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Abstract Cancer has emerged as a formidable challenge in the 21st century, impacting society, public health, and the economy. Conventional cancer treatments often exhibit limited efficacy and considerable side effects, particularly in managing the advanced stages of the disease. Photodynamic therapy (PDT), a contemporary non-invasive therapeutic approach, employs photosensitizers (PS) in conjunction with precise light wavelengths to selectively target diseased tissues, inducing the generation of reactive oxygen species and ultimately leading to cancer cell apoptosis. In contrast to conventional therapies, PDT presents a lower incidence of side effects and greater precision in targeting. The integration of intelligent nanotechnology into PDT has markedly improved its effectiveness, as evidenced by the remarkable synergistic antitumor effects observed with the utilization of multifunctional nanoplatforms in conjunction with PDT. This paper provides a concise overview of the principles underlying PS and PDT, while also delving into the utilization of nanomaterial-based PDT in the context of cancer treatment.

Abstract Toxoplasma gondii is a significant zoonotic pathogen of toxoplasmosis in humans and animals. Here a live attenuated Toxoplasma vaccine of WH3 Δrop18 was developed. The results showed that all mice vaccinated with WH3 Δrop18 were able to survive when challenge with various strains of Toxoplasma, including RH (type I), ME49 (type II), WH3 or WH6 (type Chinese 1). No cysts, if few, in the brain of the vaccinated animals were seen after challenge with cyst forming strains of ME49 or WH6. Vaccination with the WH3 Δrop18 triggered a strong immune response, including significantly increased level of the cytokines (IFN-γ, IL-12, TNF-α and IL-10) and the activation of CD4+ and CD8+ T-lymphocytes and long term of specific antibodies against Toxoplasma. Our results strongly indicate that vaccine of WH3 Δrop18 might provide effective immune protection against a wide range strains of Toxoplasma infections and be a promising live attenuated vaccine candidate.

Abstract Currently, even the most effective anti-cancer therapies are often limited by the development of drug resistance and tumor relapse, which is a major challenge facing current cancer research. A deep understanding of the molecular and biochemical bases of drug efficacy that can help predict the clinical drug resistance, coupled with the evolution of systematic genomic and proteomic technologies, have facilitated studies identifying and elucidating the underlying mechanisms. In this review, we focus on several important issues on cancer drug resistance and provide a framework for understanding the common ways by which cancers develop resistance to therapeutic agents. With the increasing arsenal of novel anticancer agents and techniques, there are now unprecedented opportunities to understand and overcome drug resistance. The proteolysis targeting chimera (PROTAC) technology, immunotherapy, nanomedicine, and real-time monitoring of drug response all provide effective approaches for combating drug resistance. In addition to the advancement of therapeutic technologies, the revolution of treatment concept is also of great importance. We can take advantage of the interplay between drug sensitive and resistant subclones for combating cancer. However, there remains a long way to go in the protracted war against cancer drug resistance.

Abstract Epstein-Barr virus (EBV) related post-transplant lymphoproliferative disorder (EBV-PTLD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT), for which no standard therapeutic means have been developed. Significant increase expression of natural killer group 2 member D ligands (NKG2DLs) was observed on B-lymphoblastoid cells of EBV-PTLD, indicating NKG2DLs as potential therapeutic targets for treatment of EBV-PTLD. In this study, the recombinant constructs of NKG2D CAR and IL-15/IL-15Rα-NKG2D CAR were generated with a retroviral vector and then transduced to human T cells to produce NKG2D CAR-T and IL-15/IL-15Rα-NKG2D CAR-T cells, respectively. B-lymphoblastoid cell lines (B-LCLs) and the xenografted mouse models were established to evaluate the efficacy of these CAR-T cells. IL-15/IL-15Rα-NKG2D CAR-T cells exhibited superior proliferation and antigen-specific cytotoxic effect compared to NKG2D CAR-T, as IL-15/IL-15Rα signaling promoted the expansion of less differentiated central memory T cells (TCM) and increased expression of CD107a and IFN-γ. Moreover, EBV DNA load was dramatically reduced, and 80% B-LCL cells were eliminated by IL-15/IL-15Rα-NKG2D CAR-T cells after co-culturing. In-vivo study confirmed that IL-15/IL-15Rα-NKG2D CAR-T cell therapy significantly enhanced antiviral efficacy in mice, as the serum load of EBV after IL-15/IL-15Rα-NKG2D CAR-T cell infusion was 1500 times lower than the untreated control (P

Abstract Tissue-resident memory T cells (TRMs) play a critical role in cancer immunity by offering quick and effective immune responses. However, the cellular heterogeneity of TRMs and their significance in cervical cancer (CC) remain unknown. In this study, we generated and analyzed single-cell RNA sequencing data from 12,945 TRMs (ITGAE + CD3D + ) and 25,627 non-TRMs (ITGAE − CD3D + ), derived from 11 CC tissues and 5 normal cervical tissues. We found that TRMs were more immunoreactive than non-TRMs, and TRMs in CC tissues were more activated than those in normal cervical tissues. Six CD8+ TRM subclusters and one CD4+ TRM subcluster were identified. Among them, CXCL13 + CD8+ TRMs were more abundant in CC tissues than in normal cervical tissues, had both cytotoxic and inhibitory features, and were enriched in pathways related to defense responses to the virus. Meanwhile, PLAC8 + CD8+ TRMs were less abundant in CC tissues than in normal cervical tissues but had highly cytotoxic features. The signature gene set scores of both cell subclusters were positively correlated with the overall survival and progression-free survival of patients with CC following radiotherapy. Of note, the association between HLA-E and NKG2A, either alone or in a complex with CD94, was enriched in CXCL13 + CD8+ TRMs interacting with epithelial cells at CC tissues. The in-depth characterization of TRMs heterogeneity in the microenvironment of CC could have important implications for advancing treatment and improving the prognosis of patients with CC.

Abstract The function of Family With Sequence Similarity 83, Member A (FAM83A) in lung squamous cell carcinoma (LUSC) is largely unknown. Here, we detected its prognostic and regulation roles in LUSC. Bioinformatics methods were applied initially to predict the expression level and prognostic value of FAM83A mRNA in LUSC. In vitro experiments, such as western blot, colony formation and cell viability assay, lipid Reactive oxygen species (ROS), malondialdehyde (MDA), reduced glutathione (GSH)/oxidized glutathione disulfide (GSSG), and 4-hydroxy-2-nonenal (4-HNE) assay, were used to investigate its mechanism. In vivo experiments were further conducted to validate the mechanism. Results from TCGA and Oncomine databases revealed significantly higher FAM83A mRNA expression levels in LUSC than in normal lung tissue. TCGA and GEO databases and our database revealed that FAM83A expression level was an independent prognostic factor for both overall survival and progression-free survival. Besides, FAM83A was significantly associated with a higher ability of growth and clonogenicity. Mechanistically, in vitro and in vivo experiments revealed that FAM83A could promote LUSC cell growth by inhibiting ferroptosis via activating the Wnt/β-catenin signaling pathway. The rescue experiment demonstrated that inhibition of the Wnt/β-catenin pathway counteracted the function of FAM83A. FAM83A is overexpressed in LUSC and could serve as a prognosis prediction biomarker for LUSC. FAM83A promotes LUSC cell growth by inhibiting ferroptosis via activating the Wnt/β-catenin signaling pathway, which provides a new potential therapeutic target for LUSC treatment.

Abstract Objective To evaluate the safety and efficacy of the granisetron transdermal delivery system (GTDS) combined with Dexamethasone for preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving Capecitabine plus Oxaliplatin (CapeOX) therapy. Design Open-label, prospective, multi-center phase II trial. Setting Three institutions. Participants Fifty-four patients scheduled to receive CapeOX chemotherapy. Interventions Participants received GTDS (3.1 mg applied to the upper arm 48 h before chemotherapy, replaced on day 5, and discarded on day 12) and Dexamethasone. Main outcome measures The primary endpoint was the complete control rate of CINV. Secondary endpoints included the duration of delayed complete control, complete control rate in the acute phase, safety, and quality of life. Results The complete control rate for delayed CINV over the entire period (25–480 h) was 72.7% (95% CI 0.57–0.88). The duration of delayed complete control was 17.2 ± 4.5 days, with 51.5% of patients experiencing no nausea during the delayed phase. The complete control rate in the acute phase was 81.8% (95% CI 0.69–0.95). No serious adverse events related to the antiemetic regimen were reported. Conclusion Prolonged administration of GTDS is safe and effective for preventing CINV in patients with gastrointestinal malignancies treated with CapeOX. Trial Registration ClinicalTrials.gov registry (NCT05325190); registered on October 10, 2021.

Abstract Background To explore challenges of liquid-based cytology (LBC) specimens for next-generation sequencing (NGS) in lung adenocarcinoma and evaluate the efficacy of targeted therapy. Methods A retrospective analysis was conducted on the NGS test of 357 cases of advanced lung adenocarcinoma LBC specimens and compared with results of histological specimens to assess the consistency. The impact of tumor cellularity on NGS test results was evaluated. The utility of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) was collected. Clinical efficacy evaluation was performed and survival curve analysis was conducted using the Kaplan-Meier method. Results There were 275 TKI-naive and 82 TKI-treated specimens, the mutation rates of cancer-related genes detected in both groups were similar (86.2% vs. 86.6%). The EGFR mutation rate in the TKI treated group was higher than that in the TKI-naive group (69.5% > 54.9%, P = 0.019). There was no significant difference in the EGFR mutation frequency among different tumor cellularity in the TKI-naive group. However, in the TKI treated group, the frequency of EGFR sensitizing mutation and T790M resistance mutation in specimens with

Abstract Background Gastric cancer is one of the most common tumors worldwide, and most patients are deprived of treatment options when diagnosed at advanced stages. PRDM14 has carcinogenic potential in breast and non-small cell lung cancer. however, its role in gastric cancer has not been elucidated. Methods We aimed to elucidate the expression of PRDM14 using pan-cancer analysis. We monitored the expression of PRDM14 in cells and patients using quantitative polymerase chain reaction, western blotting, and immunohistochemistry. We observed that cell phenotypes and regulatory genes were influenced by PRDM14 by silencing PRDM14. We evaluated and validated the value of the PRDM14-derived prognostic model. Finally, we predicted the relationship between PRDM14 and small-molecule drug responses using the Connectivity Map and The Genomics of Drug Sensitivity in Cancer databases. Results PRDM14 was significantly overexpressed in gastric cancer, which identified in cell lines and patients’ tissues. Silencing the expression of PRDM14 resulted in apoptosis promotion, cell cycle arrest, and inhibition of the growth and migration of GC cells. Functional analysis revealed that PRDM14 acts in epigenetic regulation and modulates multiple DNA methyltransferases or transcription factors. The PRDM14-derived differentially expressed gene prognostic model was validated to reliably predict the patient prognosis. Nomograms (age, sex, and PRDM14-risk score) were used to quantify the probability of survival. PRDM14 was positively correlated with sensitivity to small-molecule drugs such as TPCA-1, PF-56,227, mirin, and linsitinib. Conclusions Collectively, our findings suggest that PRDM14 is a positive regulator of gastric cancer progression. Therefore, it may be a potential therapeutic target for gastric cancer.

Abstract Nuclear lamin B1 (LMNB1) is a member of the nuclear lamin protein family. LMNB1 can maintain and ensure the stability of nuclear structure and influence the process of cell senescence by regulating chromatin distribution, DNA replication and transcription, gene expression, cell cycle, etc. In recent years, several studies have shown that the abnormal expression of LMNB1, a classical biomarker of cell senescence, is highly correlated with the progression of various malignant tumors; LMNB1 is therefore considered a new potential tumor marker and therapeutic target. However, the mechanism of action of LMNB1 is influenced by many factors, which are difficult to clarify at present. This article focuses on the recent progress in understanding the role of LMNB1 in cell senescence and malignant tumors and offers insights that could contribute to elucidating the mechanism of action of LMNB1 to provide a new direction for further research.

PURPOSEStronger Together is a peer mentoring model that seeks to address the severe lack of mental health and psychosocial support for patients with cancer in many low- and middle-income countries (LMICs). This article presents the results of the Stronger Together pilot study among patients with breast and gynecologic cancer in Viet Nam (VN).METHODSEligible participants comprised women age 25 years or older with a diagnosis of breast or gynecologic cancers and receiving treatment at four participating hospitals. Participants were asked whether they wanted to proceed with usual care or be matched with a trained and supervised peer mentor (a cancer survivor). Surveys were administered at baseline (0) and 2, 4, and 6 months and assessed depression, anxiety, stress, mental health and physical health components of quality of life (QOL), self-efficacy, and social support. We computed and compared 2-, 4-, and 6-month changes in scores from baseline and conducted difference-in-difference analyses to estimate the intervention effect at 6 months.RESULTSThe sample size included N = 186 participants. Mentees (n = 91) exhibited improvements in depression, anxiety, stress, and mental health QOL across all time points, whereas usual care participants (n = 95) experienced these improvements at later periods (4 and 6 months). Compared with usual care participants, mentees reported greater improvements in depression at 2 and 4 months, mental health QOL at all time points, and self-efficacy and social support at 4 and 6 months. Greater improvements in stress were also seen in the breast cancer subsample.CONCLUSIONStronger Together is a promising model to improve mental health and psychosocial outcomes among patients with breast and gynecologic cancer in VN and can help fill gaps in cancer peer support interventions in many LMICs.

BackgroundPeripherally inserted central catheters (PICC) are increasingly used in clinical practice, which also leads to an increased incidence of PICC-related thrombosis. Local thrombus formation could be prevented by limb ischemic preconditioning (IPC). This study aimed to determine whether IPC can prevent deep vein thrombosis in patients with PICC.MethodsA total of 600 breast cancer patients receiving PICC were randomized into two groups between July 2016 and July 2018 at the Department of Radiation Oncology. In the preconditioning group, 5 min of ischemic preconditioning was performed three times before PICC, whereas no preconditioning was performed in the sham group. The coagulation function levels, the PICC-related complications, the length of hospital stay, the cost of hospitalization, and the satisfaction of patients were compared.ResultsThe coagulation function levels of patients in the preconditioning group were more normal than in patients from the sham group. In total, 56/300 patients in the sham group had presence of PICC-related thrombosis, with only 23/300 in the IPC group, with no significant difference in other complications between the two groups. However, a longer hospital stay was observed in the sham group compared to the IPC group. Moreover, the cost of hospitalization was also reduced in the IPC group, which also improved the satisfaction of patients.ConclusionLimb ischemic preconditioning may attenuate the severity of vein thrombosis in patients with PICC, which contributes to reducing the incidence of PICC-related thrombosis in clinical practice.

Gastric cancer (GC) has become the first malignant tumor with highest incidence rate and mortality of cancer in China, finding therapeutic targets for gastric cancer is of great significant for improving the survival rate of patients with GC. Recently, many of studies have shown that LncRNAs is involved in multiple biological progresses in the development of GC. This study, we screened for abnormally high expression of LncSHANK3 in GC through the TCGA database, and found that LncSHANK3 sponge adsorbs miR-4530, further competing with MNX1 and binding to miR-4530. We demonstrated the interaction between LncSHANK3 and miR-4530 through luciferase reporting analysis, with miR-4530 negatively regulating MNX1.Through CCK8, colony formation, transwell, and wound healing assays, it was found that LncSHANK3 affects the occurrence of GC through cell proliferation, migration and invasion. In conclusion, LncSHANK3/miR-4530/MNX1 axis is a potential mechanism for the treatment of GC.

Abstract Protein degraders, emerging as a novel class of therapeutic agents, have gained widespread attention due to their advantages. They have several advantages over traditional small molecule inhibitors, including high target selectivity and ability to target “undruggable” targets and overcome inhibitor drug resistance. Tremendous research and development efforts and massive investment have resulted in rapid advancement of protein degrader drug discovery in recent years. Here, we overview the latest clinical and preclinical updates on protein degraders presented at the 2023 ASH Annual Meeting.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer with high aggressive phenotype and poor prognosis. Accumulating evidence suggests that circRNAs have been identified as pivotal mediators in cancers. However, the role of circRNAs in ccRCC progression remains elusive. Methods The differentially expressed circRNAs in 4 paired human ccRCC and adjacent noncancerous tissues ccRCC were screened using circRNA microarrays and the candidate target was selected based on circRNA expression level using weighted gene correlation network analysis (WGCNA) and the gene expression omnibus (GEO) database. CircPDHK1 expression in ccRCC and adjacent noncancerous tissues (n = 148) were evaluated along with clinically relevant information. RT-qPCR, RNase R digestion, and actinomycin D (ActD) stability test were conducted to identify the characteristics of circPDHK1. The subcellular distribution of circPDHK1 was analyzed by subcellular fractionation assay and fluorescence in situ hybridization (FISH). Immunoprecipitation-mass spectrometry (IP-MS) and immunofluorescence (IF) were employed to evaluate the protein-coding ability of circPDHK1. ccRCC cells were transfected with siRNAs, plasmids or lentivirus approach, and cell proliferation, migration and invasion, as well as tumorigenesis and metastasis in nude mice were assessed to clarify the functional roles of circPDHK1 and its encoded peptide PDHK1-241aa. RNA-sequencing, western blot analysis, immunoprecipitation (IP) and chromatin immunoprecipitation (ChIP) assays were further employed to identify the underlying mechanisms regulated by PDHK1-241aa. Results CircPDHK1 was upregulated in ccRCC tissues and closely related to WHO/ISUP stage, T stage, distant metastasis, VHL mutation and Ki-67 levels. CircPDHK1 had a functional internal ribosome entry site (IRES) and encoded a novel peptide PDHK1-241aa. Functionally, we confirmed that PDHK1-241aa and not the circPDHK1 promoted the proliferation, migration and invasion of ccRCC. Mechanistically, circPDHK1 was activated by HIF-2A at the transcriptional level. PDHK1-241aa was upregulated and interacted with PPP1CA, causing the relocation of PPP1CA to the nucleus. This thereby inhibited AKT dephosphorylation and activated the AKT-mTOR signaling pathway. Conclusions Our data indicated that circPDHK1-encoded PDHK1-241aa promotes ccRCC progression by interacting with PPP1CA to inhibit AKT dephosphorylation. This study provides novel insights into the multiplicity of circRNAs and highlights the potential use of circPDHK1 or PDHK1-241aa as a therapeutic target for ccRCC.

Han Wang,1,* Jun-Jie Chen,2,* Shu-Yi Yin,3,* Xia Sheng,4 Hong-Xia Wang,5 Wan Yee Lau,6 Hui Dong,1 Wen-Ming Cong1 1Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, People’s Republic of China; 2Department of Radiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, People’s Republic of China; 3Department of Pathology, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People’s Republic of China; 4Department of Pathology, Minhang Hospital, Fudan University, Shanghai, People’s Republic of China; 5Department of Pathology, Jiading District Central Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, People’s Republic of China; 6Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China*These authors contributed equally to this workCorrespondence: Hui Dong; Wen-Ming Cong, Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, 225 Changhai Road, Shanghai, 200438, People’s Republic of China, Tel +86-021-81875191 ; +86-021-81875192, Email huidongwh@126.com; wmcong@smmu.edu.cnBackground: Microvascular invasion (MVI) is closely correlated with poor clinical outcomes in patients with hepatocellular carcinoma (HCC). A grading system of MVI is needed to assist in the management of HCC patient.Methods: Multicenter data of HCC patients who underwent liver resection with curative intent was analyzed. This grading system was established by detected number and distance from tumor boundary of MVI. Survival outcomes were compared among patients in each group. This system was verified by time-receiver operating characteristic curve, time-area under the curve, calibration curve, and decision curve analyses. Cox regression analysis was performed to study the associated factors of prognosis. Logistic analysis was used to study the predictive factors of MVI.Results: All patients were classified into 4 groups: M0: no MVI; M1: 1~5 proximal MVIs (≤ 1 cm from tumor boundary); M2a: > 5 proximal MVIs (≤ 1 cm from tumor boundary); M2b: ≥ 1 distal MVIs (> 1 cm from tumor boundary). The recurrence-free survival (RFS), overall survival (OS), and early RFS rates among all the individual groups were significantly different. Based on the number of proximal MVI (0~5 vs > 5), patients in the M2b group were further divided into two subgroups which also showed different prognosis. Multiple methods showed this grading system to be significantly better than the MVI two-tiered system in prognostic evaluation. Four multivariate models for RFS, OS, early RFS, late RFS, and a predictive model of MVI were then established and were shown to satisfactorily evaluate prognosis and have a great discriminatory power, respectively.Conclusion: This MVI grading system could precisely evaluate prognosis of HCC patients after liver resection with curative intent and it could be employed in routine pathological reports. The severity of MVI from both adjacent and distant from tumor boundary should be stated. A hypothesis about two occurrence modes of distal MVI was proposed. Keywords: hepatocellular carcinoma, microvascular invasion, hepatectomy, hepatic resection, pathology

Abstract Background Liver cancer is a highly malignant disease and the third leading cause of cancer death worldwide. Abnormal activation of PI3K/Akt signaling is common in cancer, but whether phosphoinositide‐3‐kinase regulatory subunit 3 (PIK3R3) plays a role in liver cancer is largely unexplored. Methods We determined the expression of PIK3R3 in liver cancer by using TCGA data and our clinical samples and knocked it down by siRNA or overexpressing it by the lentivirus vector system. We also investigated the function of PIK3R3 by colony formation, 5‐Ethynyl‐2‐Deoxyuridine, flow cytometry assay, and subcutaneous xenograft model. The downstream of PIK3R3 was explored by RNA sequence and rescue assays. Results We found that PIK3R3 was significantly upregulated in liver cancer and correlated with prognosis. PIK3R3 promoted liver cancer growth in vitro and in vivo by controlling cell proliferation and cell cycle. RNA sequence revealed that hundreds of genes were dysregulated upon PIK3R3 knockdown in liver cancer cells. CDKN1C, a cyclin‐dependent kinase inhibitor, was significantly upregulated by PIK3R3 knockdown, and CDKN1C siRNA rescued the impaired tumor cell growth. SMC1A was partially responsible for PIK3R3 regulated function, and SMC1A overexpression rescued the impaired tumor cell growth in liver cancer cells. Immunoprecipitation demonstrated there is indirect interaction between PIK3R3 and CNKN1C or SMC1A. Importantly, we verified that PIK3R3‐activated Akt signaling determined the expression of CDKN1C and SMC1A, two downstream of PIK3R3 in liver cancer cells. Conclusion PIK3R3 is upregulated in liver cancer and activates Akt signaling to control cancer growth by regulation of CDNK1C and SMC1A. Targeting PIK3R3 could be a promising treatment strategy for liver cancer that deserves further investigation.

Preeclampsia (PE) manifests as a pregnancy-specific complication arising from compromised placentation characterized by inadequate trophoblast invasion. A growing body of evidence underscores the pivotal involvement of pseudogenes, a subset of long noncoding RNAs, in the pathological processes of PE. This study presents a novel finding, demonstrating a significant downregulation of the pseudogene PDIA3P1 in PE placental tissues compared to normal tissues. In vitro functional assays revealed that suppressing PDIA3P1 hindered trophoblast proliferation, invasion, and migration, concurrently upregulating the expression of secreted frizzled-related protein 1 (SFRP1). Further exploration of the regulatory role of PDIA3P1 in PE, utilizing human trophoblasts, established that PDIA3P1 exerts its function by binding to HuR, thereby enhancing the stability of Snail expression in trophoblasts. Overall, our findings suggest a crucial role for PDIA3P1 in regulating trophoblast properties and contributing to the pathogenesis of PE, offering potential targets for prognosis and therapeutic intervention.

Abstract Introduction Locoregional recurrent breast cancers have a poor prognosis. Little is known about the prognostic impact of immune microenvironment, and tertiary lymphoid structures (TLSs) in particular have not been reported. Thus, we aimed to characterize the immune microenvironment in locoregional recurrent breast tumors and to investigate its relationship with prognosis. Methods We retrospectively included 112 patients with locoregional recurrent breast cancer, and hematoxylin–eosin staining and immunohistochemical staining (CD3, CD4, CD8, CD19, CD38, and CD68) were performed on locoregional recurrent tumor samples. The association of immune cells and TLSs with progression‐free survival (PFS) were analyzed by survival analysis. Results We found more immune cells in the peritumor than stroma. After grouping according to estrogen receptor (ER) status, a low level of peritumoral CD3+ cells in ER+ subgroup (p = 0.015) and a low level of stromal CD68+ cells in ER− subgroup (p = 0.047) were both associated with longer PFS. TLSs were present in 68% of recurrent tumors, and CD68+ cells within TLSs were significantly associated with PFS as an independent prognostic factor (p = 0.035). TLSs and immune cells (CD3, CD38, and CD68) within TLSs were associated with longer PFS in ER− recurrent tumors (p = 0.044, p = 0.012, p = 0.050, p

BackgroundGallbladder neuroendocrine carcinoma (GB-NEC) is an extremely rare cancer with a poor prognosis in the clinic. Although surgical resection remains the primary and preferred therapeutics, many patients are in a late stage and lose the opportunity for surgery. However, due to the extremely low morbidity, the specific treatment guidelines for GB-NEC have not been established.Case presentationA 52-year-old woman was admitted to our hospital with the chief complaint of “almost 1 month after palliative surgery for metastatic gallbladder carcinoma.” According to the results of pathological findings and imaging manifestations, the patient was diagnosed with GB-NEC with a clinical stage of pT3N1M1 (IVB). The patient then received tislelizumab plus EP chemotherapy (etoposide 100 mg + cisplatin 30 mg, d1–3) every 3 weeks for 8 cycles from 12 November, 2021, followed by maintenance therapy (tislelizumab alone) every 3 weeks until now. The tumor response was evaluated as complete remission since 13 February, 2023. As of the last follow-up, the patient remains alive, with no complaints of discomfort.ConclusionsGallbladder NEC has no specific symptoms, and the diagnosis is based on pathological and immunohistochemical results. The therapeutic course and efficacy of the case in this study indicates that the application of PD-1 inhibitor might be a feasible therapeutic option for GB-NEC. However, this potential strategy needs validation by further clinical studies in the future.

Background: To investigate the expression of high mobility group box B-1 (HMGB-1) in patients with colorectal cancer (CRC) and its association with clinicopathological features and prognosis in colorectal carcinoma by combining bioinformatics and clinical data analysis, and to clarify the role of HMGB-1. To examine whether HMGB-1 expression is related to the damage of the intestinal mucosal barrier, and then explore the potential HMGB-1-dependent mechanisms affecting the progression of CRC. Methods: CRC datasets of GSE12945, GSE17536, and GSE17537 from the public gene chip database were screened and downloaded. Clinical information and CRC tissue samples from patients with stage I-III CRC from the hospital were collected. Serum samples of patients were applied by enzyme-linked immunosorbent assay on HMGB-1, and were divided into high and low HMGB-1 expression, which was examined by 16S rDNA sequencing. Immunohistochemistry was performed to examine the relationship between the expression of HMGB-1 and tight junction protein, occludin, tumor necrosis factor-α, and interferon-γ. Results: Based on the Cutoff value of 10.24 ng/mL, the CRC patients were divided into high and low expression groups. In the HMGB-1H patient group, the TNM staging, overall survival, disease-free survival, recurrence, and metastasis were inferior to the HMGB-1L group. The results of 16S rDNA sequencing demonstrated that the Providencia genus was found to be enriched in the HMGB-1L group. Immunohistochemical results showed that HMGB-1 expression was negatively correlated with the expression of ZO-1 and occludin ( R = 0.035, R = 0.003, P

Abstract The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had and continues to have a significant impact on global public health. One of the characteristics of SARS-CoV-2 is a surface homotrimeric spike protein, which is primarily responsible for the host immune response upon infection. Here we present the preclinical studies of a broadly protective SARS-CoV-2 subunit vaccine developed from our trimer domain platform using the Delta spike protein, from antigen design through purification, vaccine evaluation and manufacturability. The pre-fusion trimerized Delta spike protein, PF-D-Trimer, was highly expressed in Chinese hamster ovary (CHO) cells, purified by a rapid one-step anti-Trimer Domain monoclonal antibody immunoaffinity process and prepared as a vaccine formulation with an adjuvant. Immunogenicity studies have shown that this vaccine candidate induces robust immune responses in mouse, rat and Syrian hamster models. It also protects K18-hACE2 transgenic mice in a homologous viral challenge. Neutralizing antibodies induced by this vaccine show cross-reactivity against the ancestral WA1, Delta and several Omicrons, including BA.5.2. The formulated PF-D Trimer is stable for up to six months without refrigeration. The Trimer Domain platform was proven to be a key technology in the rapid production of PF-D-Trimer vaccine and may be crucial to accelerate the development and accessibility of updated versions of SARS-CoV-2 vaccines.

Abstract Background Non-small cell cancer (NSCLC) patients with concomitant epidermal growth factor receptor (EGFR) and TP53 mutations have a poor prognosis with the treatment of tyrosine kinase inhibitors (TKIs), and may benefit from a combination regimen preferentially. The present study aims to compare the benefits of EGFR-TKIs and its combination with antiangiogenic drugs or chemotherapy in patients with NSCLC harboring EGFR and TP53 co-mutation in a real-life setting. Methods This retrospective analysis included 124 patients with advanced NSCLC having concomitant EGFR and TP53 mutations, who underwent next-generation sequencing prior to treatment. Patients were classified into the EGFR-TKI group and combination therapy group. The primary end point of this study was progression-free survival (PFS). The Kaplan–Meier (KM) curve was drawn to analyze PFS, and the differences between the groups were compared using the logarithmic rank test. Univariate and multivariate cox regression analysis was performed on the risk factors associated with survival. Results The combination group included 72 patients who received the regimen of EGFR-TKIs combined with antiangiogenic drugs or chemotherapy, while the EGFR-TKI monotherapy group included 52 patients treated with TKI only. The median PFS was significantly longer in the combination group than in the EGFR-TKI group (18.0 months; 95% confidence interval [CI]: 12.1–23.9 vs. 7.0 months; 95% CI: 6.1–7.9; p

ObjectiveWe explored the role of maximum intensity projection (MIP) based on high frame rate contrast-enhanced ultrasound (H-CEUS) for the differentiation of breast tumors.MethodsMIP imaging was performed in patients with breast tumors who underwent H-CEUS examinations. The microvasculature morphology of breast tumors was assessed. The receiver operating characteristic curve was plotted to evaluate the diagnostic performance of MIP.ResultsForty-three breast tumors were finally analyzed, consisting of 19 benign and 24 malignant tumors. For the ≤30-s and >30-s phases, dot-, line-, or branch-like patterns were significantly more common in benign tumors. A tree-like pattern was only present in the benign tumors. A crab claw-like pattern was significantly more common in the malignant tumors. Among the tumors with crab claw-like patterns, three cases of malignant tumors had multiple parallel small spiculated vessels. There were significant differences in the microvasculature morphology for the ≤30-s and >30-s phases between the benign and malignant tumors (all p < 0.001). The area under the curve, sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the ≤30-s phase were all higher than those of the >30-s phase for the classification of breast tumors.ConclusionMIP based on H-CEUS can be used for the differentiation of breast tumors, and the ≤30-s phase had a better diagnostic value. Multiple parallel small spiculated vessels were a new finding, which could provide new insight for the subsequent study of breast tumors.

IntroductionThe prognosis of patients with non-central recurrent cervical cancer (NRCC) remains poor, and treatment options are limited. We aimed to explore the accuracy and safety of the 3D-printed non-coplanar template (3D-PNCT)-assisted 192Ir interstitial brachytherapy (ISBT) in the treatment of NRCC.Material and methodsA total of 36 patients with NRCC who received 3D-PNCT-guided 192Ir ISBT in the First Affiliated Hospital of Zhengzhou University from January 2021 to July 2022 were included in this study. There were 36 3D-PNCTs that were designed and printed. The prescribed dose was 30–36 Gy, divided into five to six times, once a week. To evaluate whether the actual parameters were consistent with the preoperative design, the dosimetric parameters of pre- and postoperative treatment plans were compared, including dose of 90% high-risk clinical target volume (HR-CTV D90), volume percentage of 100% and 150% prescribed dose V100% and V150%, homogeneity index (HI), conformal index (CI), external index (EI), and dose received by 2 cm3 (D2cm3) of the rectum, colon, bladder, and ileum. The safety parameters including occurrence of bleeding, infection, pain, radiation enteritis, and radiation cystitis within 3 months after operation were recorded.ResultsAll patients successfully completed the treatment and achieved the goals of the preoperative plan. There was no significant difference in the accuracy (HRCTVD90, V100%, EI, CI, and HI) and safety (D2cm3 of rectum, colon, bladder, and ileum) parameters of the postoperative plan compared with the preoperative plan (all p>0.05). Major side effects included bleeding at the puncture site (13.9%), postoperative pain (8.3%), acute radiation cystitis (13.9%), and radiation enteritis (19.4%). There were no serious perioperative complications and no grade 3–4 acute radiotherapy side effects.Conclusion3D-PNCT-assisted 192Ir ISBT can be accurately and safely applied in the treatment of patients with NRCC.

IntroductionThe hepatobiliary-specific phase can help in early detection of changes in lesion tissue density, internal structure, and microcirculatory perfusion at the microscopic level and has important clinical value in hepatocellular carcinoma (HCC). Therefore, this study aimed to construct a preoperative nomogram for predicting the positive expression of glypican-3 (GPC3) based on gadoxetic acid-enhanced (Gd-EOB-DTPA) MRI hepatobiliary phase (HBP) radiomics, imaging and clinical feature.MethodsWe retrospectively included 137 patients with HCC who underwent Gd-EOB-DTPA-enhanced MRI and subsequent liver resection or puncture biopsy at our hospital from January 2017 to December 2021 as training cohort. Subsequently collected from January 2022 to June 2023 as a validation cohort of 49 patients, Radiomic features were extracted from the entire tumor region during the HBP using 3D Slicer software and screened using a t-test and least absolute shrinkage selection operator algorithm (LASSO). Then, these features were used to construct a radiomics score (Radscore) for each patient, which was combined with clinical factors and imaging features of the HBP to construct a logistic regression model and subsequent nomogram model. The clinicoradiologic, radiomics and nomogram models performance was assessed by the area under the curve (AUC), calibration, and decision curve analysis (DCA). In the validation cohort,the nomogram performance was assessed by the area under the curve (AUC).ResultsIn the training cohort, a total of 1688 radiomics features were extracted from each patient. Next, radiomics with ICCs400ng/mL, and non-smooth tumor margin (AUC=0.888, sensitivity 77.7%, specificity 91.2%) was superior to the radiomics (AUC=0.822, sensitivity 81.6%, specificity 70.6%) and clinicoradiologic (AUC=0.746, sensitivity 76.7%, specificity 64.7%) models, with good consistency in calibration curves. DCA also showed that the nomogram had the highest net clinical benefit for predicting GPC3 expression.In the validation cohort, the ROC curve results showed predicted GPC3-positive expression nomogram model AUC, sensitivity, and specificity of 0.800, 58.5%, and 100.0%, respectively.ConclusionHBP radiomics features are closely associated with GPC3-positive expression, and combined clinicoradiologic factors and radiomics features nomogram may provide an effective way to non-invasively and individually screen patients with GPC3-positive HCC.

IntroductionThe overdiagnosing of papillary thyroid carcinoma (PTC) in China necessitates the development of an evidence-based diagnosis and prognosis strategy in line with precision medicine. A landscape of PTC in Chinese cohorts is needed to provide comprehensiveness.Methods6 paired PTC samples were employed for whole-exome sequencing, RNA sequencing, and data-dependent acquisition mass spectrum analysis. Weighted gene co-expression network analysis and protein-protein interactions networks were used to screen for hub genes. Moreover, we verified the hub genes' diagnostic and prognostic potential using online databases. Logistic regression was employed to construct a diagnostic model, and we evaluated its efficacy and specificity based on TCGA-THCA and GEO datasets.ResultsThe basic multiomics landscape of PTC among local patients were drawn. The similarities and differences were compared between the Chinese cohort and TCGA-THCA cohorts, including the identification of PNPLA5 as a driver gene in addition to BRAF mutation. Besides, we found 572 differentially expressed genes and 79 differentially expressed proteins. Through integrative analysis, we identified 17 hub genes for prognosis and diagnosis of PTC. Four of these genes, ABR, AHNAK2, GPX1, and TPO, were used to construct a diagnostic model with high accuracy, explicitly targeting PTC (AUC=0.969/0.959 in training/test sets).DiscussionMultiomics analysis of the Chinese cohort demonstrated significant distinctions compared to TCGA-THCA cohorts, highlighting the unique genetic characteristics of Chinese individuals with PTC. The novel biomarkers, holding potential for diagnosis and prognosis of PTC, were identified. Furthermore, these biomarkers provide a valuable tool for precise medicine, especially for immunotherapeutic or nanomedicine based cancer therapy.

Abstract Objectives To quantify the dose-response relationship of changes in pelvic bone marrow (PBM) functional MR radiomic features (RF) during concurrent chemoradiotherapy (CCRT) for patients with cervical cancer and establish the correlation with hematologic toxicity to provide a basis for PBM sparing. Methods A total of 54 cervical cancer patients who received CCRT were studied retrospectively. Patients underwent MRI IDEAL IQ and T2 fat suppression (T2fs) scanning pre- and post-CCRT. The PBM RFs were extracted from each region of interest at dose gradients of 5–10 Gy, 10–15 Gy, 15–20 Gy, 20–30 Gy, 30–40 Gy, 40–50 Gy, and > 50 Gy, and changes in peripheral blood cell (PBC) counts during radiotherapy were assessed. The dose-response relationship of RF changes and their correlation with PBC changes were investigated. Results White blood cell, neutrophils (ANC) and lymphocyte counts during treatment were decreased by 49.4%, 41.4%, and 76.3%, respectively. Most firstorder features exhibited a significant dose-response relationship, particularly FatFrac IDEAL IQ, which had a maximum dose-response curve slope of 10.09, and WATER IDEAL IQ had a slope of − 7.93. The firstorder-Range in FAT IDEAL IQ and firstorder-10Percentile in T2fs, showed a significant correlation between the changes in ANC counts under the low dose gradient of 5–10 Gy (r = 0.744, -0.654, respectively, p

Objective: For early-stage cervical cancer patients experiencing radical surgery, postoperative radiotherapy was recommended for patients with a combination of intermediate-risk factors. However, there was no consensus on whether to administer concurrent chemotherapy. The aim of the study was to confirm the clinical value of the controlling nutritional status (CONUT) score in guiding the use of concurrent chemotherapy during postoperative radiotherapy. Methods: A total of 969 patients with FIGO stage IB-IIA cervical cancer were retrospectively analyzed. Kaplan-Meier survival analysis was performed to compare disease-free survival (DFS) and cancer-specific survival (CSS) rates between different group. A Cox proportional hazards regression test was used to conduct multivariate analyses. Results: For the patients in the high CONUT group (≥3), the addition of concurrent chemotherapy had better 5-year DFS (91.2 % vs. 72.8 %, P = 0.005) and CSS (93.8 % vs. 77.4 %, P = 0.013) than those without it. Meanwhile, the patients with concurrent chemotherapy had less rate of locoregional recurrence (8.5 % vs 16.7 %, P = 0.034) and distant metastases (11.7 % vs 30.4 %, P = 0.015). The multivariate analysis showed that concurrent chemotherapy was detected to be a factor significantly associated with DFS (P = 0.011), local control (P = 0.041), distant metastasis (P = 0.005) and CSS (P = 0.023). For the patients in low CONUT group (

IntroductionThe successful use of machine learning (ML) for medical diagnostic purposes has prompted myriad applications in cancer image analysis. Particularly for hepatocellular carcinoma (HCC) grading, there has been a surge of interest in ML-based selection of the discriminative features from high-dimensional magnetic resonance imaging (MRI) radiomics data. As one of the most commonly used ML-based selection methods, the least absolute shrinkage and selection operator (LASSO) has high discriminative power of the essential feature based on linear representation between input features and output labels. However, most LASSO methods directly explore the original training data rather than effectively exploiting the most informative features of radiomics data for HCC grading. To overcome this limitation, this study marks the first attempt to propose a feature selection method based on LASSO with dictionary learning, where a dictionary is learned from the training features, using the Fisher ratio to maximize the discriminative information in the feature.MethodsThis study proposes a LASSO method with dictionary learning to ensure the accuracy and discrimination of feature selection. Specifically, based on the Fisher ratio score, each radiomic feature is classified into two groups: the high-information and the low-information group. Then, a dictionary is learned through an optimal mapping matrix to enhance the high-information part and suppress the low discriminative information for the task of HCC grading. Finally, we select the most discrimination features according to the LASSO coefficients based on the learned dictionary.Results and discussionThe experimental results based on two classifiers (KNN and SVM) showed that the proposed method yielded accuracy gains, compared favorably with another 5 state-of-the-practice feature selection methods.

Here we present a rare case of breast cancer with both invasive ductal carcinoma and choriocarcinoma components in a 55-year-old woman. Firstly, the serum human chorionic gonadotropin level showed 15.9mIU/ml preoperatively. And adequate immunohistochemical tests were performed on the specimen. Secondly, High-throughput sequencing was performed to detect the molecular characteristics of the two components, respectively. Then, DNA short tandem repeat (STR) analysis confirmed the homology of the two components, indicating the somatic origin of choriocarcinoma components. Finally, the clinical course and pathological characteristics of the case were reviewed and a literature search for other cases was performed.

Molecular testing of indeterminate thyroid nodules informs about the presence of point mutations, insertions/deletions, copy number variants, RNA fusions, transcript alterations and miRNA expression. American Thyroid Association (ATA) guidelines suggest molecular testing of indeterminate thyroid nodules may be considered to supplement risk of malignancy (ROM). Although these recommendations have been incorporated in clinical practices in the United States, molecular testing of indeterminate thyroid nodules is not common practice in Asia. Here, we performed molecular testing of 140 indeterminate nodules from Chinese patients using a novel molecular platform composed of RNA and DNA‐RNA classifiers, which is similar to Afirma GEC and ThyroSeq v3. Compared with reports from North America, the new RNA and DNA‐RNA classifiers had a higher positive predictive value (p1 = 0.000 and p2 = 0.020) but a lower negative predictive value (p1 = 0.004 and p2 = 0.098), with no significant differences in sensitivity (p1 = 0.625 and p2 = 0.179) or specificity (p1 = 0.391 and p2 = 0.264). Out of 58 resected nodules, 10 were borderline and 33 malignant, indicating a 74.1% ROM, which was higher than reports in North America (10–40% ROM). Our findings emphasize molecular testing with the newly reported RNA and DNA‐RNA classifiers can be used as a ‘rule‐in’ test when ROM is high.

Abstract Objectives To quantify the pelvic bone marrow (PBM) fat content changes receiving different radiation doses of concurrent chemoradiotherapy for cervical cancer and to determine association with peripheral blood cell counts. Methods The data of 54 patients were prospectively collected. Patients underwent MRI iterative decomposition of water and fat with echo asymmetrical and least squares estimation (IDEAL IQ) scanning at RT-Pre, RT mid-point, RT end, and six months. The changes in proton density fat fraction (PDFF%) at 5–10 Gy, 10–15 Gy, 15–20 Gy, 20–30 Gy, 30–40 Gy, 40–50 Gy, and > 50 Gy doses were analyzed. Spearman’s rank correlations were performed between peripheral blood cell counts versus the differences in PDFF% at different dose gradients before and after treatment. Results The lymphocytes (ALC) nadirs appeared at the midpoint of radiotherapy, which was only 27.6% of RT-Pre; the white blood cells (WBC), neutrophils (ANC), and platelets (PLT) nadirs appeared at the end of radiotherapy which was 52.4%, 65.1%, and 69.3% of RT-Pre, respectively. At RT mid-point and RT-end, PDFF% increased by 46.8% and 58.5%, respectively. Six months after radiotherapy, PDFF% decreased by 4.71% under 5–30 Gy compared to RT-end, while it still increased by 55.95% compared to RT-Pre. There was a significant positive correlation between PDFF% and ANC nadirs at 5–10 Gy (r = 0.62, P = 0.006), and correlation was observed between PDFF% and ALC nadirs at 5–10 Gy (r = 0.554, P = 0.017). Conclusion MRI IDEAL IQ imaging is a non-invasive approach to evaluate and track the changes of PBM fat content with concurrent chemoradiotherapy for cervical cancer. The limitation of low-dose bone marrow irradiation volume in cervical cancer concurrent chemoradiotherapy should be paid more attention to.

Abstract Background Alternative splicing (AS) plays important roles in transcriptome and proteome diversity. Its dysregulation has a close affiliation with oncogenic processes. This study aimed to evaluate AS-based biomarkers by machine learning algorithms for lung squamous cell carcinoma (LUSC) patients. Method The Cancer Genome Atlas (TCGA) database and TCGA SpliceSeq database were utilized. After data composition balancing, Boruta feature selection and Spearman correlation analysis were used for differentially expressed AS events. Random forests and a nested fivefold cross-validation were applied for lymph node metastasis (LNM) classifier building. Random survival forest combined with Cox regression model was performed for a prognostic model, based on which a nomogram was developed. Functional enrichment analysis and Spearman correlation analysis were also conducted to explore underlying mechanisms. The expression of some switch-involved AS events along with parent genes was verified by qRT-PCR with 20 pairs of normal and LUSC tissues. Results We found 16 pairs of splicing events from same parent genes which were strongly related to the splicing switch (intrapair correlation coefficient = − 1). Next, we built a reliable LNM classifier based on 13 AS events as well as a nice prognostic model, in which switched AS events behaved prominently. The qRT-PCR presented consistent results with previous bioinformatics analysis, and some AS events like ITIH5-10715-AT and QKI-78404-AT showed remarkable detection efficiency for LUSC. Conclusion AS events, especially switched ones from the same parent genes, could provide new insights into the molecular diagnosis and therapeutic drug design of LUSC.

Malignant mixed Müllerian tumor (MMMT) of the fallopian tube is rare and has a poor prognosis. For the patient with fallopian tube MMMT, complete resection of the tumor invading the viscera and the peritoneum is a prerequisite for long-term survival. We report a case of stage IIIc MMMT of the fallopian tube treated by cytoreductive surgery (CRS), peritoneal resection, and adjuvant chemotherapy (paclitaxel plus carboplatin), with 5-year tumor-free survival. Postoperative chemotherapy combining platinum and paclitaxel is the most potent adjuvant therapy.

Abstract Molecular mechanisms underlying breast cancer lymph node metastasis remain unclear. Using single-cell sequencing, we investigated the transcriptome profile of 96,796 single cells from 15 paired samples of primary tumors and axillary lymph nodes. We identified nine cancer cell subclusters including CD44 + / ALDH2 + /ALDH6A1 + breast cancer stem cells (BCSCs), which had a copy-number variants profile similar to that of normal breast tissue. Importantly, BCSCs existed only in primary tumors and evolved into metastatic clusters infiltrating into lymph nodes. Furthermore, transcriptome data suggested that NECTIN2-TIGIT-mediated interactions between metastatic breast cancer cells and tumor microenvironment (TME) cells, which promoted immune escape and lymph node metastasis. This study is the first to delineate the transcriptome profile of breast cancer lymph node metastasis using single-cell RNA sequencing. Our findings offer novel insights into the mechanisms underlying breast cancer metastasis and have implications in developing novel therapies to inhibit the initiation of breast cancer metastasis.

Abstract Background This study focused on comparing the safety and therapeutic effects between icotinib monotherapy and icotinib plus bevacizumab combined therapy in non‐small cell lung cancer (NSCLC) cases harboring EGFR mutations. Methods Data were collected retrospectively from the Cancer Institute and Hospital of Tianjin Medical University between October 2018 and December 2019, where the NSCLC cases that harbored EGFR mutations underwent first‐line therapy with icotinib in the presence or absence of bevacizumab. This study included 90 cases, of which 60 patients were in the icotinib group (I) and 30 in the icotinib plus bevacizumab group (IB). Results The follow‐up period to evaluate median PFS in our study was 18 months. Median PFS was 18.0 months (95% confidence interval [CI]: 14.7–21.3) with icotinib plus bevacizumab and 11 months (95% CI: 8.9–13.1) with icotinib alone (hazard ratio 0·54, 95% CI: 0.31–0.92; p = 0.029). According to the subgroup analyses based on the type of EGFR genomic aberration, a prolonged median PFS was observed in the cases harboring exon 21 point mutation (Ex21.L858R) in the IB group compared to the I group (not reached vs. 11 months [8.8–13.2], p = 0.021). However, the difference between the cases harboring exon 19 deletions in the EGFR gene was not significant. The DCR and ORR were comparable between both groups. Substantially higher incidences of hypertension and proteinuria were observed in the combined group compared to the icotinib monotherapy group. Conclusions This is the first study to provide further evidence of the benefits of applying icotinib in combination with bevacizumab as first‐line treatment for advanced NSCLC cases harboring EGFR mutations. However, these findings need to be verified through prospective phase 3 clinical studies.

Background: Studies determining which patients with International Federation of Gynecology and Obstetrics (FIGO) stage IIIB disease benefit from prophylactic extended-field irradiation (EFRT), which can reduce para-aortic lymph node (PALN) failure rates, are limited. The study was designed to evaluate the value of the controlling nutritional status (CONUT) score as a risk factor for predicting PALN recurrence and identifying potential indications of prophylactic EFRT. Methods: From 2010 to 2015, a retrospective review was conducted among patients with FIGO stage IIIB cervical cancer who were treated with definitive pelvic radiotherapy or concurrent chemoradiotherapy. We analyzed para-aortic lymph node metastasis-free survival (PALNMFS) using Kaplan-Meier curves. Multivariate analyses were performed using Cox regression models. Results: A total of 116 patients with FIGO stage IIIB cervical cancer were included in the study and the median follow-up was 42.2 months (range: 3.5-104.2 months). Multivariate analysis revealed that the CONUT score (HR: 3.141; 95% CI: 2.321-5.436; P

Bone metastasis is one of the comorbidities of advanced lung cancer, eventually leading to an impaired quality of life. We present a case of a lung adenocarcinoma patient with synchronous bone metastasis. The patient possessed a superior survival time of more than five years under multidisciplinary treatment. Considering the balance of life expectancy and limb function, the metastatic site on the right humerus was successively surgically managed. Based on the present case, we emphasized the importance of treatment choice between anti-tumor and bone management in the long-term survival of cancer patients with synchronous bone metastasis.

ObjectivesTo evaluate the diagnostic performance of conventional magnetic resonance imaging (cMRI) combined with diffusion-weighted MRI (DWI) in discrimination of cellular leiomyoma, uterine sarcoma, and atypical leiomyoma.MethodsThis retrospective study enrolled 106 patients with uterine masses, including 51 cellular leiomyomas (CLs), 32 uterine sarcomas (USs) and 23 degenerated leiomyomas (LMs) confirmed by histopathologic examination. Clinical data and imaging findings were assessed. Chi-squared test for qualitative variables and one way ANOVA analysis for quantitative variables were performed. Logistic regression analysis and the receiver operating characteristic (ROC) analysis were performed to determine the cut-off point and diagnostic performances for significant numeric values or multiple models.ResultsMorphology (Odds ratio [OR] = 6.36) and margin (OR = 13.84) derived from cMRI were independent indicators for differentiating CLs from USs, and T2WI signal (OR = 0.23) were an independent indicator for differentiating CLs from degenerated LMs (all P < 0.05). The cutoff value of apparent diffusion coefficient (ADC) derived from DWI for differentiating CLs from USs was 839 ×10-6 mm2/sec and was 1239 ×10-6 mm2/sec for differentiating CLs from degenerated LMs. Compared with the use of cMRI features and ADC value alone, combination of independent indicators and ADC value achieved higher AUCs for both differentiations (all P < 0.05).ConclusionscMRI is a reliable tool for differentiating CLs from USs and atypical leiomyoma, especially degenerated LMs. The combined use of cMRI and DWI can improve the differential diagnostic performance.

ObjectiveThis work was designed to investigate the performance of the International Ovarian Tumor Analysis (IOTA) ADNEX (Assessment of Different NEoplasias in the adneXa) model combined with human epithelial protein 4 (HE4) for early ovarian cancer (OC) detection.MethodsA total of 376 women who were hospitalized and operated on in Women and Children’s Hospital of Chongqing Medical University were selected. Ultrasonographic images, cancer antigen-125 (CA 125) levels, and HE4 levels were obtained. All cases were analyzed and the histopathological diagnosis serves as the reference standard. Based on the IOTA ADNEX model post-processing software, the risk prediction value was calculated. We analyzed receiver operating characteristic curves to determine whether the IOTA ADNEX model alone or combined with HE4 provided better diagnostic accuracy.ResultsThe area under the curve (AUC) of the ADNEX model alone or combined with HE4 in predicting benign and malignant ovarian tumors was 0.914 (95% CI, 0.881–0.941) and 0.916 (95% CI, 0.883–0.942), respectively. With the cutoff risk of 10%, the ADNEX model had a sensitivity of 0.93 (95% CI, 0.87–0.97) and a specificity of 0.73 (95% CI, 0.67–0.78), while combined with HE4, it had a sensitivity of 0.90 (95% CI, 0.84–0.95) and a specificity of 0.81 (95% CI, 0.76–0.86). The IOTA ADNEX model combined with HE4 was better at improving the accuracy of the differential diagnosis between different OCs than the IOTA ADNEX model alone. A significant difference was found in separating borderline masses from Stage II–IV OC (p = 0.0257).ConclusionsA combination of the IOTA ADNEX model and HE4 can improve the specificity of diagnosis of ovarian benign and malignant tumors and increase the sensitivity and effectiveness of the differential diagnosis of Stage II–IV OC and borderline tumors.

The co-occurrence of multiple primary cancers with hematological malignancies is uncommon, and acute promyelocytic leukemia (APL) with MPC is even rarer, with only a few cases reported in the literature. Herein, we introduce the diagnosis and treatment of 2 cases of MPC complicated with APL in our hospital and review the relevant literature. Both patients were primary solid tumor patients and were treated with surgery and chemotherapy, and had stable disease (SD). However, more than 1 year after the primary tumor was diagnosed, clinical symptoms were found and APL was diagnosed. Both patients received standard remission-induction therapy, but unfortunately died in the short term due to hemorrhagic complications. In conclusion, treatment of hematological neoplasms, especially acute leukemia combined with multiple primary cancers, is challenging. The prognostic factors and survival analysis of MPC patients with combined APL still need further clinical research and analysis.

ObjectiveCancer-associated mesenchymal stem cells (MSCs) regulate the progression of cancers through exosome-delivered components, while few studies are conducted on hepatocellular carcinoma (HCC). This study aimed to evaluate the effect of exosomes from HCC-associated MSCs (HCC-MSCs) on HCC cellular functions and the potential regulatory mechanism.MethodsHCC cells (Huh7 and PLC) were cultured normally or co-cultured with HCC-MSCs, HCC-MSCs plus GW4869, or HCC-MSC-derived exosomes; then mRNA sequencing and RT-qPCR validation were conducted. Subsequently, candidate genes were sorted out and modified in HCC cells. Next, TMBIM6-modified HCC-MSCs were used to treat HCC cells.ResultsBoth HCC-MSCs and their derived exosomes promoted proliferation, invasion, sphere formation ability but suppressed apoptosis in HCC cells (all p < 0.05); however, the effect of HCC-MSCs on these cellular functions was repressed by exosome inhibitor (GW4869). Subsequently, TMBIM6, EEF2, and PRDX1 were sorted out by mRNA sequencing and RT-qPCR validation as candidate genes implicated in the regulation of HCC cellular functions by HCC-MSC-derived exosomes. Among them, TMBIM6 had a potent effect (all p < 0.05), while EEF2 and PRDX1 had less effect on regulating HCC cell viability and invasion. Next, direct silencing TMBIM6 repressed viability, sphere formation, invasion, epithelial–mesenchymal transition (EMT), and PI3K/AKT pathway but promoted apoptosis in HCC cells; however, overexpressing TMBIM6 showed the opposite effect. Furthermore, incubating with exosomes from TMBIM6-modified HCC-MSCs presented a similar effect as direct TMBIM6 modification in HCC cells.ConclusionHCC-MSC-derived exosomes transmit TMBIM6 to promote malignant behavior via PI3K/AKT pathway in HCC.

ObjectivesAcute myeloid leukemia (AML) is a highly heterogeneous hematologic malignancy with widely variable prognosis. For this reason, a more tailored-stratified approach for prognosis is urgently needed to improve the treatment success rates of AML patients.MethodsIn the investigation of metabolic pattern in AML patients, we developed a metabolism-related prognostic model, which was consisted of metabolism-related gene pairs (MRGPs) identified by pairwise comparison. Furthermore, we analyzed the predictive ability and clinical significance of the prognostic model.ResultsGiven the significant differences in metabolic pathways between AML patients and healthy donors, we proposed a metabolism-related prognostic signature index (MRPSI) consisting of three MRGPs, which were remarkedly related with the overall survival of AML patients in the training set. The association of MRPSI with prognosis was also validated in two other independent cohorts, suggesting that high MRPSI score can identify patients with poor prognosis. The MRPSI and age were confirmed to be independent prognostic factors via multivariate Cox regression analysis. Furthermore, we combined MRPSI with age and constructed a composite metabolism-clinical prognostic model index (MCPMI), which demonstrated better prognostic accuracy in all cohorts. Stratification analysis and multivariate Cox regression analysis revealed that the MCPMI was an independent prognostic factor. By estimating the sensitivity of anti-cancer drugs in different AML patients, we selected five drugs that were more sensitive to patients in MCPMI-high group than those in MCPMI-low group.ConclusionOur study provided an individualized metabolism-related prognostic model that identified high-risk patients and revealed new potential therapeutic drugs for AML patients with poor prognosis.

Abstract Background Lung adenocarcinoma (LUAD) metastasis significantly reduces patient survival; hence inhibiting the metastatic ability of lung cancer cells will greatly prolong patient survival. Alkaline phosphatase (ALPL), a homodimeric cell surface phosphohydrolase, is reported to play a controversial role in prostate cancer and ovarian cancer cell migration; however, the function of ALPL in LUAD and the related mechanisms remain unclear. Methods TCGA database was used to analysis the expression of ALPL, and further verification was performed in a cohort of 36 LUAD samples by qPCR and western blot. Soft-agar assay, transwell assay and lung metastasis assay were employed to detect the function of ALPL in LUAD progression. The qPCR, luciferase promoter reporter assay and western blot were used to clarify the molecular mechanisms of ALPL in promoting metastasis in LUAD. Results ALPL was downregulated in LUAD, and the disease-free survival rate of patients with low ALPL was significantly reduced. Further studies showed that overexpression of ALPL in LUAD cell lines did not significantly affect cell proliferation, but it did significantly attenuate lung metastasis in a mouse model. ALPL downregulation in LUAD led to a decrease in the amount of phosphorylated (p)-ERK. Because p-ERK promotes the classical c-Myc degradation pathway, the decrease in p-ERK led to the accumulation of c-Myc and therefore to an increase in RhoA transcription, which enhanced LUAD cell metastasis. Conclusion ALPL specially inhibits the metastasis of LUAD cells by affecting the p-ERK/c-Myc/RhoA axis, providing a theoretical basis for the targeted therapy of clinical LUAD.

Telomerase reverse transcriptase (TERT) promoter mutations are frequently found in tumors or urine from patients with urothelial carcinoma (UC). TERT promoter mutations are also detected in urine from patients with no evidence of cancer but are associated with subsequent UC development. Mutations in the TERT promoter are thought to be present in nonmalignant urothelium (NMU) during early stages of tumor formation prior to pathological change, but this has not been proven directly. In this proof‐of‐concept study, we investigated the clinical utility of TERT promoter mutation analysis in NMU of patients with non‐muscle‐invasive bladder cancer (NMIBC). This single‐institute study included 53 primary tumors and 428 systematic bladder biopsy specimens from 54 patients with NMIBC. All patients underwent systematic random biopsy and transurethral resection of the bladder tumor. Genomic DNA was analyzed for TERT C228T and C250T mutations using droplet digital PCR (ddPCR). The association between TERT promoter mutation of NMU and bladder recurrence was examined by the Kaplan–Meier method and Cox proportional hazards model. Of the 54 patients, 16 (29.6%) had a TERT C228T mutation and three (5.6%) had a TERT C250T mutation in NMU. Of 428 biopsy specimens, the TERT C228T mutation was detected in 9% (31/364) of normal urothelium, 27% (4/15) of urothelial dysplasia (UD), 50% (9/18) of UD suspicious for carcinoma in situ (CIS), and 58% (18/31) of CIS. During follow‐up (median: 3.7 years), 22 (40.7%) patients experienced bladder recurrence and five (9.3%) experienced disease progression. Cox proportional hazard analysis showed that TERT C228T mutation in NMU was significantly associated with bladder recurrence after adjustment for cofounding factors (P = 0.0128). Thus, TERT C228T mutation was detected in NMU, which was a reliable independent prognostic factor of bladder tumor recurrence.

Wei Dong,1,2,* Hua Yu,1,2,* Yu-Yao Zhu,1,2,* Zhi-Hong Xian,1,2 Jia Chen,1,2 Hao Wang,3 Chun-Chao Shi,4 Guang-Zhi Jin,5 Hui Dong,1,2 Wen-Ming Cong1,2 1Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, People’s Republic of China; 2Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Second Military Medical University, The Ministry of Education, Shanghai 200438, People’s Republic of China; 3Department of Hepatobiliary Diseases, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, People’s Republic of China; 4Second Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai 200438, People’s Republic of China; 5Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200050, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui DongDepartment of Pathology, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, People’s Republic of ChinaEmail 13917078308@126.comWen-Ming CongDepartment of Pathology, Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, People’s Republic of ChinaEmail wmcong@smmu.edu.cnPurpose: This study aimed to propose an effective quantitative pathological scoring system and to establish nomogram to assess the stage of cirrhosis and predict postoperative survival of hepatocellular carcinoma (HCC) with cirrhosis patients after hepatectomy.Methods: The scoring system was based on a retrospective study on 163 patients who underwent partial hepatectomy for HCC with cirrhosis. The clinicopathological and follow-up data of 163 HCC with cirrhosis patients who underwent hepatectomy in our hospital from 2010 to 2014 were retrospectively reviewed. A scoring system was established based on the total value of independent predictive factors of cirrhosis. The results were validated using 97 patients operated on from 2011 to 2015 at the same institution. Nomogram was then formulated using a multivariate Cox proportional hazards model to analyze.Results: The scoring system was ultimately composed of 4 independent predictive factors and was divided into 3 levels. The new cirrhosis system score strongly correlated with Child–Pugh score (r=0.8058, P< 0.0001) 3 months after surgery; higher cirrhosis system scores predicted poorer liver function and stronger liver damage 3 months after surgery. Then, a four-factor nomogram for survival prediction was established. The concordance indices were 0.79 for the survival-prediction nomogram. The calibration curves showed good agreement between predictions by the nomogram and actual survival outcomes.Conclusion: This new scoring system of cirrhosis can help us predict the liver function and liver injury 3 months after surgery, and the nomogram enabled accurate predictions of risk of overall survival in patients of HCC with cirrhosis after hepatectomy.Keywords: cirrhosis, hepatocellular carcinoma, HCC, pathology, scoring system, nomogram

Background and objective Pembrolizumab, an immunotherapy for advanced non-small cell lung cancer (NSCLC), needs to predict treatment response based on test results including immunohistochemistry (IHC), which detects the expression of programmed death ligand 1 (PD-L1). The aim of this study was to evaluate the feasibility of immunocytochemistry (ICC) in NSCLC cytology to detect PD-L1 and to investigate the correlation between PD-L1 expression and clinical pathology and molecular features. Methods Sixty cases of lung adenocarcinoma pleural cytology were collected and PD-L1 sp263 reagent was used for immunocytochemical staining according to the manufacturer's instructions. Next-generation sequencing (NGS) was performed on pleural cytology specimens to explore its correlation. Results Of the 60 cases of lung adenocarcinoma pleural effusion cell block, 35 cases were positive for PD-L1 expression, and the positive expression rate was 58.3%. The positive rate of PD-L1 expression in the specimens of our hospital was 33.3%, and there was no significant difference between the cytological specimens and the histological specimens (P>0.05). Of the 60 cytological specimens, 26 were tested for NGS, and 15 (57.7%) were found to have epidermal growth factor receptor (EGFR) mutations. No correlation was found between PD-L1 expression and EGFR mutation. The positive expression rate of PD-L1 were not correlated with the age and gender in the study population (P>0.05). Conclusion When no surgical specimens are available, pleural cytology cell block specimens can be used for immunocytochemical detection of PD-L1, and the results are feasible.

Abstract Aims We aimed to establish a nomogram for lung cancer using patients' characteristics and potential hematological biomarkers. Methods Principle component analysis was used to reduce the dimensions of the data, and each component was transformed into categorical variables based on cutoff values obtained using the X‐tile software. Multivariate analysis was used to determine potential prognostic biomarkers. Five components were used in the predictive nomogram. Internal validation of the model was performed by bootstrapping of samples, while external validation was performed on a separate cohort from Shandong Cancer Hospital. The predictive accuracy of the model was measured by concordance index and risk group stratification. Decision curve analysis was performed to evaluate the net benefit of the models. Results One hundred patients in the Discovery group and 111 patients in the Validation group were retrospectively analyzed in this study. Forty‐seven indexes were sorted into eight subgroups. Five components based on cox regression analysis were enrolled into the predictive nomogram. The nomogram prediction of the probability of 3‐ and 5‐year overall survival was in great concordance with the actual observations. Of interest, the nomogram allowed better risk stratification of patients and better accuracy in predicting patients' survival compared with pathological tumor‐node‐metastasis staging system. Conclusion A nomogram was established for prognosis of lung cancer, which can be used for treatment selection and clinical care management.