRNA levels were also determined in liver cancer and adjacent cancer tissue (paracancer; ParaCa) from 65 HCC patients. The online database UALCAN was used to analyze the association between CXCL10 and pathological manifestations of liver cancer. In addition, the diagnostic value of CXCL10/MIP-3a and AFP in HCC patients was determined by analyzing the Receiver Operating Characteristic Curve (ROC).The protein concentrations of CXCL10 and MIP-3a were significantly higher in the HCC group than in the LC, CHB and HC groups. CXCL10 in sera and liver cancer tissues is significantly positively correlated with ALT, but no significance between CXCL10 in ParaCa tissues and sera-ALT. Their mRNA is significantly higher in cancer tissues than in ParaCa tissues. The areas under the ROC curve of CXCL10, MIP-3a, CXCL10 and MIP-3a combined and AFP were 0.9169, 0.9261, 0.9299 and 0.7880, respectively. Elevated chemokines CXCL10 and MIP-3a in HCC patients may be associated with the clinical manifestation of HCC and could be a potential molecular marker for prognostic evaluation or a therapeutic target for HCC.

Abstract Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression.

Abstract Background The prognostic significance of tumor burden score (TBS) in relation to carcinoembryonic antigen (CEA) has not been investigated among patients undergoing hepatectomy for intrahepatic cholangiocarcinoma (ICC). This study aimed to develop and validate a simplified model, a combination of TBS and CEA (CTC grade), for predicting the long-term outcomes of postoperative ICC patients. Methods Patients who underwent curative − intent resection of ICC between 2011 and 2019 were identified from a large multi − institutional database. The impact of TBS, CEA, and the CTC grade on overall survival (OS) and recurrence − free survival (RFS) was evaluated in both the derivation and validation cohorts. The receiver operating characteristic curve was utilized for assessing the predictive accuracy of the model. Subgroup analyses were performed across 8th TNM stage system stratified by CTC grade to assess the discriminatory capacity within the same TNM stage. Results A total of 812 patients were included in the derivation cohort and 266 patients in the validation cohort. Survival varied based on CEA (low: 36.7% vs. high: 9.0%) and TBS (low: 40.3% vs. high: 17.6%) in relation to 5 − year survival (both p

Abstract Objective To investigate the clinical features, treatment strategies, and prognosis of neuroblastoma with bilateral blindness. Methods The clinical data of five patients with bilateral blindness neuroblastoma admitted to Beijing Children’s Hospital from April 2018 to September 2020 were retrospectively collected to summarize their clinical characteristics. Results All patients were female and the median age at presentation was 25 (23, 41) months. The median intervention time from the onset of symptoms of bilateral blindness to the start of treatment was 10 (10, 12) days. All five cases were staged as stage M and grouped as high risk. Four cases were MYCN gene amplification and one case was MYCN acquisition. Five children were treated according to a high-risk neuroblastoma treatment protocol. Four children did not recover their vision after treatment, and one case improved to have light perception. All patients were effectively followed up for a median of 20 (12, 31) months, with three deaths, one tumor-free survival, and one recurrent tumor-bearing survival. Conclusion Neuroblastoma with bilateral blindness is rare in the clinic, mostly in children of young age, and is often associated with MYCN amplification and multiple metastases. Early hormone shock therapy and optic nerve decompression are beneficial for preserving the child’s vision. A joint multi-disciplinary treatment may help in the formulation of treatment decisions. Achieving a balance between good visual preservation and survival within the short optic nerve neurotherapeutic window is extremely challenging.

BackgroundThe utility of pre- and post-operative alpha-fetoprotein (AFP) and des-gamma (γ)-carboxy prothrombin (DCP) expression patterns and their dynamic changes as predictors of the outcome of hepatic resection for hepatocellular carcinoma (HCC) has yet to be well elucidated.MethodsFrom a multicenter database, AFP and DCP data during the week prior to surgery and the first post-discharge outpatient visit (within 1-2 months after surgery) were collected from patients with HCC who underwent hepatectomy. AFP-DCP expression patterns were categorized according to the number of positive tumor markers (AFP ≥ 20ng/mL, DCP ≥ 40mAU/mL), including double-negative, single-positive, and double-positive. Changes in the AFP-DCP expression patterns were delineated based on variations in the number of positive tumor markers when comparing pre- and post-operative patterns.ResultsPreoperatively, 53 patients (8.3%), 337 patients (52.8%), and 248 patients (38.9%) exhibited double-negative, single-positive, and double-positive AFP-DCP expression patterns, respectively. Postoperatively, 463 patients (72.6%), 130 patients (20.4%), and 45 patients (7.0%) showed double-negative, single-positive, and double-positive AFP-DCP expression patterns, respectively. Survival analysis showed a progressive decrease in recurrence-free (RFS) and overall survival (OS) as the number of postoperative positive tumor markers increased (both P < 0.001). Multivariate analysis showed that postoperative AFP-DCP expression pattern, but not preoperative AFP-DCP expression pattern, was an independent risk factor for RFS and OS. Further analysis showed that for patients with positive preoperative markers, prognosis gradually improves as positive markers decrease postoperatively. In particular, when all postoperative markers turned negative, the prognosis was consistent with that of preoperative double-negative patients, regardless of the initial number of positive markers.ConclusionsAFP-DCP expression patterns, particularly postoperative patterns, serve as vital sources of information for prognostic evaluation following hepatectomy for HCC. Moreover, changes in AFP-DCP expression patterns from pre- to post-operation enable dynamic prognostic risk stratification postoperatively, aiding the development of individualized follow-up strategies.

Abstract Background Routine clinical staging for hepatocellular carcinoma (HCC) incorporates liver function, general health, and tumor morphology. Further refinement of prognostic assessments and treatment decisions may benefit from the inclusion of tumor biological marker alpha-fetoprotein (AFP) and systemic inflammation indicator C-reactive protein (CRP). Methods Data from a multicenter cohort of 2770 HCC patients undergoing hepatectomy were analyzed. We developed the PACE risk score (Prognostic implications of AFP and CRP Elevation) after initially assessing preoperative AFP and CRP’s prognostic value. Subgroup analyzes were performed in BCLC cohorts A and B using multivariable Cox analysis to evaluate the prognostic stratification ability of the PACE risk score and its complementary utility for BCLC staging. Results Preoperative AFP ≥ 400ng/mL and CRP ≥ 10 mg/L emerged as independent predictors of poorer prognosis in HCC patients who underwent hepatectomy, leading to the creation of the PACE risk score. PACE risk score stratified patients into low, intermediate, and high-risk groups with cumulative 5-year overall (OS) and recurrence-free survival (RFS) rates of 59.6%/44.9%, 43.9%/38.4%, and 20.6%/18.0% respectively (all P

Abstract Adropin, a secreted protein, coded by energy homeostasis-associated gene (Enho), is recently reported to modulate atherogenesis, with endothelial-to-mesenchymal transition (EndMT) involved in the early process. We explored whether adropin may alleviate atherosclerosis by regulating EndMT. We found that an intraperitoneal injection of adropin [105 μg/(kg·d) for 13 weeks] inhibited the progression of high-fat diet (HFD)-induced aortic atherosclerosis in apolipoprotein E-deficient mice (ApoE–/–) and those with double gene deletion (ApoE–/–/Enho–/–), as detected by Oil Red O and haematoxylin-eosin staining. In the aortas of ApoE–/– mouse, adropin treatment ameliorated the decrease in the mRNA expression of endothelial cell markers (leukocyte differentiation antigen 31, CD31, and vascular endothelial cadherin, VE-cadherin), but increased that of EndMT markers (alpha smooth muscle actin, α-SMA, and fibroblasts specific protein-1). In vitro, an adropin treatment (30 ng/ml) arrested the hydrogen peroxide (H2O2)-induced EndMT in human umbilical vein endothelial cells (HUVECs), attenuated the morphological changes of HUVECs, reduced the number of immunofluorescence-positive α-SMA, increased the mRNA and protein expressions of CD31 and VE-cadherin, and decreased those of α-SMA. Furthermore, the adropin treatment decreased the mRNA and protein expressions of transforming growth factor (TGF)-β1 and TGF-β2, and suppressed the phosphorylation of downstream signal protein Smad2/3 in HUVECs. These mitigative effects of adropin on H2O2-induced EndMT were reversed by the transfection of TGF-β plasmid. The findings signify that adropin treatment may alleviate the atherosclerosis in ApoE–/–/Enho–/– mice by inhibiting EndMT via the TGF-β/Smad2/3 signaling pathway.

Abstract Background To clarify the relationship between p53 immunohistochemistry (IHC) staining and TP53 alterations (including mutations and deletions) in large B-cell lymphomas (LBCLs) and to explore the possibility of p53 IHC expression patterns as surrogate markers for TP53 alterations. Methods A total of 95 patients diagnosed with LBCLs were selected, and paraffin samples were taken for TP53 gene sequencing, fluorescence in situ hybridization and p53 IHC staining. The results were interpreted by experienced pathologists and molecular pathologists. Results Forty-three nonsynonymous TP53 mutations and p53 deletions were detected in 40 cases, whereas the remaining 55 cases had wild-type TP53 genes. The majority of TP53 mutations (34/43, 79.1%) occurred in exons 4-8, and R248Q was the most common mutation codon (4/43, 9.3%). The highest frequency single nucleotide variant was C > T (43.6%). p53 expression was interpreted as follows: Pattern A: p53 staining was positive in 0%-3% of tumor cells, Pattern B: p53 staining was positive in 4-65% of tumor cells, Pattern C: more than 65% of tumor cells were stained positive for p53. The p53 IHC expression patterns were associated with TP53 alterations. Gain of function variants and wild-type TP53 tended to exhibit type C and B p53 expression patterns, but loss of function variants were exclusively seen in type A cases. Additionally, interpretation of the staining by various observers produced significant reproducibility. Conclusions The p53 IHC expression patterns can be used to predict TP53 alterations and are reliable for diverse alteration types, making them possible surrogate biomarkers for TP53 alterations in LBCLs.

Abstract Objectives The purpose of this study was to develop and validate a radiomics nomogram for predicting thymidylate synthase (TYMS) status in hepatocellular carcinoma (HCC) by using Gd-DTPA contrast enhanced MRI. Methods We retrospectively enrolled 147 consecutive patients with surgically confirmed HCC and randomly allocated to training and validation set (7:3). The TYMS status was immunohistochemical determined and classified into low TYMS (positive cells ≤ 25%) and high TYMS (positive cells > 25%) groups. Radiomics features were extracted from the arterial phases and portal venous phase of Gd-DTPA contrast enhanced MRI. Least absolute shrinkage and selection operator (LASSO) were applied for generating the Rad score. Clinical data and MRI findings were assessed to build a clinical model. Rad score combined with clinical features was used to construct radiomics nomogram. Results A total of 2260 features were extracted and reduced to 7 features as the most important discriminators to build the Rad score. InAFP was identified as the only independent clinical factors for TYMS status. The radiomics nomogram showed good discrimination in training (AUC, 0.759; 95% CI 0.665–0.838) and validation set (AUC, 0.739; 95% CI 0.585–0.860), and showed better discrimination capability (P

Abstract Background The role of guanylate‐binding proteins (GBPs) in various cancers has been elucidated recently. However, our knowledge of the clinical relevance and biological characteristics of GBPs in hepatocellular carcinoma (HCC) remains limited. Methods A total of 955 HCC patients were enrolled from five independent public HCC cohorts. The role of GBP molecules in HCC was preliminarily investigated, and a GBP family signature, termed GBPs‐score, was constructed by principal component analysis to combine the GBP molecule values. We revealed the effects of GBP genes and GBPs‐score in HCC via well‐established bioinformatics methods and validated GBP1‐5 experimentally in a tissue microarray (TMA) cohort. Results GBPs molecules were closely associated with the prognosis of patients with HCC, and a high GBPs‐score highly inferred a favorable survival outcome. We also revealed high GBPs‐score was related to anti‐tumor immunity, the immune‐hot tumor microenvironment (TME), and immunotherapy response. Among the GBPs members, GBP1‐5 rather than GBP6/7 may be dominant in these fields. The TMA analysis based on immunohistochemistry showed positive correlations between GBP1‐5 and the immune‐hot TME with abundant infiltration of CD8+ T cells in HCC. Conclusions Our integrative study revealed the genetic and immunologic characterizations of GBPs in HCC and highlighted their potential values as promising biomarkers for prognosis and immunotherapy.

Abstract Objective To investigate the differences in efficacy and safety between haploidentical donor hematopoietic stem cell transplantation (HID‐HSCT) and matched sibling donor HSCT (MSD‐HSCT) in patients with T‐cell lymphoblastic lymphoma (T‐LBL). Methods In this retrospective analysis, we enrolled 38 patients who had undergone allogeneic HSCT at our institution between 2013 and 2021. The study participants included 28 patients who underwent HID‐HSCT and 10 patients who underwent MSD‐HSCT. We compared the patient characteristics and treatment effectiveness and safety between the two groups and evaluated potential prognostic variables for patients with T‐LBL. Results The median follow‐up durations in the HID‐HSCT and MSD‐HSCT groups were 23.5 (range: 4–111) and 28.5 (range: 13–56) months, respectively. All patients showed full‐donor chimerism after hematopoietic stem cell transplantation (HSCT). Except for two patients in the HID‐HSCT cohort who developed poor graft function, all patients showed neutrophil and platelet engraftments after HSCT. The cumulative incidences of grades III–IV acute graft‐versus‐host disease were 37.5% and 28.57% in the HID‐HSCT and MSD‐HSCT groups, respectively (p = 0.84). The cumulative incidences of limited (34.13% vs. 28.57%, p = 0.82) and extensive (31.22% vs. 37.50%, p = 0.53) chronic graft‐versus‐host disease did not differ between the two cohorts. In the HID‐HSCT and MSD‐HSCT cohorts, the estimated 2‐year overall survival rates were 70.3% (95% confidence interval [CI]: 54.9%–90.0%) and 56.2% (95% CI: 31.6%–100%), respectively (p = 1.00), and the estimated 2‐year progression‐free survival (PFS) rates were 48.5% (95% CI: 32.8%–71.6%) and 48.0% (95% CI: 24.6%–93.8%), respectively (p = 0.94). Furthermore, the Cox proportional‐hazards model showed that a positive positron emission tomography/computed tomography (PET/CT) status before HSCT in patients who had completed chemotherapy was an independent risk factor for PFS in the multivariate analysis (p = 0.0367). Conclusion This study showed that HID‐HSCT had comparable effectiveness and safety to MSD‐HSCT in treating T‐LBL. HID‐HSCT could serve as an alternate treatment option for T‐LBL in patients without an eligible identical donor. Achievement of the PET/CT‐negative status before HSCT may contribute to better survival.

Conclusion: In conclusion, this study provides evidence of a causal relationship between mitochondrial function and breast cancer in both European and East Asian populations. Additional research is warranted to further elucidate the mechanisms underlying this association.

Abstract Background Anaplastic lymphoma kinase (ALK) overexpression and gene alterations have been detected in several mesenchymal tumors, with significant implications for diagnosis, therapy and prognosis. However, few studies have investigated the correlation between ALK expression status and clinicopathological characteristics in patients with gastrointestinal stromal tumors (GISTs). Methods A total of 506 GIST patients were enrolled. Sanger sequencing was employed to detect c-KIT and PDGFRA gene mutations. The tissue microarray (TMA) technique and immunohistochemistry were employed to identify the ALK (clone: 1A4 and D5F3) expression status in the tumor tissues. The ALK gene variants of IHC-positive cases were analyzed by fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS). The clinicopathological data were analyzed using SPSS Statistics 26.0. Results Among the 506 GIST patients, the c-KIT mutation accounted for 84.2% (426/506), followed by PDGFRA mutation (10.3%, 52/506), while the wild-type accounted for the least (5.5%, 28/506). ALK-positive expression was detected in PDGFRA-mutant GISTs (7.7%, 4/52) but negative for c-KIT-mutant or wild-type GISTs by IHC. Four ALK IHC-positive patients were all male. The tumors all occurred outside the stomach. The predominant patterns of growth were epithelioid (2/4), spindle (1/4), and mixed type (1/4). They were all identified as high-risk classification according to the National Institutes of Health (NIH) classification. Aberrant ALK mutations were not identified by DNA-based NGS except in one of the 4 cases with amplification by FISH. Conclusion Our study revealed 7.7% (4/52) of ALK expression in PDGFRA-mutant GISTs, indicating that molecular tests were required to rule out the possibility of PDGFRA-mutant GISTs when encountering ALK-positive mesenchymal tumors with CD117-negative or weakly positive in immunohistochemical staining.

Abstract Objective To explore the criteria, safety and efficacy of laparoscopic surgery in pediatric neuroblastoma (NB). Methods A retrospective study of 87 patients with NB without image-defined risk factors (IDRFs) between December 2016 and January 2021 at Beijing Children’s Hospital was conducted. Patients were divided into two groups according to the surgical procedure. Results Between the 87 patients, there were 54 (62.07%) cases in the open surgery group and 33 (37.93%) cases in the laparoscopic surgery group. There were no significant differences between the two groups regarding demographic characteristics, genomic and biological features, operating time or postoperative complications. However, in terms of intraoperative bleeding (p = 0.013) and the time to start postoperative feeding after surgery (p = 0.002), the laparoscopic group was obviously better than the open group. Furthermore, there was no significant difference in the prognosis between the two groups, and no recurrence or death was observed. Conclusion For children with localized NB who have no IDRFs, laparoscopic surgery could be performed safely and effectively. Surgeons who are skilled in this can help children reduce surgical injuries, speed up postoperative recovery, and obtain the same prognosis as open surgery.

Abstract Background Inflammation is implicated in tumorigenesis and has been reported as an important prognostic factor in cancers. In this study, we aimed to develop and validate a novel inflammation score (IFS) system based on 12 inflammatory markers and explore its impact on intrahepatic cholangiocarcinoma (ICC) survival after hepatectomy. Methods Clinical data of 446 ICC patients undergoing surgical treatment were collected from the Primary Liver Cancer Big Data, and then served as a training cohort to establish the IFS. Furthermore, an internal validation cohort including 175 patients was used as internal validation cohort of the IFS. A survival tree analysis was used to divide ICC patients into three groups (low-, median-, and high- IFS-score groups) according to different IFS values. Kaplan-Meier (KM) curves were used to compare the overall survival (OS) and recurrence-free survival (RFS) rates among three different groups. Cox regression analyses were applied to explore the independent risk factors influencing OS and RFS. Results In the training cohort, 149 patients were in the low-IFS-score group, 187 in the median-IFS-score group, and 110 in the high-IFS-score group. KM curves showed that the high-IFS-score group had worse OS and RFS rates than those of the low- and median-IFS-score groups (P

Abstract Objective To study the feasibility, safety, and efficacy of thoracoscopic surgery in the treatment of pediatric mediastinal neurogenic tumors, and summarize the treatment experiences and surgical skills. Methods A single‐center retrospective analysis of 37 patients with pediatric mediastinal neurogenic tumors was conducted. Clinical charactersistics and postoperative complications were all analyzed. Results All the operations were successfully completed. There was no statistically significant difference in tumor diameter between the two groups (p > 0.05). The open surgery group had an average operation time of 96.5 ± 32.38 min, while the thoracoscopic surgery group had an average operation time of 78.3 ± 24.51 min (p

Abstract Background Pulmonary sarcomatoid carcinoma (PSC) is a rare and unconventional non-small-cell lung cancer (NSCLC) that appears to be aggressive, with a poor prognosis and response to conventional treatment. Approximately 30% of PSCs have potentially targetable genomic alterations, but few studies have involved RET gene fusions, and corresponding targeted therapies are lacking. Case presentation In this report, we describe a patient with PSC harboring a KIF5B-RET gene fusion who was initially diagnosed with stage IVb lung cancer. Due to the poor performance status, the patient was unable to tolerate any radiotherapy or chemotherapy. Based on the next-generation sequencing (NGS) result of RET gene fusion, the patient was treated with pralsetinib. Two months after the treatment, the patient achieved a partial response. Conclusions Our case indicates that RET is one of the main driver oncogenes of PSC and provides useful information for precise RET inhibitor administration in the future. Thus, the use of comprehensive genomic profiling may provide important treatment options for PSC.

Abstract Little is known on the relationship between the expression of pyroptosis related genes (PRGs) and prognosis of hepatocellular carcinoma (HCC). In this study, a specific PRGs prognostic model was developed with an aim to improve therapeutic efficiency among HCC patients. In total, 42 PRGs that were differentially expressed between HCC tissues and adjacent tissues and we exhibited the mutation frequency, classification, the location of copy number variation (CNV) alteration and the CNV variation frequency of PRGs. Two clusters were distinguished by the consensus clustering analysis based on the 42 differentially expressed genes (DEGs). There were significant differences in clinical features including T stage, grade, gender, and stage among different clusters. Kaplan–Meier curve analysis showed that cluster 1 had a better prognosis than cluster 2. The prognostic value of PRGs for survival was evaluated to construct a multigene signature using The Cancer Genome Atlas (TCGA) cohort. Based on the univariate analysis and multivariate analysis, a 10-gene signature was built and all HCC patients in the TCGA cohort were divided into low-risk group and high-risk group. HCC patients in the high-risk group showed significantly lower survival possibilities than those in the low-risk group (P

Abstract Background The accuracy of lymph node ratio (LNR) as a prognostic index remains to be proven for gastric cancer patients after neoadjuvant chemotherapy (NACT). This study sought to investigate the prognostic value of LNR in locally advanced gastric cancer (LAGC) patients after NACT. Methods LAGC patients with clinical TNM stages 2–3, Her2(−), and Eastern Cooperative Oncology Group, scores 0–2 are routinely scheduled with NACT. Patients with LAGC after NACT and surgical operation between January 2012 and October 2020 were retrospectively reviewed. The correlation between LNR and survival was investigated. Results Overall, 148 patients were enrolled: 103 with low-LNR (LNR ≤ 30%) and 45 with high-LNR (LNR > 30%). Approximately, 50.5% and 24.4% patients responded to NACT at the primary site in the low-LNR and high-LNR groups, respectively. The overall survival (OS) and progression-free survival (PFS) of low-LNR group were considerably better than those of high-LNR group (3-year OS: 81.9% vs 18.5%, P < 0.001; 3-year PFS: 72.6% vs 13.5%, P < 0.001). In the low-LNR group, OS and PFS were superior in patients with tumor regression grade (TRG) 0–2 than in those with TRG 3 (3-year OS: 89.2% vs 73.2%, P = 0.086; 3-year PFS: 80.3% vs 66.5%, P = 0.036). In association with OS and PFS, the degree of tumor differentiation, TRG, and LNR were identified as predictive factors, and LNR was identified as the independent prognostic factor in univariate and multivariate analyses, respectively. Conclusions LNR is a prospective index of prognosis in patients with LAGC after NACT.

ObjectiveNeuronavigation and classification of craniopharyngiomas can guide surgical approaches and prognostic information. The QST classification has been developed according to the origin of craniopharyngiomas; however, accurate preoperative automatic segmentation and the QST classification remain challenging. This study aimed to establish a method to automatically segment multiple structures in MRIs, detect craniopharyngiomas, and design a deep learning model and a diagnostic scale for automatic QST preoperative classification.MethodsWe trained a deep learning network based on sagittal MRI to automatically segment six tissues, including tumors, pituitary gland, sphenoid sinus, brain, superior saddle cistern, and lateral ventricle. A deep learning model with multiple inputs was designed to perform preoperative QST classification. A scale was constructed by screening the images.ResultsThe results were calculated based on the fivefold cross-validation method. A total of 133 patients with craniopharyngioma were included, of whom 29 (21.8%) were diagnosed with type Q, 22 (16.5%) with type S and 82 (61.7%) with type T. The automatic segmentation model achieved a tumor segmentation Dice coefficient of 0.951 and a mean tissue segmentation Dice coefficient of 0.8668 for all classes. The automatic classification model and clinical scale achieved accuracies of 0.9098 and 0.8647, respectively, in predicting the QST classification.ConclusionsThe automatic segmentation model can perform accurate multi-structure segmentation based on MRI, which is conducive to clearing tumor location and initiating intraoperative neuronavigation. The proposed automatic classification model and clinical scale based on automatic segmentation results achieve high accuracy in the QST classification, which is conducive to developing surgical plans and predicting patient prognosis.

Purpose: In recent years, a rising number of multiple primary lung cancers have been detected with the advancement of imaging technology. No detailed study has assessed the prognosis of multiple primary lung adenocarcinomas based on computed tomography characteristics. The present study aimed to analyze outcomes and determine valuable factors for predicting the prognosis of multiple primary lung adenocarcinoma. Methods: This single-center retrospective study was performed from January 2013 to October 2021. All patients were divided into 3 groups based on tumor density as follows: multi-pure ground-glass nodules, at least one part-solid nodule without solid nodules, and at least one solid nodule. Clinicopathologic features, computed tomography signs, and survival outcomes were compared between these groups. The Kaplan-Meier method was used for survival analysis. The multivariable Cox proportional hazards regression model was used to identify independent predictors for recurrence-free survival and overall survival. Results: The sample included 283 patients with 623 lesions who met the inclusion criteria for multiple primary lung adenocarcinoma. Of these patients, 71 (25.1%) presented with multi-pure ground-glass nodules, 100 (35.3%) with at least one part-solid nodule without solid nodule, and 112 (39.6%) with at least one solid nodule. The 3 groups had distinguished clinicopathologic and radiological features of age, adjuvant therapy, types of tumor resection, TNM stage, pathological subtypes, pleural indentation, spicule, and vacuole (all P

Purpose/backgroundMicrosatellite instability (MSI) status is a significant biomarker for the response to immune checkpoint inhibitors, response to 5-fluorouracil-based adjuvant chemotherapy, and prognosis in colorectal carcinoma (CRC). This study investigated the predictive value of intratumoral-metabolic heterogeneity (IMH) and conventional metabolic parameters derived from 18F-FDG PET/CT for MSI in patients with stage I–III CRC.MethodsThis study was a retrospective analysis of 152 CRC patients with pathologically proven MSI who underwent 18F-FDG PET/CT examination from January 2016 to May 2022. Intratumoral-metabolic heterogeneity (including heterogeneity index [HI] and heterogeneity factor [HF]) and conventional metabolic parameters (standardized uptake value [SUV], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) of the primary lesions were determined. MTV and SUVmean were calculated on the basis of the percentage threshold of SUVs at 30%–70%. TLG, HI, and HF were obtained on the basis of the above corresponding thresholds. MSI was determined by immunohistochemical evaluation. Differences in clinicopathologic and various metabolic parameters between MSI-High (MSI-H) and microsatellite stability (MSS) groups were assessed. Potential risk factors for MSI were assessed by logistic regression analyses and used for construction of the mathematical model. Area under the curve (AUC) were used to evaluate the predictive ability of factors for MSI.ResultsThis study included 88 patients with CRC in stages I–III, including 19 (21.6%) patients with MSI-H and 69 (78.4%) patients with MSS. Poor differentiation, mucinous component, and various metabolic parameters including MTV30%, MTV40%, MTV50%, and MTV60%, as well as HI50%, HI60%, HI70%, and HF in the MSI-H group were significantly higher than those in the MSS group (all P < 0.05). In multivariate logistic regression analyses, post-standardized HI60% by Z-score (P = 0.037, OR: 2.107) and mucinous component (P < 0.001, OR:11.394) were independently correlated with MSI. AUC of HI60% and our model of the HI60% + mucinous component was 0.685 and 0.850, respectively (P = 0.019), and the AUC of HI30% in predicting the mucinous component was 0.663.ConclusionsIntratumoral-metabolic heterogeneity derived from 18F-FDG PET/CT was higher in MSI-H CRC and predicted MSI in stage I–III CRC patients preoperatively. HI60% and mucinous component were independent risk factors for MSI. These findings provide new methods to predict the MSI and mucinous component for patients with CRC.

IntroductionCentral lymph node metastasis (CLNM) is common in papillary thyroid carcinoma (PTC). Prophylactic central lymph node dissection (PCLND) in clinically negative central compartment lymph node (cN0) PTC patients is still controversial. How to predict CLNM before the operation is very important for surgical decision making.MethodsIn this article, we retrospectively enrolled 243 cN0 PTC patients and gathered data including clinical characteristics, ultrasound (US) characteristics, pathological results of fine-needle aspiration (FNA), thyroid function, eight gene mutations, and immunoenzymatic results. Least absolute shrinkage and selection operator (LASSO) analysis was used for data dimensionality reduction and feature analysis.ResultsAccording to the results, the important predictors of CLNM were identified. Multivariable logistic regression analysis was used to establish a new nomogram prediction model. The receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) curve were used to evaluate the performance of the new prediction model.DiscussionThe new nomogram prediction model was a reasonable and reliable model for predicting CLNM in cN0 PTC patients, but further validation is warranted.

Abstract Objective We explored the impact of clinically significant portal hypertension (CSPH) on short‐ and long‐term outcomes of intrahepatic cholangiocarcinoma (ICC) after liver resection (LR). Methods Data of 352 ICC patients with cirrhosis who underwent LR were extracted from the Primary Liver Cancer Big Data (PLCBD) between 2005 and 2015 and reviewed. A nomogram based on logistic analyses was developed to illustrate the influencing factors of post‐hepatectomy liver failure (PHLF). The impact of CSPH on long‐term survival was explored through propensity score matching (PSM) analysis, log‐rank test, Cox proportional hazards model, and Kaplan–Meier curves. Results A total of 106 patients had CSPH, and 246 patients did not. A nomogram established based on GGT level, CSPH, intraoperative blood loss, and multiple tumors had an area under the receiver operating characteristic curve of 0.721 (95% confidence interval [CI] = 0.630–0.812), which displayed a better PHLF predictive value than the MELD score (0.639, 95% CI = 0.532–0.747) and Child–Pugh score (0.612, 95% CI = 0.506–0.719). Moreover, the patients with CSPH had worse overall survival (OS) rates than the patients without CSPH in the whole cohort (p = 0.011) and PSM cohort (p = 0.017). After PSM, multivariable Cox analyses identified that CSPH was an independent risk factor for OS (hazard ratio = 1.585, 95% CI = 1.107–2.269; p = 0.012). Conclusion CSPH is a significant risk factor for PHLF and OS in ICC patients with cirrhosis after surgery. Selecting the proper patients before operation can effectively avoid PHLF and improve the prognosis of ICC.

Abstract Background LYRM4 is necessary to maintain the stability and activity of the human cysteine desulfurase complex NFS1-LYRM4-ACP. The existing experimental results indicate that cancer cells rely on the high expression of NFS1. However, the role of LYRM4 in liver hepatocellular carcinoma (LIHC) remains unclear. Methods In this study, we combined bioinformatics analysis and clinical specimens to evaluate the mRNA, protein expression, and gene regulatory network of LYRM4 in LIHC. Furthermore, we detected the activity of several classical iron-sulphur proteins in LIHC cell lines through UV-vis spectrophotometry. Results The mRNA and protein levels of LYRM4 were upregulated in LIHC. Subsequent analysis revealed that the LYRM4 mRNA expression was related to various clinical stratifications, prognosis, and survival of LIHC patients. In addition, the mRNA expression of LYRM4 was significantly associated with ALT, tumour thrombus, and encapsulation of HBV-related LIHC patients. IHC results confirmed that LYRM4 was highly expressed in LIHC tissues and showed that the expression of LYRM4 protein in LIHC was significantly correlated with age and serum low-density lipoprotein (LDL) and triglyceride (TG) content. In particular, the mRNA expression of key iron- sulphur proteins POLD1 and PRIM2 was significantly overexpressed and correlated with poor prognosis in LIHC patients. Compared with hepatocytes, the activities of mitochondrial complex I and aconitate hydratase (ACO2) in LIHC cell lines were significantly increased. These results indicated that the iron-sulphur cluster (ISC) biosynthesis was significantly elevated in LIHC, leading to ISC-dependent metabolic reprogramming. Changes in the activity of ISC-dependent proteins may also occur in paracancerous tissues. Further analysis of the biological interaction and gene regulation networks of LYRM4 suggested that these genes were mainly involved in the citric acid cycle and oxidative phosphorylation. Finally, LYRM4 expression in LIHC was significantly positively correlated with the infiltrating levels of six immune cell types, and both factors were strongly associated with prognosis. Conclusion LYRM4 could be a novel prognostic biomarker and molecular target for LIHC therapy. In particular, the potential regulatory networks of LYRM4 overexpression in LIHC provide a scientific basis for future research on the role of the ISC assembly mechanism and LYRM4-mediated sulphur transfer routes in carcinogenesis.

Background and purposeVarious operative methods are used for reconstructing pelvic girdle after resection of primary malignant periacetabular tumor has been reported. The objective of this study was to evaluate the accuracy, effectiveness, and safety of customized three dimensional-printed prosthesis (3DP) in the reconstruction of bone defects compared with conventional reconstruction using the screw-rod-cage system.MethodsA retrospective case–control analysis of 40 patients who underwent pelvic tumor resection and reconstruction with a customized 3D-printed prosthesis (3DP), or screw-rod-cage system (SRCS) between January 2010 and December 2019 was performed. The minimum follow-up time for patients alive was 2 years. Blood loss, operation time, complications, surgical margin, local recurrence, distant metastases, status at time of latest follow-up, MSTS-93 score, Harris hip score, and postoperative radiographic parameters were recorded. Moreover, overall survival, tumor-free survival, and prosthesis survival rates in both groups were compared.ResultsCustomized 3DP reconstruction was performed in 15 patients, and SRCS reconstruction was done in 25 patients. The group of patients treated with customized 3DP reconstruction had significantly shorter operation time (323.7 ± 83.7 vs. 393.6 ± 98.8 min; P = 0.028) and more precise (all P < 0.05) radiographic reconstruction parameters than patients in the SRCS group. Fewer complications (P = 0.026), better MSTS score (P = 0.030), and better Harris hip score (P = 0.016) were achieved in the 3DP group. Furthermore, the survival rate of prosthesis was also significantly better in the 3DP group (P = 0.039). However, blood loss, surgical margin, local recurrence, distant metastases, and status at time of latest follow-up had no significant difference between two groups.ConclusionCompared with the screw-rod-cage system reconstruction, the customized 3D-printed prosthesis reconstruction is equally safe and effective, but it is more accurate and time-saving and is associated with fewer complications.

BackgroundGastrointestinal stromal tumours (GISTs) rarely arise in the esophagus. The clinical course and treatment options for esophageal GISTs are poorly understood because of their rarity. In general, the mutation spectrum of esophageal GISTs resembles that of gastric GISTs. Wild-type (WT) GISTs lacking KIT and PDGFRA gene mutations occasionally occur in adults; primary esophageal GISTs are commonly WT.Case presentationHerein, we report the case of a 41-year-old female patient who presented with a 1-week history of anterior upper chest pain. Chest computed tomography revealed a 3.7 cm × 2.8 cm × 6.7 cm soft tissue mass in the right posterior mediastinum adjacent to the esophagus. The patient underwent thoracoscopic mediastinal tumor resection and was subsequently diagnosed with an esophageal GIST. Neither KIT nor PDGFRA mutations were detected by Sanger sequencing; however, next-generation sequencing (NGS) identified an FGFR2-KIAA1217 gene fusion in the tumor tissue. No relapse was observed in this patient during the 8-month treatment-free follow-up period.ConclusionTo the best of our knowledge, this report is the first to describe an FGFR2-KIAA1217 fusion in a patient with a quadruple WT esophageal GIST. When WT KIT/PDGFRA GISTS are suspected, intensive genetic analysis is recommended, and obtaining a better molecular characterization of these tumours might reveal novel therapeutic avenues.

We report a rare case of spontaneous biliary pleural fistula in a patient whose diagnosis was aided by the use of near-infrared I/II fluorescence imaging. When both 99mTc-mebrofenin hepatobiliary scintigraphy and CT examination were diagnostically difficult, we found strong fluorescent signals in the patient’s pleural drainage fluid and sputum using NIR I/II fluorescence imaging, and therefore diagnosed the patient with a biliary pleural fistula. This provides a safe and effective test for diagnosing biliary pleural fistulas.

Ribonucleotide reductase (RNR) is the key enzyme that catalyzes the production of deoxyribonucleotides (dNTPs) for DNA replication and it is also essential for cancer cell proliferation. As the RNR inhibitor, Gemcitabine is widely used in cancer therapies, however, resistance limits its therapeutic efficacy and curative potential. Here, we identified that mTORC2 is a main driver of gemcitabine resistance in non-small cell lung cancers (NSCLC). Pharmacological or genetic inhibition of mTORC2 greatly enhanced gemcitabine induced cytotoxicity and DNA damage. Mechanistically, mTORC2 directly interacted and phosphorylated RNR large subunit RRM1 at Ser 631. Ser631 phosphorylation of RRM1 enhanced its interaction with small subunit RRM2 to maintain sufficient RNR enzymatic activity for efficient DNA replication. Targeting mTORC2 retarded DNA replication fork progression and improved therapeutic efficacy of gemcitabine in NSCLC xenograft model in vivo. Thus, these results identified a mechanism through mTORC2 regulating RNR activity and DNA replication, conferring gemcitabine resistance to cancer cells.

Abstract Purpose We aimed to develop and validate a radiomics model for differentiating hepatocellular carcinoma (HCC) from focal nodular hyperplasia (FNH) in non-cirrhotic livers using Gd-DTPA contrast-enhanced magnetic resonance imaging (MRI). Methods We retrospectively enrolled 149 HCC and 75 FNH patients treated between May 2015 and May 2019 at our center. Patients were randomly allocated to a training (n=156) and validation set (n=68). In total, 2260 radiomics features were extracted from the arterial phase and portal venous phase of Gd-DTPA contrast-enhanced MRI. Using Max-Relevance and Min-Redundancy, random forest, least absolute shrinkage, and selection operator algorithm for dimensionality reduction, multivariable logistic regression was used to build the radiomics model. A clinical model and combined model were also established. The diagnostic performance of the models was compared. Results Eight radiomics features were chosen for the radiomics model, and four clinical factors (age, sex, HbsAg, and enhancement pattern) were chosen for the clinical model. A combined model was built using the factors from the previous models. The classification accuracy of the combined model differentiated HCC from FNH in both the training and validation sets (0.956 and 0.941, respectively). The area under the receiver operating characteristic curve of the combined model was significantly better than that of the clinical model for both the training (0.984 vs. 0.937, p=0.002) and validation (0.972 vs. 0.903, p=0.032) sets. Conclusions The combined model provided a non-invasive quantitative method for differentiating HCC from FNH in non-cirrhotic liver with high accuracy. Our model may assist clinicians in the clinical decision-making process.

ObjectivesSpread through air spaces (STAS), a new invasive pattern in lung adenocarcinoma (LUAD), is a risk factor for poor outcome in early-stage LUAD. This study aimed to develop and validate a CT-based radiomics model for predicting STAS in stage IA LUAD.MethodsA total of 395 patients (169 STAS positive and 226 STAS negative cases, including 316 and 79 patients in the training and test sets, respectively) with stage IA LUAD before surgery were retrospectively included. On all CT images, tumor size, types of nodules (solid, mix ground-glass opacities [mGGO] and pure GGO [pGGO]), and GGO percentage were recorded. Region of interest (ROI) segmentation was performed semi-automatically, and 1,037 radiomics features were extracted from every segmented lesion. Intraclass correlation coefficients (ICCs), Pearson’s correlation analysis and least absolute shrinkage and selection operator (LASSO) penalized logistic regression were used to filter unstable (ICC < 0.75) and redundant features (r > 0.8). A temporary model was established by multivariable logistic regression (LR) analysis based on selected radiomics features. Then, seven radiomics features contributing the most were selected for establishing the radiomics model. We then built two predictive models (clinical-CT model and MixModel) based on clinical and CT features only, and the combination of clinical-CT and Rad-score, respectively. The performances of these three models were assessed.ResultsThe radiomics model achieved good performance with an area under of curve (AUC) of 0.812 in the training set, versus 0.850 in the test set. Furthermore, compared with the clinical-CT model, both radiomics model and MixModel showed higher AUC and better net benefit to patients in the training and test cohorts.ConclusionThe CT-based radiomics model showed satisfying diagnostic performance in early-stage LUAD for preoperatively predicting STAS, with superiority over the clinical-CT model.

Zanubrutinib, a next-generation non-covalent Bruton’s tyrosine kinase (BTK) inhibitor, shows great efficacy in the treatment of B cell malignancies. Some patients may experience a series of side effects after the treatment of zanubrutinib. Grade 4 dermatological toxicities are rare, which present as severe rash and skin infection. Herein, we retrospectively reported the grade 4 dermatological toxicities of zanubrutinib in three consecutive patients. They were treated with zanubrutinib 160 mg twice daily orally. One patient was diagnosed with Primary Breast Diffuse Large B-cell Lymphoma(PB-DLBCL) and two patients were diagnosed with Chronic Lymphocytic Leukemia(CLL). Within one month after zanubrutinib treatment, all three patients developed grade 4 dermatological toxicities, including bruising, maculopapular rash, petechiae, ecchymosis, hemorrhagic blister, acne-Like rash, papulopustular rash, and skin infections. Zanubrutinib was discontinued in two patients due to unacceptable dermatological toxicities. Safety data from pre-licensing clinical trials showed that zanubrutinib-related side effects were frequent but well tolerated. To date, no severe dermatological toxicities were reported. The majority of patients can be relieved with symptomatic treatment, but a very small percentage of patients may face discontinuation of the drug.

Abstract Background An accurate intraoperative prediction of lymph node metastatic risk can help surgeons in choosing precise surgical procedures. We aimed to develop and validate nomograms to intraoperatively predict patterns of regional lymph node (LN) metastasis in patients with esophageal cancer. Methods The prediction model was developed in a training cohort consisting of 487 patients diagnosed with esophageal cancer who underwent esophagectomy with complete LN dissection from January 2016 to December 2016. Univariate and multivariable logistic regression were used to identify independent risk factors that were incorporated into a prediction model and used to construct a nomogram. Contrast-enhanced computed tomography reported LN status and was an important comparative factor of clinical usefulness in a validation cohort. Nomogram performance was assessed in terms of calibration, discrimination, and clinical usefulness. An independent validation cohort comprised 206 consecutive patients from January 2017 to December 2017. Results Univariate analysis and multivariable logistic regression revealed three independent predictors of metastatic regional LNs, three independent predictors of continuous regional LNs, and two independent predictors of skipping regional LNs. Independent predictors were used to build three individualized prediction nomograms. The models showed good calibration and discrimination, with area under the curve (AUC) values of 0.737, 0.738, and 0.707. Application of the nomogram in the validation cohort yielded good calibration and discrimination, with AUC values of 0.728, 0.668, and 0.657. Decision curve analysis demonstrated that the three nomograms were clinically useful in the validation cohort. Conclusion This study presents three nomograms that incorporate clinicopathologic factors, which can be used to facilitate the intraoperative prediction of metastatic regional LN patterns in patients with esophageal cancer.

Abstract Background In multiple primary lung adenocarcinomas (MPLAs), the relationship between imaging and gene mutations remains unclear. This retrospective study aimed to identify the correlation of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) status with CT characteristics in MPLA patients. Methods Sixty-seven patients (135 lesions) with MPLAs confirmed by pathology were selected from our institution. All subjects were tested for EGFR mutations and ALK status and underwent chest CT prior to any treatment. The criteria for MPLA definitions closely adhered to the comprehensive histologic assessment (CHA). Results Among MPLA patients, EGFR mutations were more common in females (p = 0.002), in those who had never smoked (p = 0.010), and in those with less lymph node metastasis (p

A 71-year-old woman was diagnosed with advanced gastroesophageal junction cancer with bulky lymph nodes along the cardiac region and the lower mediastinum (GE-Circ type 3 T3 N3 M0 H0 stage III) and received treatment with S-1 and oxaliplatin (SOX) as first-line chemotherapy. After 3 cycles of SOX, severe anorexia and diarrhea were observed. We converted from this regimen of systemic chemotherapy to ramucirumab (RAM) monotherapy as second-line chemotherapy. This treatment resulted in a reduction in size of the metastatic lymph nodes along the cardiac region and the lower mediastinum. However, progression of lymph node metastasis and the primary tumor was observed following 7 months of RAM monotherapy. Therefore, nivolumab was initiated as third-line chemotherapy 14 months after the initial treatment. After 3 months of nivolumab administration, a 47% reduction in metastatic lymph nodes was achieved and a regression of the primary gastric tumor as seen on an enhanced computed tomography scan. After 7 months of nivolumab monotherapy, the diameter of the target lymph nodes had reduced by 81% from baseline, and there was no evidence of malignancy upon pathological assessment of the primary tumor site biopsy. The patient survived with nivolumab monotherapy for approximately 2 years after her first visit, without any adverse reaction to nivolumab.

Abstract Background The presence of microvascular invasion (MVI) in intrahepatic cholangiocarcinoma (ICC) is a significant adverse prognostic factor. This study sought to investigate the correlation between preoperative imaging parameters and MVI in ICC. Methods A total of 108 patients with surgically resected single ICC tumors (34 MVI-positive and 74 MVI-negative lesions) who underwent MRI examination, including T1WI, T2WI, DWI, and dynamic enhancement imaging, were enrolled in this retrospective study. The following qualitative and quantitative characteristics were evaluated: tumor morphology, signal features on T1WI and T2WI, intrahepatic duct dilatation, hepatic capsule retraction, target sign on DWI, dynamic enhancement pattern, arterial phase enhancement pattern, dot−/band-like enhancement inside the tumor, visible vessel penetration inside the tumor (hepatic artery, portal vein, or hepatic vein), integrity of the enhancement edge of the arterial phase, peripheral hepatic enhancement, tumor size, maximum enhancement edge thickness, arterial edge enhancement ratio, and delayed phase enhancement ratio. Other clinicopathological features were also used to predict and evaluate MVI in ICC. Chi-square test, Fisher’s exact test, and independent t-test were used for univariate analysis to determine the relationships among the presence of MVI and these MR parameters. Logistic regression analysis was used to identify predictors of MVI among these MR parameters. Results Among MRI characteristics, tumor morphology, intrahepatic duct dilatation, arterial phase enhancement pattern, visible hepatic artery penetration sign, maximum diameter of the tumor and the arterial phase edge enhancement ratio were correlated with MVI (P = 0.007, 0.003, 0.008, 0.000, 0.003, and 0.002, respectively). Furthermore, higher CA19–9 levels (≥37 U/ml) and pathological tumor grade III were also related to MVI (P = 0.014 and 0.004, respectively). However, multivariate logistic regression analysis demonstrated that none of the parameters were independent risk factors for the diagnosis of MVI in ICCs. Conclusion For the preoperative prediction of MVI in ICC, six qualitative and quantitative data obtained on preoperative MRI, as well as one tumorigenic marker and the pathological tumor grade, were statistically significant. More research is needed to identify MR characteristics that can be used as independent risk factors.

Abstract Background Vaccinia viruses have emerged as attractive therapeutic candidates for cancer treatment due to their inherent ability of tumor tropism and oncolytic property. Cytosine deaminase (CD), which is derived from bacteria or yeast, can convert a relatively nontoxic prodrug 5-fluorocytosine (5-FC) into the active anticancer drug 5-Fluorouracil (5-FU). Vaccinia virus armed with the prodrug-activator CD gene would result in augmented antitumor effects that combined the effect of vaccinia virus and 5-FU together, and particularly limited the anticancer drug to tumor regions. Methods The attenuated vaccinia Tian Tan strain Guang 9 (VG9), with active yeast CD expression and thymidine kinase (TK) deficiency, was successfully constructed. Then, in vitro and in vivo antitumor efficacy of vaccinia VG9-CD plus 5-FC administration was evaluated in colorectal cancer cells. Results Vaccinia viruses displayed different oncolytic potency in vitro cells, no relationship with whether they were cancer cells or normal cells. In colorectal tumor models, mice treated with vaccinia VG9-TK− showed better tumor remission ability and prolonged survival. Moreover, vaccinia VG9-CD in combination with gavage administration of 5-FC displayed the best antitumor efficacy, especially for the prolongation of survival. Conclusions Vaccinia VG9-CD in combination with 5-FC plays combined effect of vaccinia virus and chemotherapy, and becomes a promising virotherapy for cancer.

ObjectiveSeveral studies were conducted to explore the clinical significance of cyclooxygenase-2 (COX-2) overexpression in laryngeal cancer. However, the associations between COX-2 overexpression and clinicopathological characteristics of laryngeal cancer patients remained unclear. Here, we performed a meta-analysis to eva-TY -40luate the role of COX-2 overexpression in the risk, clinical progression, and progno\sis of laryngeal cancer.MethodsThe eligible literature was obtained from PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) databases. Odds ratio (OR), risk ratio (RR), and 95% confidence interval (CI) were calculated to assess the strength of the associations, and I2 statistics were used to evaluate heterogeneity among studies. Publication bias was detected with Begg’s test and Egger’s test.ResultsA total of 47 eligible articles were included for the meta-analysis after screening. COX-2 expression levels in the laryngeal cancer patients were significantly higher than those in the normal controls (OR = 11.62, 95% CI: 6.96–19.40, P < 0.05). The pooled results also showed that there were significant correlations between COX-2 overexpression and clinicopathological characteristics (tumor stage, OR = 3.26, 95% CI: 2.13–4.98, P < 0.05; lymph node metastasis, in Asians, OR = 2.35, 95% CI: 1.53–3.60, P < 0.05; recurrence, OR = 10.71, 95% CI: 3.54–32.38, P < 0.05; T stage, in Asians, OR = 2.52, 95% CI: 1.66–3.83, P < 0.05). In addition, significant correlations between COX-2 overexpression and overall survival of laryngeal cancer were found both in Asians and in Caucasians (total, HR = 1.73, 95% CI: 1.23–2.24, P < 0.05; survival in Asians, HR = 2.59, 95% CI: 1.27–3.92, P < 0.05; survival in Caucasians, HR = 1.59, 95% CI: 1.03–2.14, P < 0.05).ConclusionsThe meta-analysis results suggested that COX-2 overexpression was significantly associated with the increased risk, worse clinicopathological progression, and poorer prognosis of laryngeal cancer.

Introduction The prototype DNA hypomethylating agents 5-azacytidine (5AC) and decitabine (DAC) are currently FDA-approved for treatment of blood and bone marrow disorders like myelodysplastic syndrome. 5AC and DAC are considered similar drugs and were shown to induce histone modifications that modulate gene expression. The aim of this study is to compare the effect of both drugs on histone acetylation and methylation at multiple histone amino acids residues. Methods Mass spectrometry was used to compare the effect of both drugs on 95 different histone posttranslational modifications (PTMs) in leukemia cells. ChIP-Seq analysis was used to compare the impact of both drugs on the genome-wide acetylation of the H3K9 mark using primary leukemia cells from six de-identified AML patients. Results Both DAC and 5AC induced histone PTMs in different histone isoforms like H1.4, H2A, H3, H3.1, and H4. Changes in both histone methylation and acetylation were observed with both drugs; however, there were distinct differences in the histone modifications induced by the two drugs. Since both drugs were shown to increase the activity of the HDAC SIRT6 previously, we tested the effect of 5AC on the acetylation of H3K9, the physiological substrate SIRT6, using ChIP-Seq analysis and compared it to the previously published DAC-induced changes. Significant H3K9 acetylation changes ( P < .05) were detected at 925 genes after 5AC treatment vs only 182 genes after DAC treatment. Nevertheless, the gene set modified by 5AC was different from that modified by DAC with only ten similar genes modulated by both drugs. Conclusion Despite similarity in chemical structure and DNA hypomethylating activity, 5AC and DAC induced widely different histone PTMs and considering them interchangeable should be carefully evaluated. The mechanism of these histone PTM changes is not clear and may involve modulation of the activity or the expression of the enzymes inducing histone PTMs.

Interferon-induced protein 44-like (IFI44L), a type I interferon-stimulated gene (ISG), has been reported to be involved in innate immune processes and to act as a tumor suppressor in several cancers. However, its immune implication on lung cancer remains unclear. Here, we systemically analyzed the immune association of IFI44L with multiple tumor-infiltrating immune cells (TIICs) and immunomodulators through bioinformatics methods in The Cancer Genome Atlas (TCGA) lung cancer cohorts. Then, the IFI44L-related immunomodulators were selected to construct the prognostic signatures in the lung adenocarcinoma (LUAD) cohort and the lung squamous cell carcinoma (LUSC) cohort, respectively. Concordance index and time-dependent receiver operating characteristics (ROC) curves were applied to evaluate the prognostic signatures. GSE72094 and GSE50081 were used to validate the TCGA-LUAD signature and TCGA-LUSC signature, respectively. A nomogram was established by risk score and clinical features in the LUAD cohort. Finally, the prognostic value and biological function of IFI44L were verified in a real-world cohort and in vitro experiments. The results indicated that IFI44L showed significant correlation with TIICs in LUAD and LUSC samples. Functional enrichment analysis showed that IFI44L may participate in various cancer/immune-related pathways, including JAK/STAT signaling pathway and NF-κB signaling pathway. A total of 44 immunomodulators presented obvious association with IFI44L in the TCGA-LUAD cohort and a robust 10-immunomodulator signature was constructed. Patients in the higher-risk group presented worse prognosis than those in the lower-risk group. Notably, the risk signature was successfully validated in GSE72094. Multivariate Cox regression suggested that the risk signature could act as independent prognostic factors in both TCGA-LUAD and GSE72094 cohorts. Besides, a 17-immunomodulator signature was established in the TCGA-LUSC cohort and similar results were presented through analysis. The nomogram exhibited good accuracy in predicting overall survival (OS) outcome among TCGA-LUAD patients than the risk signature and other clinical features, with the area under curve values being 0.782 at 1 year, 0.825 at 3 years, and 0.792 at 5 years. Finally, tissue microarray analysis indicated that higher expression of IFI44L presented opposite relationship with pathological stage (p = 0.016) and a better outcome among lung cancer patients (p = 0.024). Functional experiments found that IFI44L overexpression significantly inhibited the proliferation, migration, and invasion in LUAD and LUSC cells; RT-qPCR experiments verified the correlation between the expression level of IFI44L with multiple immunomodulators in SPC-A-1 and NCI-H520 cells. In conclusion, our research highlighted that IFI44L is associated with tumor immune infiltration and provided information on IFI44L’s immune implication, which indicates that IFI44L has potential clinical immunotherapeutic value and the proposed nomogram is a promising biomarker for non-small cell lung cancer patients.