Search

Abstract Background Chromosomal 1q gains and amplifications (+1q21) are frequently observed in patients with newly diagnosed multiple myeloma (NDMM). However, the interpretation of the high‐risk (HR) prognostic implications stemming from 1q21 abnormalities remain challenging to implement effectively. Methods In a comprehensive analysis of 367 consecutive patients with symptomatic MM, we assessed the prognostic significance of +1q21 using FISH with a threshold of 7.4%. The patient cohort was randomly divided into a training set (66.5%, n = 244) and a validation set (33.5%, n = 133). A multivariate Cox regression analysis was conducted to identify significant prognostic factors associated with PFS. Weight scores were assigned to each risk factor based on the β‐value of the corresponding regression coefficient. A predictive risk‐scoring model involving +1q21 was then developed, utilizing the total score derived from these weight scores. The model's discriminative ability was evaluated using the AUC in both the training and validation sets. Finally, we compared the performance of the +1q21‐involved risk with the established R‐ISS and R2‐ISS models. Results Upon initial diagnosis, 159 patients (43.32%) exhibited +1q21, with 94 (59.11%) having three copies, referred to as Gain(1q21), and 65 (40.89%) possessing four or more copies, referred to as Amp (1q21). Both were significantly linked to a reduced PFS in myeloma (p

Abstract Background Brain metastasis is one of the main causes of recurrence and death in non-small cell lung cancer (NSCLC). Although radiotherapy is the main local therapy for brain metastasis, it is inevitable that some cancer cells become resistant to radiation. Microglia, as macrophages colonized in the brain, play an important role in the tumor microenvironment. Radiotherapy could activate microglia to polarize into both the M1 and M2 phenotypes. Therefore, searching for crosstalk molecules within the microenvironment that can specifically regulate the polarization of microglia is a potential strategy for improving radiation resistance. Methods We used databases to detect the expression of MIF in NSCLC and its relationship with prognosis. We analyzed the effects of targeted blockade of the MIF/CD74 axis on the polarization and function of microglia during radiotherapy using flow cytometry. The mouse model of brain metastasis was used to assess the effect of targeted blockade of MIF/CD74 axis on the growth of brain metastasis. Result Our findings reveals that the macrophage migration inhibitory factor (MIF) was highly expressed in NSCLC and is associated with the prognosis of NSCLC. Mechanistically, we demonstrated CD74 inhibition reversed radiation-induced AKT phosphorylation in microglia and promoted the M1 polarization in combination of radiation. Additionally, blocking the MIF-CD74 interaction between NSCLC and microglia promoted microglia M1 polarization. Furthermore, radiation improved tumor hypoxia to decrease HIF-1α dependent MIF secretion by NSCLC. MIF inhibition enhanced radiosensitivity for brain metastasis via synergistically promoting microglia M1 polarization in vivo. Conclusions Our study revealed that targeting the MIF-CD74 axis promoted microglia M1 polarization and synergized with radiotherapy for brain metastasis in NSCLC.

BackgroundTelehealth has emerged as a popular channel for providing outpatient services in many countries. However, the majority of telehealth systems focus on operational functions and offer only a sectional patient journey at most. Experiences with incorporating longitudinal real-world medical record data into telehealth are valuable but have not been widely shared. The feasibility and usability of such a telehealth platform, with comprehensive, real-world data via a live feed, for cancer patient care are yet to be studied. ObjectiveThe primary purpose of this study is to understand the feasibility and usability of cancer patient care using a telehealth platform with longitudinal, real-world data via a live feed as a supplement to hospital electronic medical record systems specifically from physician’s perspective. MethodsA telehealth platform was constructed and launched for both physicians and patients. Real-world data were collected and curated using a comprehensive data model. Physician activities on the platform were recorded as system logs and analyzed. In February 2023, a survey was conducted among the platform’s registered physicians to assess the specific areas of patient care and to quantify their before and after experiences, including the number of patients managed, time spent, dropout rate, visit rate, and follow-up data. Descriptive and inferential statistical analyses were performed on the data sets. ResultsOver a period of 15 months, 16,035 unique users (13,888 patients, 1539 friends and family members, and 174 physician groups with 608 individuals) registered on the platform. More than 382,000 messages including text, reminders, and pictures were generated by physicians when communicating with patients. The survey was completed by 78 group leaders (45% of the 174 physician groups). Of the participants, 84% (65.6/78; SD 8.7) reported a positive experience, with efficient communication, remote supervision, quicker response to questions, adverse event prevention, more complete follow-up data, patient risk reduction, cross-organization collaboration, and a reduction in in-person visits. The majority of the participants (59/78, 76% to 76/78, 97.4%) estimated improvements in time spent, number of patients managed, the drop-off rate, and access to medical history, with the average ranging from 57% to 105%. When compared with prior platforms, responses from physicians indicated better experiences in terms of time spent, the drop-off rate, and medical history, while the number of patients managed did not significantly change. ConclusionsThis study suggests that a telehealth platform, equipped with comprehensive, real-world data via a live feed, is feasible and effective for cancer patient care. It enhances inpatient management by improving time efficiencies, reducing drop-off rates, and providing easy access to medical history. Moreover, it fosters a positive experience in physician-patient interactions.

Abstract Background Aponermin, a circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, is a potential death receptor 4/5-targeted antitumour candidate. Previous phase 1/2 studies have demonstrated the efficacy of aponermin in patients with relapsed or refractory multiple myeloma (RRMM). To confirm the superiority of aponermin plus thalidomide and dexamethasone (aponermin group) over placebo plus thalidomide and dexamethasone (placebo group) in RRMM, a randomized, double-blinded, placebo controlled phase 3 trial was performed. Methods Four hundred seventeen patients with RRMM who had previously received at least two regimens were randomly assigned (2:1) to receive aponermin, thalidomide, and dexamethasone or placebo, thalidomide, and dexamethasone. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and overall response rate (ORR). Results A total of 415 patients received at least one dose of trial treatment (276 vs. 139). The median PFS was 5.5 months in the aponermin group and 3.1 months in the placebo group (hazard ratio, 0.62; 95% confidence interval [CI], 0.49–0.78; P

Tendon Sheath Giant Cell Tumor (TGCT) is a benign tumor that primarily grows within joints and bursae. However, it has a high postoperative recurrence rate, ranging from 15% to 45%. Although radiotherapy may reduce this recurrence rate, its applicability as a standard treatment is still controversial. Furthermore, the pathogenic mechanisms of TGCT are not clear, which limits the development of effective treatment methods. The unpredictable growth and high recurrence rate of TGCT adds to the challenges of disease management. Currently, our understanding of TGCT mainly depends on pathological slice analysis due to a lack of stable cell models. In this study, we first reviewed the medical records of two female TGCT patients who had undergone radiotherapy. Then, by combining bioinformatics and machine learning, we interpreted the pathogenesis of TGCT and its associations with other diseases from multiple perspectives. Based on a deep analysis of the case data, we provided empirical support for postoperative radiotherapy in TGCT patients. Additionally, our further analysis revealed the signaling pathways of differentially expressed genes in TGCT, as well as its potential associations with osteoarthritis and synovial sarcomas.

BackgroundSince no randomized controlled trials have directly compared the efficacy and safety of immunotherapy with daratumumab versus lenalidomide/bortezomib/dexamethasone (RVD) in the frontline treatment of transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM), this study systematically reviewed the clinical studies regarding immunotherapy with daratumumab and RVD regimen in the treatment of TIE-NDMM to explore the optimization direction of the best first-line therapy.MethodsThe Cochrane Library, PubMed, Embase, and Web of Science databases were searched to collect studies on regimens containing daratumumab or RVD/RVD-lite for TIE-NDMM. Pooled and meta-analysis was then performed to compare the overall response rate (ORR), stringent complete remission (sCR) and CR rate, progression-free survival (PFS), overall survival (OS) and treatment-related discontinuation rate between daratumumab-containing immunotherapy regimen and RVD/RVD-lite regimen by using R 4.3.1 software.ResultsNine prospective clinical trials were included, including 1795 TIE-NDMM or NDMM without intent for immediate ASCT. Among them, 938 patients were treated with daratumumab-based immunotherapy and 857 with RVD/RVD-lite regimens. Meta-analysis results showed that The daratumumab-based regimen showed a significantly higher CR/sCR rate than RVD/RVD-lite for TIE-NDMM (47% vs. 24%, P

Abstract Purpose Pyroptosis, a type of programmed cell death, is implicated in the tumorigenesis, development and migration of cancer, which can be regulated by long non‐coding RNAs (lncRNAs). Our research aimed to investigate the prognostic role of pyroptosis‐related lncRNAs and the relationship to the tumor immune microenvironment through bioinformatics analysis. Methods The clinical and RNA‐sequencing data of bladder cancer patients were downloaded from The Cancer Genome Atlas (TCGA). And 412 bladder cancer subjects with clinical information were divided into training and testing cohort. And 52 reported pyroptosis‐related genes were used to screen pyroptosis‐related lncRNAs. A pyroptosis‐related lncRNA signature was constructed based on Cox regression analyses. Results A 9‐pyroptosis‐related‐lncRNA signature was identified to separate patients with bladder cancer into two groups. The prognosis of bladder cancer patients in the high‐risk group was significantly inferior compared with those in the low‐risk group. Risk scores were validated to develop an independent prognostic indicator based on multivariate Cox regression analysis. Receiver operating characteristic curve (ROC) analysis examined the signature on overall survival. The area under time‐dependent ROC curve (AUC) at 1‐, 3, and 5‐years measured 0.747, 0.783, and 0.768, respectively. Analysis of the immune landscape and PD‐L1 expression showed that PD‐L1 is upregulated in the high‐risk group. The immunocyte subtypes of the two groups were different. Conclusion A novel pyroptosis‐related lncRNA signature was identified with prognostic value for bladder cancer patients. Pyroptosis‐related lncRNAs have a potential role in cancer immunology and may serve as prognostic or therapeutic targets.

Abstract Objective Despite the availability of new agents, elderly patients with multiple myeloma (MM) usually present with poor outcomes due to the heterogeneity of disease conditions, especially immune deficiency. Regulatory B cells (Bregs) can be involved in immune defects by exerting immune regulatory functions in MM. In order to provide more evidence‐based practice for the elderly MM, the study established and assessed a stratified therapeutic model with studies on Bregs for Chinese Elderly Multiple Myeloma in 2021 (CEMM2021). Methods In this open‐label, non‐interventional, prospective study in the real world, 159 newly diagnosed MM (NDMM) patients over 65 years old were sequentially recruited and bone marrow aspirates prior to treatment were obtained to detect the ratios of Bregs by flow cytometry. Results Based on the CEMM2021 model, 147 patients had received at least one cycle of induction therapy, including bortezomib/dexamethasone (Bd) (n = 80), lenalidomide/dexamethasone (Rd) (n = 27), Bd with a third agent X (Bd + X) (n = 27), and other regimens (n = 13). The proportions of patients achieving very good partial response or better were comparable among Bd, Bd + X, and Rd groups (41.9% vs. 54.5% vs. 44.0%, p = 0.472). Besides, the progression‐free survival (PFS) and overall survival (OS) were not significantly different among Rd, Bd, and Bd + X groups. Multivariable analysis showed that induction efficacy less than partial response (PR) were poor prognostic factors for PFS, while Revised‐International Staging System (R‐ISS) III and efficacy less than PR were poor prognostic factors for OS. This study also found that the ratios of bone marrow Bregs 4.2 (p = 0.000) were closely correlated with OS in the elderly MM. Conclusions For the elderly NDMM, the CEMM2021 algorithm in our center might provide a valuable reference for the guidance of therapeutic strategies, with the combination of Bregs resulting in an effective and clinically meaningful prediction in contemporary treatment.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte-associated antigen-4 have shown significantly durable clinical benefits and tolerable toxicities and have improved the survival of patients with various types of cancer. Since 2018, the National Medical Products Administration of China has approved 17 ICIs as the standard treatment for certain advanced or metastatic solid tumors. As ICIs represent a broad-spectrum antitumor strategy, the populations eligible for cancer immunotherapy are rapidly expanding. However, the clinical applications of ICIs in cancer patient populations with special issues, a term that refers to complex subgroups of patients with comorbidities, special clinical conditions, or concomitant medications who are routinely excluded from prospective clinical trials of ICIs or are underrepresented in these trials, represent a great real-world challenge. Although the Chinese Society of Clinical Oncology (CSCO) has provided recommendations for screening before the use of ICIs in special populations, the recommendations for full-course management remain insufficient. The CSCO Expert Committee on Immunotherapy organized leading medical oncology and multidisciplinary experts to develop a consensus that will serve as an important reference for clinicians to guide the proper application of ICIs in special patient populations. This article is a translation of a study first published in Chinese in The Chinese Clinical Oncology (ISSN 1009-0460, CN 32-1577/R) in May 2022 (27(5):442–454). The publisher of the original paper has provided written confirmation of permission to publish this translation in Therapeutic Advances in Medical Oncology .

ObjectivePreoperative noninvasive diagnosis of the benign or malignant solitary pulmonary nodule (SPN) is still important and difficult for clinical decisions and treatment. This study aimed to assist in the preoperative diagnosis of benign or malignant SPN using blood biomarkers.MethodsA total of 286 patients were recruited for this study. The serum FR+CTC, TK1, TP, TPS, ALB, Pre-ALB, ProGRP, CYFRA21-1, NSE, CA50, CA199, and CA242 were detected and analyzed.ResultsIn the univariate analysis, age, FR+CTC, TK1, CA50, CA19.9, CA242, ProGRP, NSE, CYFRA21-1, and TPS showed the statistical significance of a correlation with malignant SPNs (P

Background: The COVID-19 pandemic is a significant worldwide health crisis. Breast cancer patients with COVID-19 are fragile and require particular clinical care. This study aimed to identify the clinical characteristics of breast cancer patients with COVID-19 and the risks associated with anti-cancer treatment. Methods: The medical records of breast cancer patients with laboratory-confirmed COVID-19 were collected among 9559 COVID-19 patients from seven designated hospitals from 13th January to 18th March 2020 in Hubei, China. Univariate and multivariate analyses were performed to assess risk factors for COVID-19 severity. Results: Of the 45 breast cancer patients with COVID-19, 33 (73.3%) developed non-severe COVID-19, while 12 (26.7%) developed severe COVID-19, of which 3 (6.7%) patients died. The median age was 62 years, and 3 (6.7%) patients had stage IV breast cancer. Univariate analysis showed that age over 75 and the Eastern Cooperative Oncology Group (ECOG) score were associated with COVID-19 disease severity (P

Abstract Ferroptosis is an iron-dependent cell death characterized by the accumulation of hydroperoxided phospholipids. Here, we report that the NUPR1 inhibitor ZZW-115 induces ROS accumulation followed by a ferroptotic cell death, which could be prevented by ferrostatin-1 (Fer-1) and ROS-scavenging agents. The ferroptotic activity can be improved by inhibiting antioxidant factors in pancreatic ductal adenocarcinoma (PDAC)- and hepatocellular carcinoma (HCC)-derived cells. In addition, ZZW-115-treatment increases the accumulation of hydroperoxided lipids in these cells. We also found that a loss of activity and strong deregulation of key enzymes involved in the GSH- and GPX-dependent antioxidant systems upon ZZW-115 treatment. These results have been validated in xenografts induced with PDAC- and HCC-derived cells in nude mice during the treatment with ZZW-115. More importantly, we demonstrate that ZZW-115-induced mitochondrial morphological changes, compatible with the ferroptotic process, as well as mitochondrial network disorganization and strong mitochondrial metabolic dysfunction, which are rescued by both Fer-1 and N-acetylcysteine (NAC). Of note, the expression of TFAM, a key regulator of mitochondrial biogenesis, is downregulated by ZZW-115. Forced expression of TFAM is able to rescue morphological and functional mitochondrial alterations, ROS production, and cell death induced by ZZW-115 or genetic inhibition of NUPR1. Altogether, these results demonstrate that the mitochondrial cell death mediated by NUPR1 inhibitor ZZW-115 is fully rescued by Fer-1 but also via TFAM complementation. In conclusion, TFAM could be considered as an antagonist of the ferroptotic cell death.

Abstract Background Increasing evidence suggests that hepatitis C virus (HCV) infection is associated with non-Hodgkin’s lymphoma (NHL). However, no clear consensus has been reached about the clinical features and effective treatment of HCV-associated NHL patients. We therefore performed a systematic review and meta-analysis to explore the clinical characteristics and effectiveness of antiviral treatment or rituximab administration among NHL patients with HCV infection. Methods Eight electronic databases, including PubMed, OVID, EMBASE, Cochrane Library, ClinicalTrials, WANFANG, CNKI, and VIP, were searched for eligible studies up to July 31, 2021. The hazard ratio (HR) or odds ratio (OR) corresponding to the 95% confidence interval (CI) was calculated to estimate the outcomes. Publication bias was assessed by Egger’s and Begg’s tests. Statistical analysis was performed with RevMan 5.4 software and Stata version 15. Results There were 27 shortlisted articles out of a total of 13,368 NHL patients included in the current meta-analysis. Our results demonstrated that NHL patients with HCV infection had a significantly shorter overall survival (OS: HR 1.89; 95% CI 1.42–2.51, P

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. There are many uncommon and rare mutations in the EGFR gene. The efficacy of the EGFR-TKIs is largely unknown for cancers harboring uncommon or rare EGFR mutations.Case PresentationA 69-year-old woman was diagnosed with adenocarcinoma cT4N2M1c, stage IVB. Next-generation sequencing (NGS) confirmed a rare EGFR V786M mutation. During chemotherapy, immune checkpoint inhibitor (ICI), and anti-angiogenic treatment, no radiological response was observed. Subsequent third-generation EGFR TKI showed a remarkable therapeutic effect. Structural prediction revealed that the V786M mutation induces conformational change at the dimer interface, without altering the ATP binding to the EGFR tyrosine kinase domain (TKD). Consistently, docking simulations indicated that the affinity of ATP to the V786M mutant was not disturbed, which explained the TKI sensitivity.ConclusionsOur data confirmed the activating role on EGFR V786M mutation. Together with structural predictions and clinical evidence for activity of TKIs against EGFR V786M mutations, these findings warrant further investigation.

Anaplastic lymphoma kinase (ALK) alterations in non-small cell lung cancer (NSCLC) can be effectively treated with a variety of ALK-targeted drugs. After the approval of the first-generation ALK inhibitor crizotinib which achieved better results in prolonging the progression-free survival (PFS) compared with chemotherapy, a number of next-generation ALK inhibitors have been developed including ceritinib, alectinib, brigatinib, and ensartinib. Recently, a potent, third-generation ALK inhibitor, lorlatinib, has been approved by the Food and Drug Administration (FDA) for the first-line treatment of ALK-positive (ALK+) NSCLC. These drugs have manageable toxicity profiles. Responses to ALK inhibitors are however often not durable, and acquired resistance can occur as on-target or off-target alterations. Studies are underway to explore the mechanisms of resistance and optimal treatment options beyond progression. Efforts have also been undertaken to develop further generations of ALK inhibitors. This review will summarize the current situation of targeting the ALK signaling pathway.

Abstract Background Bruton tyrosine kinase (BTK) inhibitors have demonstrated a high degree of efficacy in the treatment of B cell malignancies characterized by constitutive B cell receptor activation, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Methods The efficacy and safety of zanubrutinib, an investigational highly selective BTK inhibitor, was evaluated in this single-arm, phase 2 study of Chinese patients with relapsed/refractory CLL/SLL. The primary endpoint was overall response rate as assessed by an independent review committee. Results Of the 91 evaluable patients, 77 (84.6%) achieved a response, with three (3.3%), 54 (59.3%), and 20 (22%) patients achieving a complete response, partial response, and partial response with lymphocytosis, respectively, after a median follow-up of 15.1 months. The estimated 12-month event-free rate for duration of response was 92.9%. The most commonly reported grade ≥ 3 adverse events (AEs) were neutropenia (44%), thrombocytopenia (15.4%), lung infection/pneumonia (13.2%), upper respiratory tract infection (9.9%), and anemia (8.8%). The 12-month overall survival rate was 96%. Eight (9.0%) patients discontinued zanubrutinib due to AEs, and seven (8.0%) patients required at least one dose reduction. Conclusion Treatment of patients with relapsed/refractory CLL/SLL with zanubrutinib was generally well tolerated and resulted in a high overall response rate, thereby conferring a favorable benefit-risk profile. Trial registration Prospectively registered in China public registry (CTR20160890) on December 7, 2016: http://www.chinadrugtrials.org.cn/ . Retrospectively registered in ClinicalTrials.gov ( NCT03206918 ) on July 2, 2017.

BackgroundThe current clinical workflow for esophageal gross tumor volume (GTV) contouring relies on manual delineation with high labor costs and inter-user variability.PurposeTo validate the clinical applicability of a deep learning multimodality esophageal GTV contouring model, developed at one institution whereas tested at multiple institutions.Materials and MethodsWe collected 606 patients with esophageal cancer retrospectively from four institutions. Among them, 252 patients from institution 1 contained both a treatment planning CT (pCT) and a pair of diagnostic FDG-PET/CT; 354 patients from three other institutions had only pCT scans under different staging protocols or lacking PET scanners. A two-streamed deep learning model for GTV segmentation was developed using pCT and PET/CT scans of a subset (148 patients) from institution 1. This built model had the flexibility of segmenting GTVs via only pCT or pCT+PET/CT combined when available. For independent evaluation, the remaining 104 patients from institution 1 behaved as an unseen internal testing, and 354 patients from the other three institutions were used for external testing. Degrees of manual revision were further evaluated by human experts to assess the contour-editing effort. Furthermore, the deep model’s performance was compared against four radiation oncologists in a multi-user study using 20 randomly chosen external patients. Contouring accuracy and time were recorded for the pre- and post-deep learning-assisted delineation process.

BackgroundAlternative splicing (AS) is a gene regulatory mechanism that drives protein diversity. Dysregulation of AS is thought to play an essential role in cancer initiation and development. This study aimed to construct a prognostic signature based on AS and explore the role in the tumor immune microenvironment (TIME) in lung adenocarcinoma.MethodsWe analyzed transcriptome profiling and clinical lung adenocarcinoma data from The Cancer Genome Atlas (TCGA) database and lists of AS-related and immune-related signatures from the SpliceSeq. Prognosis-related AS events were analyzed by univariate Cox regression analysis. Gene set enrichment analyses (GSEA) were performed for functional annotation. Prognostic signatures were identified and validated using univariate and multivariate Cox regression, LASSO regression, Kaplan–Meier survival analyses, and proportional hazards model. The context of TIME in lung adenocarcinoma was also analyzed. Gene and protein expression data of Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) were obtained from ONCOMINE and Human Protein Atlas. Splicing factor (SF) regulatory networks were visualized.ResultsA total of 19,054 survival-related AS events in lung adenocarcinoma were screened in 1,323 genes. Exon skip (ES) and mutually exclusive exons (ME) exhibited the most and fewest AS events, respectively. Based on AS subtypes, eight AS prognostic signatures were constructed. Patients with high-risk scores were associated with poor overall survival. A nomogram with good validity in prognostic prediction was generated. AUCs of risk scores at 1, 2, and 3 years were 0.775, 0.736, and 0.759, respectively. Furthermore, the prognostic signatures were significantly correlated with TIME diversity and immune checkpoint inhibitor (ICI)-related genes. Low-risk patients had a higher StromalScore, ImmuneScore, and ESTIMATEScore. AS-based risk score signature was positively associated with CD8+ T cells. CDKN2A was also found to be a prognostic factor in lung adenocarcinoma. Finally, potential functions of SFs were determined by regulatory networks.ConclusionTaken together, our findings show a clear association between AS and immune cell infiltration events and patient outcome, which could provide a basis for the identification of novel markers and therapeutic targets for lung adenocarcinoma. SF networks provide information of regulatory mechanisms.

BackgroundTargeted therapies have led to significant improvement in the management and prognosis of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). We performed a network meta-analysis of frontline treatment options of ALK-positive NSCLC to provide clinical guidance.MethodsPubMed, Embase, ClinicalTrials.gov, and international conference databases were searched to identify relevant trials from inception to June 30, 2021. Phase III randomized controlled trials (RCTs) comparing treatments for patients with ALK-positive advanced NSCLC in the first-line setting were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcomes: progression-free survival (PFS), overall survival (OS), risk of the central nervous system (CNS) progression, adverse events (AEs) of grade (G) 3 or higher (G3 AEs), or serious AEs (SAEs). Hazard ratios (HRs) and CI for primary outcome of PFS and secondary outcome of OS and risk of CNS progression were obtained. A multivariate, consistency model, fixed-effects analysis was used in the network meta-analysis. Data on G3 AEs and SAEs were abstracted and meta-analyzed. Risk of bias (RoB) was assessed using the Cochrane Collaboration’s tool.ResultsNine RCTs comprising 2,484 patients were included with seven treatments: alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Compared with chemotherapy, ALK-tyrosine kinase inhibitors (TKIs) significantly prolong PFS and reduced risk of CNS progression except for ceritinib. Lorlatinib appears superior at reducing risk of CNS progression. None of the ALK-TKIs have a significantly prolonged OS as compared with chemotherapy. Lorlatinib increases the risk of G3 AEs as compared with alectinib (odds ratio 4.26 [95% CrI 1.22 to 15.53]), while alectinib caused the fewest G3 AEs.ConclusionsLorlatinib is associated with the highest PFS benefit and lowest risk of CNS progression benefits for patients with advanced ALK-positive NSCLC, compared with other first-line treatments, but with higher toxicity. The implementation of a newer generation of ALK-TKIs in the first-line treatment of ALK-positive NSCLC into current clinical practice is evolving rapidly.

BackgroundThe therapeutic efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced EGFR-mutant lung squamous cell carcinoma (SCC) patients remains uncertain. Furthermore, the factors underlying the responsiveness have not been fully investigated. We therefore investigated the link between genomic profiles and EGFR-TKI efficacy.Material and MethodsWe consecutively enrolled stage IV, EGFR-mutant, and EGFR-TKI–treated patients with SCC. Patients with EGFR wild-type lung SCC and EGFR-mutant lung adenocarcinoma were consecutively enrolled as controls, and next-generation sequencing (NGS) was performed.ResultsIn total, 28 EGFR-mutant lung SCC, 41 EGFR-mutant lung adenocarcinoma, and 40 EGFR wild-type lung SCC patients were included. Among the patients with EGFR mutations, shorter progression-free survival (PFS) was observed in SCC compared to adenocarcinoma (4.6 vs. 11.0 months, P

BackgroundFirst-line treatment strategies for programmed death-ligand 1 (PD-L1) negative non-small cell lung cancer (NSCLC) patients include chemotherapy and combination with anti-angiogenesis drugs and/or immune checkpoint inhibitor. We conducted a Bayesian network meta-analysis to evaluate the efficacy of these therapeutic options.MethodsWe included phase III randomized controlled trials comparing two or more treatments in the first-line setting for NSCLC, including data in PD-L1–negative patients. First-line strategies were compared and ranked based on the effectiveness in terms of overall survival (OS) and progression-free survival (PFS). A rank was assigned to each treatment after Markov Chain Monte Carlo analyses.ResultsFourteen trials involving 14 regimens matched our eligibility criteria. For OS, none of the treatment were significantly more effective than chemotherapy. Nivolumab plus ipilimumab plus chemotherapy was probably the best option based on analysis of the treatment ranking (probability = 30.1%). For PFS, nivolumab plus chemotherapy plus bevacizumab, atezolizumab plus chemotherapy plus bevacizumab, and atezolizumab plus chemotherapy were statistically superior to chemotherapy in pairwise comparison. Nivolumab plus chemotherapy plus bevacizumab was likely to be the preferred option based on the analysis of the treatment ranking (probability = 72.9%).ConclusionsNivolumab plus chemotherapy, in combination with angiogenesis inhibition or anti-cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), had maximal benefits for NSCLC patient of PD-L1–negative expression. These findings may facilitate individualized treatment strategies. Safety at an individual patient level should be considered in decision making. Further validation is warranted.

Macrophage migration inhibitory factor (MIF) has been shown to promote disease progression in many malignancies, including multiple myeloma (MM). We previously reported that MIF regulates MM bone marrow homing and knockdown of MIF favors the extramedullary myeloma formation in mice. Here, based on MIF immunostaining of myeloma cells in paired intramedullary and extramedullary biopsies from 17 patients, we found lower MIF intensity in extramedullary MM (EMM) versus intramedullary MM (IMM). Flow cytometry and histology analysis in xenograft models showed a portion of inoculated human MM cells lost their MIF expression (MIFLow) in vivo. Of note, IMM had dominantly MIFHigh cells, while EMM showed a significantly increased ratio of MIFLow cells. Furthermore, we harvested the extramedullary human MM cells from a mouse and generated single-cell transcriptomic data. The developmental trajectories of MM cells from the MIFHigh to MIFLow state were indicated. The MIFHigh cells featured higher proliferation. The MIFLow ones were more quiescent and harbored abundant ribosomal protein genes. Our findings identified in vivo differential regulation of MIF expression in MM and suggested a potential pathogenic role of MIF in the extramedullary spread of disease.

Abstract Background Breast cancer is one of the most common malignancies and the major cause of cancer-related death in women. Although the importance of PIWI-interacting RNAs (piRNAs) in cancer has been increasingly recognized, few studies have been explored the functional mechanism of piRNAs in breast cancer development and progression. Methods We examined the top 20 highly expressed piRNAs based on the analysis of TCGA breast cancer data in two patient cohorts to test the roles of piRNAs in breast cancer. The effects of piRNA-36,712 on the malignant phenotypes and chemosensitivity of breast cancer cells were detected in vitro and in vivo. MS2-RIP and reporter gene assays were conducted to identify the interaction and regulation among piRNA-36,712, miRNAs and SEPW1P. Kaplan-Meier estimate with log-rank test was used to compare patient survival by different piRNA-36,712 expression levels. Results We found piRNA-36,712 level was significantly lower in breast cancer than in normal breast tissues and low level was correlated with poor clinical outcome in patients. Functional studies demonstrated that piRNA-36,712 interacts with RNAs produced by SEPW1P, a retroprocessed pseudogene of SEPW1, and subsequently inhibits SEPW1 expression through competition of SEPW1 mRNA with SEPW1P RNA for microRNA-7 and microRNA-324. We also found that higher SEPW1 expression due to downregulation of piRNA-36,712 in breast cancer may suppress P53, leading to the upregulated Slug but decreased P21 and E-cadherin levels, thus promoting cancer cell proliferation, invasion and migration. Furthermore, we found that piRNA-36,712 had synergistic anticancer effects with the paclitaxel and doxorubicin, two chemotherapeutic agents for breast cancer. Conclusions These findings suggest that piRNA-36,712 is a novel tumor suppressor and may serve as a potential predictor for the prognosis of breast cancer patients.

IntroductionPrevious studies have demonstrated that programmed cell death-ligand 1 (PD-L1) serves as biomarker for poor prognosis and survival in advanced-stage non-small cell lung cancer (NSCLC) patients. However, the merit of PD-L1 expression to predict the prognosis of early stage NSCLC patients who underwent complete resection remains controversial. In the present study, we performed a meta-analysis to investigate the relationship between PD-L1 expression and prognosis in patients with early stage resected NSCLC.MethodsElectronic databases, including PubMed, EMBASE, and the Cochrane Library, were searched until July 23 2020 for studies evaluating the expression of PD-L1 and the prognosis of resected NSCLCs. Hazard ratios (HRs) with 95% confidence intervals (CIs) of overall survival (OS) and disease-free survival (DFS) were pooled and analyzed. Heterogeneity and publication bias analyses were also assessed.ResultsA total of 15 studies involving 3,790 patients were considered in the present meta-analysis. The pooled HR indicated that PD-L1 expression related to a much shorter DFS (HR = 1.56, 95% CI: 1.18–2.05, p < 0.01), as well a significantly worse OS (HR = 1.68, 95% CI: 1.29–2.18, p < 0.01). Furthermore, our analysis indicated that PD-L1 expression was significantly associated with gender (male vs. female: OR = 1.27, 95% CI:1.01–1.59, p = 0.038), histology (ADC vs. SCC: OR = 0.54, 95% CI:0.38–0.77, p = 0.001), TNM stage (I vs. II–III: OR = 0.45, 95% CI:0.34–0.60, p = 0.000), smoking status (Yes vs No: OR = 1.43, 95% CI:1.14–1.80, p = 0.002) and lymph node metastasis (N+ vs N−: OR = 1.97, 95% CI:1.26–3.08, p = 0.003).ConclusionsThe results of this meta-analysis suggest that PD-L1 expression predicts an unfavorable prognosis in early stage resected NSCLCs. The role of personalized anti-PD-L1/PD-1 immunotherapy in the adjuvant settings of resected NSCLC warrants further investigation.

BackgroundMicrosatellite stable (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. However, a recent Japanese trial showed that regorafenib plus nivolumab had encouraging anti-cancer activity in MSS or pMMR mCRCs.Materials and MethodsWe retrospectively reviewed the efficacy and safety data of combination therapy with regorafenib plus anti-PD-1 antibody in patients with refractory MSS or pMMR mCRC in the medical centers of Shandong Province in China.ResultsTwenty-three patients with MSS or pMMR mCRC received regorafenib plus anti-PD-1 antibody. Eighteen (78.3%) patients experienced stable disease as best response, five (21.7%) patients had progressive disease, and no partial response was observed. The disease control rate (DCR) was 78.3% (18/23), and the median progression-free survival (PFS) was 3.1 months (95% CI, 2.32-3.89). Four of five (80.0%) patients with progressive disease had baseline liver metastasis, while nine of 18 (50.0%) patients with stable disease displayed no liver metastasis. One patient receiving radiofrequency ablation treatment for liver and abdominal wall metastases prior to combination treatment experienced a remarkably prolonged PFS of 9.2 months with SD. Neither liver metastasis status nor previous exposure to regorafenib was associated with treatment outcome. Treatment-related grade 3 toxicities were observed in 5/23 (21.7%) patients.ConclusionNo objective response was observed with the combination of regorafenib plus anti-PD-1 antibody, suggesting its little clinical activity in unselected Chinese patients with pMMR/MSS mCRC. Meanwhile, it exhibited some potential benefit in this cohort in terms of DCR and PFS. Adverse events were generally tolerable and manageable. Prospective studies with large sample sizes are needed to verify the findings. This combination strategy plus local ablative therapy might be worthy of further exploration.

Immune checkpoint inhibitors (ICIs) cause fewer toxicities than conventional chemotherapy. Although most of the immune-related adverse events (irAEs) are mild, reversible, and manageable, potentially severe and rare irAEs remain relevant. We present a 24-year-old man with advanced hereditary renal cancer who developed bilateral posterior uveitis and retinal detachment after systematic treatment of ICI and an anti-angiogenic drug. Axitinib and pembrolizumab were administered with a partial response and following the severe ocular irAE and systemic corticosteroid treatment was initiated. Our case indicates that ocular irAEs may occur rapidly. To the best of our knowledge, this is the first case of posterior uveitis and retinal detachment in hereditary renal cancer patients treated with ICI and anti-angiogenic drugs.

Targeted therapies are efficient in the context of oncogenic driver mutations. Epidermal growth factor receptor (EGFR)-mutant lung cancers represent a distinct subset of non-small-cell lung cancer (NSCLC) with marked sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Despite the high response rate to EGFR TKIs in EGFR-mutant lung cancer, resistance and tumor recurrence are unavoidable. Therapeutic options are restricted in patients after exhaustion of targeted therapies. Immune checkpoint inhibitors (ICIs) represent a novel therapeutic option for advanced NSCLC with significant overall survival benefit in registration trials. No superiority in terms of long-term survival was observed in the EGFR mutation subgroup when ICIs were given as monotherapy in second-line treatment in earlier studies. Thus, the appropriate application of ICIs to patients harboring EGFR mutations remains an important field of ongoing research. Here, we discuss different immune checkpoint blockade strategies, including ICIs alone and in combination with TKIs, chemotherapy, radiation, and antiangiogenic agents in EGFR-mutant NSCLC as first-line and subsequent treatments. We also summarize the evidence concerning the heterogeneous molecular features and immune signatures of EGFR mutations and their associations with ICI therapy outcomes. This study was performed to improve our understanding of the optimal mode of immune-based treatment approaches in EGFR-mutant NSCLC.

Background Subgroup analysis of clinical trials of PD-1/PD-L1 inhibitors have reported ethnic differences in outcomes. We systematically collected published data and performed a meta-analysis to compare therapeutic efficacy in Asian and non-Asian patients receiving PD-1/PD-L1 inhibitors. Methods Eligible studies included phase II and III prospective clinical trials with available subgroup data on Asian versus non-Asian populations. Overall survival (OS) and progression-free survival (PFS) were used to evaluate differences in outcome between Asian versus non-Asian cancer patients. Results A total of 11,020 cancer patients from 19 prospective randomized controlled clinical trials were included. The overall estimated HR for OS was 0.69 with 95% CI of 0.61–0.77 in Asian versus 0.82 with 95% CI of 0.77–0.88 in non-Asian patients. The estimated hazard ratio (HR) for PFS measured 0.54 (95% CI, 0.32–0.76) and 0.69 (95% CI, 0.54–0.85) in Asian and non-Asian patients, respectively. Pooled ratios of OS HRs and PFS HRs reported in Asian versus non-Asian cancer patients were 0.84 (95% CI, 0.75–0.94) and 0.78 (95% CI, 0.59–0.97), respectively. Conclusions This meta-analysis shows for the first time that Asian cancer patients have a significantly improved survival benefit than non-Asian patients receiving PD-1/PD-L1 inhibitor-based therapy.

Abstract Background We describe the first reported case of myelofibrosis as an extremely rare complication of gastric cancer during pregnancy; the clinical diagnosis and treatment of which is highly challenging due to nonspecific symptoms coupled with the conflicting needs of immediate disease control and continuation of pregnancy. Case presentation We report a 36-year-old pregnant woman who presented with cytopenia, fatigue, vomiting, and diarrhea for 20 days on the background of newly diagnosed myelofibrosis secondary to gastric signet ring adenocarcinoma. She accepted palliative care and died several months after the delivery of a healthy newborn. Conclusion Signet ring gastric adenocarcinoma is an unusual cause of myelofibrosis during pregnancy. Treatment remains a great challenge as clinicians have to consider the needs of immediate treatment against fetal well-being while taking into account patient preference and fetus rights.

Intrinsically disordered proteins (IDPs) do not have a well-defined structure, but they have key biological tasks in cancer development. By using the disordered cancer-related protein NUPR1 as a proof-of-concept, we have developed a new multidisciplinary approach to tackle drug-design against IDPs, using it to repurpose drugs for treating pancreatic adenocarcinoma (PDAC).

Abstract Background Previous research suggested that single gene expression might be correlated with acute myeloid leukemia (AML) survival. Therefore, we conducted a systematical analysis for AML prognostic gene expressions. Methods We performed a microarray-based analysis for correlations between gene expression and adult AML overall survival (OS) using datasets GSE12417 and GSE8970. Positive findings were validated in an independent cohort of 50 newly diagnosed, non-acute promyelocytic leukemia (APL) AML patients by quantitative RT-PCR and survival analysis. Results Microarray-based analysis suggested that expression of eight genes was each associated with 1-year and 3-year AML OS in both GSE12417 and GSE8970 datasets (p

Abstract Background Despite the recent development of new therapies, multiple myeloma (MM) remains an incurable disease. Thus, new, effective treatments are urgently needed, particularly for relapsed or refractory MM (RRMM). In an earlier phase I study, a novel form of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) that is currently in clinical development for the treatment of hematologic malignancies, i.e., circularly permuted TRAIL (CPT), was well tolerated at a dose of 2.5 mg/kg per day and showed promising preliminary activity in patients with RRMM. This phase II, open-label, multicenter study further investigated the efficacy and safety of 2.5-mg/kg per day CPT as single-agent therapy for patients with RRMM. Methods Patients with RRMM were treated once daily with CPT (2.5 mg/kg, intravenously) for 14 consecutive days for each 21-day cycle. Clinical response and toxicity were assessed after each treatment cycle. Results Twenty-seven patients received CPT. Using the European Group for Blood and Marrow Transplantation criteria, we calculated the overall response rate of 33.3% with 1 near-complete response (nCR) and 8 partial responses (PRs). The clinical benefit rate (48.1%) included 1 nCR, 8 PRs, and 4 minimal responses. The most common treatment-related adverse events (TRAEs) were fever, aspartate aminotransferase elevation, alanine aminotransferase elevation, leucopenia, rash, neutropenia, and thrombocytopenia. We graded toxicity using the Common Toxicity Criteria for Adverse Events, version 3.0, and determined that 37.0% of patients had at least 1 grade 3–4 TRAE. Conclusions CPT as a single agent can elicit a response in patients with RRMM and is well tolerated. Further clinical investigation is warranted. Trial Registration ChiCTR-ONC-12002065 http://www.chictr.org/cn

Osteopontin (OPN) is associated with many diseases, and its role in tumor growth and metastasis has been studied in breast cancers. Previous studies have described anti-OPN antibodies that could inhibit tumor cell adhesion and invasion in vitro, but until now, there are no systematic studies on antitumor effects of anti-OPN antibodies in vivo. In the present study, we have raised several anti-OPN single-chain variable fragments from phage antibody library and expressed them as single-chain variable fragment-constant region fragment fusion proteins in Chinese hamster ovary cells. Of them, two antibodies (1A12 and 2H8) were able to inhibit MDA-MB-435s breast cancer cell attachment, invasion, migration, and colony formation in soft agar. Furthermore, 1A12 and 2H8 inhibited the anti-apoptotic and prosurvival functions of OPN in human umbilical vein endothelial cell. In human umbilical vein endothelial cell capillary tube formation, chicken chorioallantoic membrane assay, and rabbit corneal micropocket assay, the two antibodies showed markedly inhibitory effects toward angiogenesis. We investigated antitumor effects of anti-OPN antibodies in nude mice by assessing xenograft tumor growth and lung metastasis potential. The results showed that the two antibodies were capable of delaying primary tumor growth and reducing spontaneous lung metastasis. Epitope mappings of these two anti-OPN antibodies were performed, and a new binding site of 1A12 was revealed. In summary, the present study has demonstrated the roles of anti-OPN antibodies in blocking the function of OPN, suggesting that they may have the potential to be developed for future clinical use.

Abstract Purpose Cervical cancer (CC), a significant global health threat, necessitates comprehensive understanding for improved therapeutic interventions. Many research indicates that dysregulation of the Hippo-YAP1 pathway leads to uncontrolled proliferation and invasion of tumor cells, promoting the progression of various cancers. This article aims to elucidate the role of RNF6 in CC and its regulation of the Hippo-YAP1 signaling pathway. Methods The public tumor dataset analyses, immunohistochemistry, and western blotting were used to explore the expression of RNF6 in CC. Gain- and loss-of-function assays were conducted to elucidate the role of RNF6 in the proliferation and invasion of CC cells. Transcriptome sequencing was used to explore RNF6’s role in cervical cancer, with validation of its regulation of the Hippo-YAP1 pathway through western blotting and RT-qPCR. Co-transfection of YAP overexpression plasmids into RNF6-silenced CC cells were preformed to confirm YAP1’s pivotal role in RNF6-mediated CC progression. Animal experiments were preformed to further validate RNF6 interference’s inhibitory effect on CC proliferation in vivo. Results Clinical samples and bioinformatics analysis revealed high expression of RNF6 in CC, and closely associated with advanced FIGO (International Federation of Gynecology and Obstetrics) stage, larger tumor size, and poor prognosis. Cellular functional experiments demonstrate that RNF6 promotes the proliferation, invasion, and migration of CC cells, while knockdown of RNF6 yields the opposite effect. Transcriptome sequencing further reveals that RNF6 may promote CC progression through the Hippo-YAP signaling pathway. Western blotting and RT-qPCR further unveil that RNF6 enhances the upregulation of YAP1 protein levels, thereby activating downstream oncogenes CTGF and CYR61 transcription. Additionally, exogenous overexpression of YAP1 reverses the inhibitory effect of RNF6 silencing on CC proliferation and invasion. Furthermore, RNF6 interference significantly attenuates tumor growth in vivo experiments. Conclusion Our research reveals that RNF6 is highly expressed in CC, driving malignant progression by upregulating YAP1 protein expression and enhancing the transcription of downstream target genes CTGF and CYR61, offering potential therapeutic targets for CC treatment.

Abstract Objective Radiotherapy is a crucial treatment modality for pelvic cancers, but uncertainties persist in defining the clinical target volume (CTV) for the inguinal lymphatic drainage region. Suboptimal CTV delineation may compromise treatment efficacy and result in subpar disease control. This study aimed to investigate and map the distribution of lymph node metastases (LNM) in the groin area to facilitate an improved and detailed CTV definition using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Methods Inguinal LNM in patients with biopsy-proven pelvic malignancies were identified using 18F-FDG PET/CT scan. The longitudinally nearest axial plane was determined based on six typical bony landmarks, and the axial direction relative to the femoral artery of LNM was recorded. The distances from the LNM to the nearest edge of the femoral artery were measured on the axial plane. An optimal margin to cover 95% of LNM was estimated to develop contouring recommendations. Results In this study, 500 positive LNM were identified by 18F-FDG PET/CT among 185 patients with primary pelvic malignancies. Relative to the femoral artery, lymph nodes were distributed laterally (10:00–11:00, n = 35), anteriorly (12:00–1:00, n = 213), and medially (2:00–4: 00, n = 252). For CTV delineation, the recommended distances from the femoral artery on the SFH were lateral 19 mm, anterior 19 mm, and medial 25 mm; on the SGT were lateral 26 mm, anterior 20 mm, and medial 25 mm; on the SPS were lateral 28 mm, anterior 29 mm, and medial 26 mm; on the IPS were anterior 29 mm and medial 28 mm; on the IIT were anterior 27 mm and medial 27 mm; on the ILT were anterior 25 mm and medial 23 mm. Use interpolation to contour the area between six axial slices, including any radiographically suspicious LNM. Conclusions Using 18F-FDG PET/CT, we investigated the distribution pattern of inguinal LNM and propose a more comprehensive guideline for inguinal CTV delineation.

Abstract Background In hepatocellular carcinoma (HCC) treatment, first-line targeted therapy in combination with immune checkpoint inhibitors (ICIs) has improved patient prognosis, but the 5-year survival rate is far from satisfactory. Studies have shown that the extracellular matrix (ECM) is an essential part of the tumour microenvironment (TME) and participates in the progression of malignant tumours. ECM remodelling can enhance matrix stiffness in cirrhosis patients, induce an immunosuppressive microenvironment network, and affect the efficacy of targeted therapies and ICIs for treating HCC. However, the exact mechanism is still unclear. Methods We downloaded data from public databases, selected differentially expressed ECM proteins associated with matrix stiffness, constructed and validated a prognostic model of HCC using Lasso Cox regression, and investigated the roles and mechanism of one of the ECM proteins, dynein light chain LC8-type 1 (DYNLL1), in HCC proliferation, migration, and apoptosis via in vitro experiments. Results In this study, the risk score of the matrix stiffness-related ECM protein model effectively predicted the prognosis of HCC patients. The high- and low-risk subgroups of the model also showed differences in immune cells, immune functions, and drug sensitivity. DYNLL1 promoted HCC cell progression and migration and inhibited HCC cell apoptosis through the Wnt/β-catenin pathway in vitro. Conclusion The expression of matrix stiffness-related ECM proteins could be an independent predictor of HCC prognosis. DYNLL1, an oncogenic gene in HCC, has the potential to be a new target for HCC treatment.

Background: Most breast cancer-related deaths are caused by distant metastases and drug resistance. It is important to find appropriate biomarkers to monitor the disease and to predict patient responses after treatment early and accurately. Many studies have found that clustered circulating tumor cells, with more correlations with metastatic cancer and poor survival of patients than individual ones, are promising biomarkers. Methods: Eighty samples from eleven patients with breast cancer during follow-up visits were examined. By using a microfluidic chip and imaging system, the number of circulating tumor cells and microemboli (CTC/CTM) were counted to assess the distribution in stratified patients and the potential in predicting the disease condition of patients after treatments during follow-up visits. Specific components and subtypes of CTM were also preliminarily investigated. Results: Compared to CTC, CTM displayed a distinguishable distribution in stratified patients, having a better AUC value, in predicting the disease progression of breast cancer patients during follow-up visits in this study. Four subtypes were categorized from the identified CTM by considering different components. In combination with CEA and CA153, enumerated CTC and CTM from individual patients were applied to monitor the disease condition and patient response to the therapy during follow-up visits. Conclusions: The CTM and its subtypes are promising biomarkers and valuable tools for studying cancer metastasis and longitudinally monitoring cancer patients during follow-up visits.

Abstract The 4CMenB (BexseroR) vaccine contains detergent-extracted outer membrane vesicles (OMVs) from a Neisseria meningitidis (Nm) group B strain NZ98/254 and three recombinant Nm protein antigens: Neisseria adhesin A (NadA), Factor H binding protein (FHbp, as the C-terminal protein in the GNA2091-FHbp fusion), and Neisserial Heparin Binding Antigen (NHBA, as the N-terminal protein in the NHBA-GNA1030 fusion). Previous work has shown that 4CMenB generates serum antibodies to Nm and Neisseria gonorrhoeae (Ng) OMV proteins and lipooligosaccharide (LOS). Mounting evidence indicates 4CMenB can partially protect against mucosal infections with Ng. The immunologic basis for Ng cross protection remains to be fully elucidated. Ten paired human sera obtained pre- and post-immunization with 4CMenB (1 month after a third vaccine dose) were used in ELISAs and in Western blots to determine IgG and IgA serum responses to OMVs from Nm strain NZ98/254 (OMVNm) and two Ng strains, 1291 and CNG20 (OMVNg), and gonococcal recombinant NHBA (rNHBANg) proteins. Post 4CMenB sera, but not pre-sera, showed strong IgG and variable IgA responses to the OMVNm but lower (2–11-fold difference in signal intensity) recognition of OMVNg. All post (not pre) 4CMenB sera showed strong IgG, but variable IgA, recognition of rNHBANg by ELISAs and Western blots. Three post 4CMenB sera at 10% (v/v) concentration had serum bactericidal activity (SBA) against Ng strains 1291 and CNG20 (~30–40% killing), not seen in paired pre-sera. These data confirmed 4CMenB-induced cross-reactive functional antibody responses to Ng. In competitive SBA assays, in which sera were pre-incubated with rNHBA, minimal SBA against Nm strain NZ98/254 was titrated away. However, most of the SBA against Ng strains 1291 and CNG20 required NHBA-specific antibodies, and the Δnhba mutants were resistant to killing by post 4CMenB sera. Removing NHBA-specific and LOS-specific OMV antibodies simultaneously decreased SBA significantly more than the sum of removing individual antibodies alone, suggesting synergy between anti-NHBA and anti-OMV antibodies. Anti- NHBANm antibodies induced by 4CMenB vaccination cross react with NHBANg and substantially contribute to the bactericidal response toward Ng induced by the vaccine.

Abstract Immune checkpoint blockade therapy has revolutionized cancer treatment, but resistance remains prevalent, often due to dysfunctional tumor-infiltrating lymphocytes. A key contributor to this dysfunction is mitochondrial dysfunction, characterized by defective oxidative phosphorylation, impaired adaptation, and depolarization, which promotes T cell exhaustion and severely compromises antitumor efficacy. This review summarizes recent advances in restoring the function of exhausted T cells through mitochondria-targeted strategies, such as metabolic remodeling, enhanced biogenesis, and regulation of antioxidant and reactive oxygen species, with the aim of reversing the state of T cell exhaustion and improving the response to immunotherapy. A deeper understanding of the role of mitochondria in T cell exhaustion lays the foundation for the development of novel mitochondria-targeted therapies and opens a new chapter in cancer immunotherapy.

Abstract Objective To evaluate the benefits of volumetric modulated arc therapy (VMAT) based on multicriteria optimization (MCO) for gastric cancer patients, particularly the protection of serial organs at risk (OARs) that overlap with the target volume. Methods MCO and single-criterion optimization (SCO) VMAT plans were conducted among 30 gastric cancer patients, with a prescription dose of 50.4 Gy delivered in 28 fractions. All treatment plans underwent review, and a comparison was made between the active planning time and different dose-volume parameters. Results Both the MCO and SCO VMAT plans achieved the target dose coverage, with no significant difference in the conformity index (CI) for the planning target volume (PTV), at median CI values of 0.887 and 0.891, respectively (P = 0.417). The MCO plans showed a slight but significant increase in the homogeneity index of the PTV, with a median increase of 0.029 (P

Abstract The aim of this study was to investigate the key targets and signaling pathways of paeoniflorin (PF) for the treatment of gastric cancer (GC). First, the differentially expressed genes (DEGs) of gastric cancer were obtained by analyzing GSE118916 Gene Chip, and then the active components of paeoniflorin and their targets of action were found. And the intersection genes of the two were analyzed for target and pathway analysis. In addition, cell viability after PF intervention was detected by CCK-8. Clone formation assay, wound scratch assay, transwell assay were used to detect cell migration and invasion. The qRT-PCR and Western blot methods were used to verify the mechanism of action. The results showed that a total of 286 paeoniflorin targets and 1799 DEGs were obtained. Secondly, we found that PF could treat gastric cancer through RAS/MAPK signaling pathway. In addition, through in vitro cellular experiments, we also found that PF had a significant therapeutic effect on gastric cancer. Therefore, we believe that PF inhibits the proliferation and metastasis of gastric cancer, and its effect may be exerted by regulating the RAS/MAPK signaling pathway. PF is a promising drug for the treatment of gastric cancer. Combined with the in vitro experiments, we found that the therapeutic effect of PF is related to the regulation of the RAS/MAPK signaling pathway, and the results of the present study preliminarily revealed its complex mechanism, which will lay the foundation for future clinical treatment.

Abstract Nasopharyngeal carcinoma (NPC) is the most common cancer originating in nasopharynx. Metabolic reprogramming plays a critical role in tumor progression. Exploring mechanisms underlying metabolic reprogramming contributes to deeper understanding of NPC pathogenesis. Here, we found downregulation of RORA and SPLUNC1 in NPC, and RORA downregulation indicates poor prognosis. RORA binds to SPLUNC1 promoter to induce its transcription, and RORA overexpression inhibits cell proliferation and glycolysis by directly upregulating SPLUNC1. UBR5 inhibits RORA via promoting RORA ubiquitination and degradation, and UBR5 silencing represses proliferation and glycolysis in NPC. Additionally, METTL14, which is highly expressed in NPC, facilitates UBR5 mRNA stability by promoting its m6A modification through IGF2BP2. UBR5/RORA/SPLUNC1 axis facilitates M2 polarization by activating the GPR132 signaling. UBR5 silencing inhibits tumor growth, glycolysis and M2 polarization through RORA/SPLUNC1 signaling in mice. In conclusion, UBR5 promotes proliferation, glycolysis and M2 polarization by metabolically reprograming NPC cells through suppression of the RORA/SPLUNC1 signaling.

Abstract Upper digestive tract cancers, such as oral cavity, laryngeal, esophageal, and gastric cancers, account for 10% of cancer cases and 14.5% of cancer-related deaths worldwide. Conventional treatments often provide limited survival benefits and are frequently associated with adverse effects and drug resistance. Chinese herbal drugs (CHDs) are widely used in the Far East for managing these cancers. In this narrative review, we summarize current clinical studies (published up to June 2024) on the use of 138 CHDs in the treatment of cancers and precancerous lesions of the upper digestive tract. For cancer treatment, 126 CHDs were tested, all in combination with conventional therapies. Each CHD increased the clinical efficacy and/or reduced the adverse effects of conventional therapies. The five-year survival rate is a critical metric for evaluating the clinical benefits of cancer treatments. Four of the CHDs were reported to increase five-year survival rates of patients receiving conventional therapies. The four CHDs are Sishen Jiedu Decoction, Pingxiao Tablet, Fuzheng Guben Granule, and Buyang Huanwu Tang. For managing precancerous lesions, 12 CHDs were tested: six used alone and six in combination with conventional therapies. Zengshengping is one of the CHDs used alone and is the only one that has been proven to prevent the development of esophageal cancer with convincing evidence. This review provides information about the clinical benefits of CHDs and offers a reference for their rational application in treating upper digestive tract cancers. The reviewed studies have limitations: most trials had small sample sizes and were not multi-center; only one study investigated the mechanisms of action of the studied CHD; and the active components of CHDs were not explored. To promote international recognition of CHDs, rigorously designed studies on clinical outcomes, mechanisms of action, and active components are warranted. Moreover, the studied CHDs should be standardized.

Abstract Background Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for non-small cell lung cancer (NSCLC). The variability in patient responses necessitates a blood-based, multi-cohort gene signature to predict ICI response in NSCLC. Methods We performed transcriptomic profiling of peripheral blood mononuclear cell (PBMC) and buffy coat (BC) samples from three independent cohorts of NSCLC patients treated with ICIs: a retrospective cohort (PMBCR, n = 59), a retrospective validation cohort (BC, n = 44), and a prospective validation cohort (PBMCP, n = 42). We identified a 5-gene signature (UQCRB, NDUFA3, CDKN2D, FMNL1-DT, and APOL3) predictive of ICI response and validated its clinical utility in the prospective PBMCP cohort. Response was evaluated using RECIST criteria, and patients were followed up for progression-free survival (PFS) and overall survival (OS). Results In the prospective PBMCP cohort, the 5-gene signature demonstrated high accuracy in stratifying patients into responders and non-responders (AUC = 0.89, 95% CI: 0.80–0.99). Predicted responders exhibited significantly longer PFS compared to predicted non-responders (median: 13.8 months vs. 4.2 months, HR = 0.21, 95% CI: 0.07–0.58, p = 0.005). Conclusion Our study confirms a 5-gene signature as a key biomarker for ICI response in NSCLC, enhancing treatment precision.

Abstract Developing resistance to cancer treatments is a major challenge, often leading to disease recurrence and metastasis. Understanding the underlying mechanisms of therapeutic resistance is critical for developing effective strategies. O-GlcNAcylation, a post-translational modification that adds GlcNAc from the donor UDP-GlcNAc to serine and threonine residues of proteins, plays a crucial role in regulating protein function and cellular signaling, which are frequently dysregulated in cancer. Similarly, ubiquitination, which involves the attachment of ubiquitin to to proteins, is crucial for protein degradation, cell cycle control, and DNA repair. The interplay between O-GlcNAcylation and ubiquitination is associated with cancer progression and resistance to treatment. This review discusses recent discoveries regarding the roles of O-GlcNAcylation and ubiquitination in cancer resistance, their interactions, and potential mechanisms. It also explores how targeting these pathways may provide new opportunities to overcome cancer treatment resistance in cancer, offering fresh insights and directions for research and therapeutic development.

Abstract Objective This study aimed to develop a population pharmacokinetic (PPK) model for oral apatinib in Chinese oncology patients and investigate the factors influencing the pharmacokinetics of apatinib. Methods We gathered 199 blood concentration monitoring data points from 91 inpatient oncology participants receiving oral apatinib at the Third Affiliated Hospital of Soochow University. Covariates, such as age, gender, body weight, and indices of liver and renal function, were examined to assess their influence on the pharmacokinetic parameters of apatinib. The PPK model was developed using the nonlinear mixed-effects modeling procedure (NONMEM), and model validation was conducted using the bootstrap method and normalized prediction distribution error (NPDE) method. Results The structural model adopted a one-compartment structure with first-order elimination. Notably, aspartate aminotransferase (AST) and the co-administered drug type emerged as primary covariates affecting apatinib clearance (CL/F). The finalized model was expressed as CL/F (L/h) = 56.7 × (AST/26.6)−0.298 × θ, when apatinib was combined with monoclonal antibodies, θ was 1; when combined with paclitaxel, θ was 0.58; when combined with other drugs (e.g., platinum, capecitabine, or the combination of tegafur, gimeracil, and oteracil potassium), θ was 1.60; When used as monotherapy, θ was 1.38. V/F = 674 L, and the absorption rate constant (Ka) was fixed at 0.08 h−1. Bootstrap results affirmed the model’s reliability and stability, while NPDE outcomes attested to the model’s fit. Conclusion Our study successfully established a PPK model for apatinib in oncology patients, revealing that liver function status and co-administered drug types significantly impacted apatinib CL/F. This finding underscored the potential necessity for dose adjustments to optimize efficacy, particularly in patients undergoing different chemotherapy regimens involving apatinib.

Background and purpose: Breast cancer is a major global public health problem. Bone is the most common site of distant metastasis of breast cancer, accounting for about 70% of all metastatic cases. Bone metastasis of breast cancer can cause a series of complications, including severe pain, pathological fracture, hypercalcemia, spinal cord compression, etc., which bring great inconvenience to patients' physical activities and affect their quality of life. Metastatic recurrence is the leading cause of death in breast cancer patients. Therefore, there is an urgent need to build a diagnostic model of bone metastasis in breast cancer to identify patients with a high risk of bone metastasis. The aim of this study was to develop a predictive model based on machine learning to predict the probability of breast cancer developing bone metastasis. Methods: Data of breast cancer patients diagnosed between 2010 and 2015 were extracted from The Surveillance, Epidemiology, and End Results (SEER) database. The variables were screened by least absolute shrinkage and selection operator (LASSO) regression, univariate and multivariate logistic regression analysis, and statistically significant risk factors were included to build a prediction model. In this study, nine machine learning algorithms, including decision tree, elastic network, K-nearest neighbor, lightweight gradient elevator, logistic regression, neural network, random forest, support vector machine and limit gradient lifting, were used to adjust the model hyperparameters through random search and 5x cross-validation to build a breast cancer bone metastasis prediction model. The area under the receiver operating characteristic (ROC) curve, calibration curve and decision curve were used to evaluate the model, the optimal model was obtained, and the importance of variables was analyzed based on the optimal model. Finally, a network calculator for predicting the risk of bone metastasis of breast cancer was established using the optimal model. Results: The study included 10 106 patients with breast cancer, 7 073 patients in the training set, and 3 033 patients in the validation set. We found that 4 494 (63.5%) patients in the training set and 1 927 (63.5%) patients in the validation set developed bone metastases, respectively. Race, pathologic grade, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor 2 (HER2) status, N stage, lung metastasis, radiotherapy, chemotherapy and surgery were independent predictors of bone metastasis. The training set and verification set were used to verify the model, and the limit gradient lifting algorithm was superior to other machine learning algorithms by integrating the evaluation indexes such as the area under the ROC curve, calibration curve and decision curve. Finally, we used limit gradient algorithm to build network calculator for prediction of breast cancer bone metastases (https://bcbm.shinyapps.io/DynNomapp/). Conclusion: This study developed a predictive model based on machine learning to predict the probability of bone metastases in breast cancer patients, hoping to help clinicians make more rational treatment decisions.

Introduction The adverse effects of secondhand smoke (SHS) exposure on health have been well established. Using the NHMS 2002: Adolescent Health Survey (AHS), this study attempts to evaluate the extent and factors associated with SHS exposure among Malaysian school-going adolescents. Methods We conducted the NHMS 2022: AHS to gather a representative sample of school-age teenagers. We employed a cross-sectional study design and a multi-stage sampling procedure. We utilized a pre-validated self-administered questionnaire to collect data from the selected respondents. The data analysis included adjusted odds ratios (AORs) with 95% confidence intervals (95% CIs). Additionally, we investigated the possible two-way interactions between the independent variables. Results The SHS prevalence was 42.0%. Exposure to secondhand smoke (SHS) was associated with male gender (AOR=1.28; 95 CI: 1.20–1.38), older age (AOR=1.46; 95% CI: 1.33–1.60), Malay (AOR=1.88; 95% CI: 1.49–2.37), Bumiputra Sabah (AOR=2.23; 95% CI: 1.67–2.99), Bumiputra Sarawak (AOR=2.43; 95% CI: 1.80–3.28), and Chinese ethnicity (AOR=2.89; 95 CI: % 2.30–3.64), as well as current smoking (AOR=2.78; 95% CI: 2.50–3.09), having separated or divorced parents (AOR=1.12; 95% CI: 1.02–1.23), and parental tobacco product use (AOR=4.75; 95% CI: 4.44–5.08). We found significant interactions between: 1) Age group with gender and ethnicity; 2) Gender and ethnicity; and 3) Parental smoking status with gender, response to tobacco use, parents' marital status, and ethnicity. Conclusions Parental characteristics, sociodemographic characteristics, and SHS exposure are strongly correlated. In addition, there is evidence of smoking displacement to the house from other areas by parents/guardians. This study offers a fresh perspective on how these variables influence the likelihood of SHS exposure for Malaysian school-age teenagers. More efforts should focus on parental variables and sociodemographic traits, especially parental smoking cessation support.