Head-to-head comparison of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT for the evaluation of tonsil cancer and lymph node metastases: a single-centre retrospective study.

BACKGROUND: This study aimed to compare the diagnostic value of [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT imaging for primary lesions and metastatic lymph nodes in patients with tonsil cancer. METHOD: Twenty-one tonsil cancer patients who underwent [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT scans within two weeks in our centre were retrospectively enrolled. The maximum standardized uptake value (SUVmax) and tumor-to-background ratio (TBR) of the two tracers were compared by using the Mann‒Whitney U test. In addition, the sensitivity, specificity, and accuracy of the two methods for diagnosing metastatic lymph nodes were analysed. RESULTS: In detecting primary lesions, the efficiency was higher for [68 Ga]Ga-DOTA-FAPI-04 PET/CT (20/22) than for [18F]FDG PET/CT (9/22). Although [68 Ga]Ga-DOTA-FAPI-04 uptake (SUVmax, 5.03 ± 4.06) was lower than [18F]FDG uptake (SUVmax, 7.90 ± 4.84, P = 0.006), [68 Ga]Ga-DOTA-FAPI-04 improved the distinction between the primary tumor and contralateral normal tonsillar tissue. The TBR was significantly higher for [68 Ga]Ga-DOTA-FAPI-04 PET/CT (3.19 ± 2.06) than for [18F]FDG PET/CT (1.89 ± 1.80) (p < 0.001). In lymph node analysis, SUVmax and TBR were not significantly different between [68 Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT (7.67 ± 5.88 vs. 8.36 ± 6.15, P = 0.498 and 5.56 ± 4.02 vs. 4.26 ± 3.16, P = 0.123, respectively). The specificity and accuracy of [68 Ga]Ga-DOTA-FAPI-04 PET/CT were higher than those of [18F]FDG PET/CT in diagnosing metastatic cervical lymph nodes (all P < 0.05). CONCLUSION: The availability of [68 Ga]Ga-DOTA-FAPI-04 complements the diagnostic results of [18F]FDG by improving the detection rate of primary lesions and the diagnostic accuracy of cervical metastatic lymph nodes in tonsil cancer compared to [18F]FDG.

Selpercatinib attenuates bleomycin-induced pulmonary fibrosis by inhibiting the TGF-ß1 signaling pathway.

IPF is a chronic, progressive, interstitial lung disease with high mortality. Current drugs have limited efficacy in curbing disease progression and improving quality of life. Selpercatinib, a highly selective inhibitor of receptor tyrosine kinase RET (rearranged during transfection), was approved in 2020 for the treatment of a variety of solid tumors with RET mutations. In this study, the action and mechanism of Selpercatinib in pulmonary fibrosis were evaluated in vivo and in vitro. In vivo experiments demonstrated that Selpercatinib significantly ameliorated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro, Selpercatinib inhibited the proliferation, migration, activation and extracellular matrix deposition of fibroblasts by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathway, and suppressed epithelial-mesenchymal transition (EMT) like process of lung epithelial cells via inhibiting TGF-ß1/Smad pathway. The results of in vivo pharmacological tests corroborated the results obtained from the in vitro experiments. Further studies revealed that Selpercatinib inhibited abnormal phenotypes of lung fibroblasts and epithelial cells in part by regulating its target RET. In short, Selpercatinib inhibited the activation of fibroblasts and EMT-like process of lung epithelial cells by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathways, thus alleviating BLM-induced pulmonary fibrosis in mice.

Can 18F-FES PET Improve the Evaluation of 18F-FDG PET in Patients With Metastatic Invasive Lobular Carcinoma?

PURPOSE: Invasive lobular carcinoma (ILC) exhibits a low affinity for 18F-FDG. The estrogen receptor (ER) is commonly expressed in ILCs, suggesting a potential benefit of targeting with the ER probe 18F-FES in this patient population. The objective of this study was to evaluate the diagnostic performance of 18F-FES imaging in patients with metastatic ILC and compare it with that of 18F-FDG. METHODS: We conducted a retrospective analysis of 20 ILC patients who underwent concurrent 18F-FES and 18F-FDG PET/CT examinations in our center. 18F-FES and 18F-FDG imaging were analyzed to determine the total count of tracer-avid lesions in nonbone sites and their corresponding organ systems, assess the extent of anatomical regions involved in bone metastases, and measure the SUVmax values for both tracers. RESULTS: Among 20 ILC patients, 65 nonbone lesions were found to be distributed in 13 patients, and 16 patients were diagnosed with bone metastasis, which was distributed in 54 skeletal anatomical regions. The detection rate of 18F-FDG in nonbone lesions was higher than that of 18F-FES (57 vs 37, P < 0.001). 18F-FES demonstrated a superior ability to detect nonbone lesions in 4 patients, whereas 18F-FDG was superior in 5 patients (P > 0.05). Among 9/16 patients with bone metastasis, 18F-FES demonstrated a significant advantage in the detection of bone lesions compared with 18F-FDG (P = 0.05). Furthermore, patients with only 18F-FES-positive lesions (12/12) were administered endocrine regimens, whereas patients lacking 18F-FES uptake (2/3) predominantly received chemotherapy. CONCLUSIONS: 18F-FES is more effective than 18F-FDG in detecting bone metastasis in ILC, but it does not demonstrate a significant advantage in nonbone lesions. Additionally, the results of examination with 18F-FES have the potential to guide patient treatment plans.

Imaging of Tumor Stroma Using 68Ga-FAPI PET/CT to Improve Diagnostic Accuracy of Primary Tumors in Head and Neck Cancer of Unknown Primary: A Comparative Imaging Trial.

The low detection rate of primary tumors by current diagnostic techniques remains a major concern for patients with head and neck cancer of unknown primary (HNCUP). Therefore, in this study, we aimed to investigate the potential role of 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT compared with 18F-FDG PET/CT for the detection of primary tumors of HNCUP. Methods: In this prospective comparative imaging trial conducted at Fudan University Shanghai Cancer Center, 91 patients with negative or equivocal findings of a primary tumor by comprehensive clinical examination and conventional imaging were enrolled from June 2020 to September 2022. The presence of a primary tumor was recorded by 3 experienced nuclear medicine physicians. Primary lesions were validated by histopathologic analysis and a composite reference standard. Results: Of the 91 patients (18 women, 73 men; median age, 60 y; age range, 24-76 y), primary tumors were detected in 46 (51%) patients after a thorough diagnostic work-up. 68Ga-FAPI PET/CT detected more primary lesions than 18F-FDG PET/CT (46 vs. 17, P < 0.001) and showed better sensitivity, positive predictive value, and accuracy in locating primary tumors (51% vs. 25%, 98% vs. 43%, and 51% vs. 19%, respectively). Furthermore, 68Ga-FAPI PET/CT led to treatment changes in 22 of 91 (24%) patients compared with 18F-FDG PET/CT. The Kaplan-Meier curve illustrated that patients with unidentified primary tumors had a significantly worse prognosis than patients with identified primary tumors (hazard ratio, 5.77; 95% CI, 1.86-17.94; P = 0.0097). Conclusion: 68Ga-FAPI PET/CT outperforms 18F-FDG PET/CT in detecting primary lesions and could serve as a sensitive, reliable, and reproducible imaging modality for HNCUP patients.

Preclinical Evaluation and a Pilot Clinical Positron Emission Tomography Imaging Study of [68Ga]Ga-FAPI-FUSCC-II.

Fibroblast activation protein (FAP), a type II integral membrane serine protease, is a promising target for tumor diagnosis and therapy. OncoFAP has been recently discovered for PET imaging procedures for various solid malignancies. In this study, we presented the development of manual radiolabeling procedures for the preparation of OncoFAP-based radiopharmaceuticals for cancer imaging. A novel series of [68Ga/177Lu]Ga/Lu-FAPI-FUSCC-I/II were produced with high radiochemical yields. [68Ga]Ga-FAPI-FUSCC-I/II and [177Lu]Lu-FAPI-FUSCC-I/II were stable in phosphate-buffered saline, fetal bovine serum, and human serum for at least 3 h. In vitro cellular uptake and blocking experiments implied that they had specificity to FAP. Additionally, the low nanomolar IC50 values of FAPI-FUSCC-II indicated that it had a high target affinity to FAP. The in vivo biodistribution and blocking study in mice bearing HT-1080-FAP tumors showed that both exhibited specific tumor uptake. [68Ga]Ga-FAPI-FUSCC-II showed a higher tumor uptake and a higher tumor/nontarget ratio than [68Ga]Ga-FAPI-FUSCC-I and [68Ga]Ga-FAPI-04. The results of ex vivo biodistribution were in accordance with the biodistribution results. Clinical [68Ga]Ga-FAPI-FUSCC-II-PET/CT imaging further demonstrated its favorable biodistribution and kinetics with elevated and reliable uptake by primary tumors (maximum standardized uptake value (SUVmax), 12.17 ± 6.67) and distant metastases (SUVmax, 9.24 ± 4.28). In summary, [68Ga]Ga-FAPI-FUSCC-II displayed increased tumor uptake and retention compared to [68Ga]Ga-FAPI-04, giving it potential as a promising tracer for the diagnostic imaging of malignant tumors with positive FAP expression.

Induction Toripalimab and Chemotherapy for Organ Preservation in Locally Advanced Laryngeal and Hypopharyngeal Cancer: A Single-Arm Phase II Clinical Trial.

PURPOSE: The aim of this study was to assess the efficacy, toxicities, and potential role of larynx preservation of induction chemotherapy combined with programmed cell death protein 1 (PD-1) inhibitor in locally advanced laryngeal and hypopharyngeal cancer. PATIENTS AND METHODS: This is a single-arm phase II study. Patients with histopathologically confirmed, resectable locally advanced laryngeal/hypopharyngeal squamous cell carcinoma and Eastern Cooperative Oncology Group Performance Status 0-1 were eligible. Three cycles of induction chemotherapy (paclitaxel 175 mg/m2 d1, cisplatin 25 mg/m2 d1-3) combined with PD-1 inhibitor (toripalimab 240 mg d0) were administered. Response assessment was performed after induction chemoimmunotherapy using RECIST 1.1 criteria. Patients with a complete/partial response of the primary tumor received concurrent chemoradiation, followed by maintenance therapy of toripalimab. Otherwise, patients were referred to surgery, followed by adjuvant (chemo) radiation and maintenance therapy of toripalimab. The primary endpoint is a larynx preservation rate at 3 months postradiation. RESULTS: Twenty-seven patients were enrolled. Most cases exhibited stage IV disease (81.5%), with T4 representing 37.0%. Five patients underwent pretreatment tracheostomy because of impaired larynx function. Overall response rate of induction chemoimmunotherapy was 85.2%. At 3 months postradiation, the larynx preservation rate was 88.9%. With a median follow-up of 18.7 months, the 1-year overall survival rate, progression-free survival rate, and larynx preservation rate were 84.7%, 77.6%, and 88.7%, respectively. When excluding those with pretreatment tracheostomy, the 1-year larynx preservation rate was 95.5%. Exploratory analysis revealed that relapse correlated with enrichment of RNA signature of hypoxia and M2 macrophage-associated genes. CONCLUSIONS: Induction toripalimab combined with chemotherapy provided encouraging activity, promising larynx preservation rate and acceptable toxicity in this cohort of extensively locally advanced laryngeal and hypopharyngeal cancer.

ER status conversion and subsequent treatment: an assessment of negative ER expression detected by 18F-FES PET in metastatic breast cancer patients with ER-positive primary tumors.

Background: The 18F-fluoroestradiol positron emission tomography/computed tomography (18F-FES PET/CT) technique provides a convenient method to evaluate the overall estrogen receptor (ER) expression in metastatic breast cancer (MBC) patients. There are long debates on the characteristics and treatment strategy of patients with positive primary ER lesions but negative ER expression in metastatic disease. 18F-FES PET offers an opportunity to answer this question. Objectives: This study aimed to characterize the primary ER-positive patients with advanced-stage FES negativity and investigate the real-world treatment decisions made by physicians subsequently, and compare the efficacy between different regimens. Design: This observational cohort study was conducted at Fudan University Shanghai Cancer Center, enrolling breast cancer patients with ER-positive primary tumors who showed advanced-stage FES negativity. Methods: Descriptive statistics were used in clinicopathologic characteristics and compared with a chi-square test or t-test. In addition, progression-free survival (PFS) was estimated by the Kaplan-Meier method and compared by log-rank test. Results: 16.6% (52/314) of patients with an ER-positive primary tumor had negative ER expression assessed by 18F-FES for MBC prior to receiving first-line systemic therapy, among whom adjuvant endocrine therapy was prevalently utilized (86.5%, 45/52). The rate of FES negativity in the advanced stage was negatively correlated with levels of ER expression of primary tumors. Chemotherapy (83.3%, 40/48) was the most common treatment strategy afterward, among which capecitabine monotherapy (62.5%, 25/40) was a dominant alternative. PFS was significantly prolonged with capecitabine alone versus other chemotherapy (median PFS: 13.14 versus 6.21 months, p = 0.029). Conclusion: Negative conversion of ER in MBC detected by 18F-FES occurred frequently. Patients with lower ER expression in the primary lesion were more likely to have negative ER expression in the metastasis. In real-world clinical practice, most physicians primarily opted for chemotherapy, with capecitabine monotherapy being a commonly selected regimen. Trial registration: ClinicalTrials.gov identifier: NCT05797987.

Molecular-Assisted Breeding of Cadmium Pollution-Safe Cultivars.

Cadmium (Cd) contamination in edible agricultural products, especially in crops intended for consumption, has raised worldwide concerns regarding food safety. Breeding of Cd pollution-safe cultivars (Cd-PSCs) is an effective solution to preventing the entry of Cd into the food chain from contaminated agricultural soil. Molecular-assisted breeding methods, based on molecular mechanisms for cultivar-dependent Cd accumulation and bioinformatic tools, have been developed to accelerate and facilitate the breeding of Cd-PSCs. This review summarizes the recent progress in the research of the low Cd accumulation traits of Cd-PSCs in different crops. Furthermore, the application of molecular-assisted breeding methods, including transgenic approaches, genome editing, marker-assisted selection, whole genome-wide association analysis, and transcriptome, has been highlighted to outline the breeding of Cd-PSCs by identifying critical genes and molecular biomarkers. This review provides a comprehensive overview of the development of Cd-PSCs and the potential future for breeding Cd-PSC using modern molecular technologies.

18F-FES and 18F-FDG PET/CT imaging as a predictive biomarkers for metastatic breast cancer patients undergoing cyclin-dependent 4/6 kinase inhibitors with endocrine treatment.

OBJECTIVE: The aim of this study was to investigate the potential value of dual tracers 18F-FDG and 18F-FES PET/CT in predicting response to Cyclin-Dependent 4/6 Kinase (CDK4/6) inhibitors combined with endocrine therapy for metastatic estrogen receptor (ER)-positive breast cancer patients. METHODS: This retrospective study enrolled 38 ER-positive metastatic breast cancer patients from our center who underwent both 18F-FDG and 18F-FES PET/CT scans within 1 month before CDK4/6 inhibitors combined with endocrine therapy. The extracted parameters comprised the maximum standardized uptake value (SUVmax) for both FDG and FES PET, as well as the ratio between FES and FDG SUVmax. Each parameter was dichotomized based on its median threshold. The primary endpoint was progression-free survival (PFS), which was estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: After a median follow-up of 15.6 months, progressive disease was observed in 23 out of 38 patients, and the median PFS for the whole cohort was 21.0 months [95% confidence interval (CI) 12.7-29.3]. FES and FDG PET identified 6 patients (15.8%) with FES-negative lesions, suggesting ER heterogeneity in metastatic lesions. The median PFS of these patients was only 5.3 months (95% CI 1.7-8.9), which was substantially shorter than that of patients with 100% FES-positive lesions (median PFS 22.9 months, 95% CI 17.1-28.7, P < 0.001). Patients with 100% FES-positive lesions who had high FES/FDG showed significantly shorter PFS compared to those with low FES/FDG (14.9 vs. 30.5 months, P = 0.003). CONCLUSIONS: This study shows that FDG and FES PET imaging may serve as valuable tools for patient selection in the context of CDK4/6 inhibitor therapy combined with endocrine treatment, and have the potential to function as prognostic biomarkers.

Pretreatment 18F-FDG uptake heterogeneity may predict treatment outcome of combined Trastuzumab and Pertuzumab therapy in patients with metastatic HER2 positive breast cancer.

OBJECTIVE: Intra-tumoral heterogeneity of 18F-fluorodeoxyglucose (18F-FDG) uptake has been proven to be a surrogate marker for predicting treatment outcome in various tumors. However, the value of intra-tumoral heterogeneity in metastatic Human epidermal growth factor receptor 2(HER2) positive breast cancer (MHBC) remains unknown. The aim of this study was to evaluate 18F-FDG uptake heterogeneity to predict the treatment outcome of the dual target therapy with Trastuzumab and Pertuzumab(TP) in MHBC. METHODS: Thirty-two patients with MHBC who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) scan before TP were enrolled retrospectively. The region of interesting (ROI) of the lesions were drawn, and maximum standard uptake value (SUVmax), mean standard uptake value (SUVmean), total lesion glycolysis (TLG), metabolic tumor volume (MTV) and heterogeneity index (HI) were recorded. Correlation between PET/CT parameters and the treatment outcome was analyzed by Spearman Rank Test. The ability to predict prognosis were determined by time-dependent survival receiver operating characteristic (ROC) analysis. And the survival analyses were then estimated by Kaplan-Meier method and compared by log-rank test. RESULTS: The survival analysis showed that HI50% calculated by delineating the lesion with 50%SUVmax as threshold was a significant predictor of patients with MHBC treated by the treatment with TP. Patients with HI50% (≥ 1.571) had a significantly worse prognosis of progression free survival (PFS) (6.87 vs. Not Reach, p = 0.001). The area under curve (AUC), the sensitivity and the specificity were 0.88, 100% and 63.6% for PFS, respectively. CONCLUSION: 18F-FDG uptake heterogeneity may be useful for predicting the prognosis of MHBC patients treated by TP.

Identification of cytokine-predominant immunosuppressive class and prognostic risk signatures in glioma.

PURPOSE: The advent of immune checkpoint blockade (ICB) therapies this year has changed the way glioblastoma (GBM) is treated. Meanwhile, some patients with strong PD-L1 expression remain immune checkpoint resistant. To better understand the molecular processes that influence the immune environment, there is an urgent need to characterize the immunosuppressive tumor microenvironment and identify biomarkers to predict patient survival outcomes. PATIENTS AND METHODS: Our study analyzed RNA-sequencing data from 178 GBM samples. Their unique gene expression patterns in the tumor microenvironment were analyzed by an unsupervised clustering algorithm. Through these expression patterns, a panel of T-cell exhaustion signatures, immunosuppressive cells, and clinical features correlates with immunotherapy response. The presence or absence of immune status and prognostic signatures was then validated with the test dataset. RESULTS: 38.2% of GBM patients showed increased expression of anti-inflammatory cytokines, significant enrichment of T cell exhaustion signals, higher proportion of immunosuppressive cells (macrophages and CD4 regulatory T cells) and nine inhibitory checkpoints (CTLA4, PDCD1, LAG3, BTLA, TIGIT, HAVCR2, IDO1, SIGLEC7, and VISTA). The immunodepleted class (IDC) was used to classify these immunocompromised individuals. Despite the high density of tumor-infiltrating lymphocytes shown by IDC, such patients have a poor prognosis. Although PD-L1 was highly expressed in IDC, it suggested that there might be ICB resistance. There are many IDC predictive signatures to discover. CONCLUSION: PD-1 is strongly expressed in a novel immunosuppressive class of GBM, but this cluster may be resistant to ICB therapy. A comprehensive description of this drug-resistant tumor microenvironment could provide new insights into drug resistance mechanisms and improved immunotherapy techniques.

GNPNAT1 promotes the stemness of breast cancer and serves as a potential prognostic biomarker.

Glucosamine­phosphate N­acetyltransferase 1 (GNPNAT1) is a member of the acetyltransferase superfamily, related to general control non­depressible 5 (GCN5). It has been documented that GNPNAT1 expression is increased in lung cancer, whereas its involvement in breast cancer (BC) remains to be further investigated. The present study aimed to evaluate the expression levels of GNPNAT1 in BC and its effect on BC stem cells (BCSCs). The Cancer Genome Atlas (TCGA) database was used for the analysis of the expression of GNPNAT1 and its clinical significance. Cox regression and logistic regression analyses were used to evaluate prognosis­related factors. The GNPNAT1­binding protein network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) application. The biological signaling pathways implicated in GNPNAT1 were investigated through function enrichment analysis including Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analysis. The single­sample GSEA method was used to investigate the connection between the level of immune infiltration and GNPNAT1 expression in BC. GNPNAT1 expression was upregulated in patients with BC and was significantly associated with a poor prognosis. GNPNAT1 and its co­expressed genes were mostly enriched in nuclear transport, Golgi vesicle transport, ubiquitin­like protein transferase activity and ribonucleoprotein complex binding, as determined using functional enrichment analysis. GNPNAT1 expression was positively associated with Th2 cells and T­helper cells, and negatively associated with plasmacytoid dendritic cells, CD8+ T­cells and cytotoxic cells. Additionally, the GNPNAT1 expression levels were considerably increased in BCSCs. GNPNAT1 knockdown markedly decreased the stemness ability of SKBR3 and Hs578T cells, including the production of CSC markers and mammosphere or clone formation, while GNPNAT1 overexpression increased the stemness level. Hence, the findings of the present study demonstrate that GNPNAT1 may be exploited as a novel prognostic biomarker and therapeutic target for BC.

miRNA-874-3p inhibits the migration, invasion and proliferation of breast cancer cells by targeting VDAC1.

Breast cancer is an important cause of crisis for women's life and health. Voltage-dependent anion channel 1 (VDAC1) is mainly localized in the outer mitochondrial membrane of all eukaryotes, and it plays a crucial role in the cell as the main interface between mitochondria and cellular metabolism. Through bioinformatics, we found that VDAC1 is abnormally highly expressed in breast cancer, and the prognosis of breast cancer patients with high VDAC1 expression is poor. Through in vivo and in vitro experiments, we found that VDAC1 can promote the proliferation, migration and invasion of breast cancer cells. Further research we found that VDAC1 can activate the wnt signaling pathway. Through analysis, we found that miR-874-3p can regulate the expression of VDAC1, and the expression of miR-874-3p is decreased in breast cancer, resulting in the increase of VDAC1 expression. Our findings will provide new targets and ideas for the prevention and treatment of breast cancer.

The devil is in the details: a small-lesion sensitive weakly supervised learning framework for prostate cancer detection and grading.

Prostate cancer (PCa) is a significant health concern in aging males, and the diagnosis depends primarily on histopathological assessments to determine tumor size and Gleason score. This process is highly time-consuming, subjective, and relies on the extensive experience of the pathologists. Deep learning based artificial intelligence shows an ability to match pathologists on many prostate cancer diagnostic scenarios. However, it is easy to make mistakes on some hard cases with small tumor areas considering the extensively high-resolution of whole slide images (WSIs). The absence of fine-grained and large-scale annotations of such small tumor lesions makes this problem more challenging. Existing methods usually perform uniform cropping of the foreground of WSI and then use convolutional neural networks as the backbone network to predict the classification results. However, cropping can damage the structure of tiny tumors, which affects classification accuracy. To solve this problem, we propose an Intensive-Sampling Multiple Instance Learning Framework (ISMIL), which focuses on tumor regions and improves the recognition of small tumor regions by intensively sampling the crucial regions. Experiments of prostate cancer detection show that our method achieves an area under the receiver operating characteristic curve (AUC) of 0.987 on the PANDA sets, which improves recall by at least 33% with higher specificity over the current primary methods for hard cases. The ISMIL also demonstrates comparable abilities to human experts on the prostate cancer grading task. Moreover, ISMIL has shown good robustness in independent cohorts, which makes it a potential tool to improve the diagnostic efficiency of pathologists.

Age-specific and sex-specific associations of visceral adipose tissue mass and fat-to-muscle mass ratio with risk of mortality.

BACKGROUND: Limited studies have explored the association between visceral adipose tissue (VAT) mass and fat-to-muscle mass ratio (FMR) and mortality. We aimed to evaluate the sex-specific association of VAT and FMR with all-cause and cause-specific mortality by age. METHODS: A total of 438 896 participants (49.8% men, mean age ± standard deviation: 57 ± 8 years for men; 56 ± 8 years for women) were included from the UK Biobank cohort. The nature of VAT was predictive, as obtained by sex-stratified, non-linear prediction models. Fat and muscle mass were estimated using a bioelectrical impedance assessment device. FMR was calculated as the fat mass divided by the muscle mass in the whole body. VAT and FMRs were divided into quintiles in ascending order, and the 3rd quintile was used as the reference. Cox regression analyses were used to estimate the associations between VAT, FMR and mortality. RESULTS: During a median of 12.4 years of follow-up, we documented 29 903 deaths. After adjusting for various covariates, the individuals in the highest quintiles of VAT and FMR had the highest hazard ratios (HRs) of all-cause mortality [1.24 (95% confidence interval: 1.17-1.33) for VAT and 1.24 (1.17-1.31) for FMR in men; and 1.11 (1.03-1.21) for VAT in women], except that the 1st quintile of FMR in women had the greatest HR [1.18 (1.09-1.27)]. Significant interactions were observed in both sexes according to age category (P for interaction < 0.05). Among men <50 years, participants in the 1st and 5th quintiles of VAT and FMR had significantly higher risks of mortality [1.30 (1.02-1.66) and 1.67 (1.27-2.19) in VAT; 1.25 (0.99-1.56) and 1.41 (1.11-1.79) in FMR, respectively]; in women, this phenomenon was observed in the ≥60 age group [1.16 (1.06-1.27) and 1.19 (1.08-1.31) in VAT; 1.18 (1.08-1.29) and 1.11 (1.01-1.22) in FMR, respectively]. VAT showed a linear positive association with mortality in women <60 years and a J-shaped association from respiratory disease in both sexes ≥60 years. FMR showed a linear positive association with mortality from cancer in men <60 years and a J-shaped association with mortality from cause-specific mortality in both sexes ≥60 years, except for mortality from cardiovascular disease in men. CONCLUSIONS: Most associations of VAT and FMR with all-cause mortality were J-shaped and were significantly modified by age status (<50, 50-59 and ≥60 years). The clinical implication is that regarding body composition and VAT mass, different health strategies may be adopted for people of different sexes and ages.

Pre-treatment FLT-PET parameters as a prognostic tool for patients with locally advanced recurrent nasopharyngeal carcinoma salvaged by carbon-ion radiotherapy: a pilot study.

Background: Although carbon-ion radiotherapy (CIRT) may improve outcome for patients with locoregionally recurrent nasopharyngeal carcinoma (LR-NPC), local progression still remains one of the major failure patterns. This suggests an unmet need of markers for predicting disease control after re-irradiation and potentially guiding tailored treatment. The purpose of this study was to explore the predictive value of pre-treatment 3'-deoxy-3'-[18F]fluorothymidine (FLT)-positron emission tomography (PET) for patients with locally advanced LR-NPC. Methods: In this retrospective analysis, LR-NPC patients with locally advanced stage (stage III/IV) who received pre-treatment FLT-PET between June, 2015, and August, 2017, were retrospective reviewed and included in this study. OS and local progression-free survival (LPFS) were calculated using the Kaplan-Meier method. Univariable and multivariable Cox regression analyses of LPFS were performed. FLT-derived parameters, including SUVmax, metabolic tumor volume (MTV), and total lesion thymidine (TLT) were examined. The relationship between FLT-derived parameters and mucosal necrosis was tested by the Wilcoxon test. Results: A total of 27 patients with a median follow-up of 31.3 months were included in this analysis. The 2-year OS and LPFS rates were 85.2% and 47.9%, respectively. In multivariable analysis, except for TLT-40% (P=0.059), all pre-treatment MTVs (P=0.040 for MTV-40%; P=0.021 for MTV-50%; P=0.026 for MTV-60%) and TLTs (P=0.043 for TLT-50%; P=0.048 for TLT-60%) were significantly related to LPFS. Moreover, MTVs and TLTs with various boundaries (except for MTV-40%) were also associated with the development of mucosal necrosis after CIRT. Conclusions: In the current study, a significant association between pre-treatment FLT-PET and LPFS was observed in patients with locally advanced LR-NPC. Further investigations are warranted to confirm the predictive role of FLT-PET.

Temporal Heterogeneity of HER2 Expression and Spatial Heterogeneity of 18F-FDG Uptake Predicts Treatment Outcome of Pyrotinib in Patients with HER2-Positive Metastatic Breast Cancer.

Background: This study aimed to evaluate tumor heterogeneity of metastatic breast cancer (MBC) and investigate its impact on the efficacy of pyrotinib in patients with HER2-positive MBC. Methods: MBC patients who underwent 18F-FDG PET/CT before pyrotinib treatment were included. Temporal and spatial tumor heterogeneity was evaluated by the discordance between primary and metastatic immunohistochemistry (IHC) results and baseline 18F-FDG uptake heterogeneity (intertumoral and intratumoral heterogeneity indexes: HI-inter and HI-intra), respectively. Progression-free survival (PFS) was estimated by the Kaplan−Meier method and compared by a log-rank test. Results: A total of 572 patients were screened and 51 patients were included. In 36 patients with matched IHC results, 25% of them had HER2 status conversion. Patients with homogenous HER2 positivity had the longest PFS, followed by patients with gained HER2 positivity, while patients with HER2 negative conversion could not benefit from pyrotinib (16.8 vs. 13.7 vs. 3.6 months, p < 0.0001). In terms of spatial heterogeneity, patients with high HI-intra and HI-inter had significantly worse PFS compared to those with low heterogeneity (10.6 vs. 25.3 months, p = 0.023; 11.2 vs. 25.3 months, p = 0.040). Conclusions: Temporal heterogeneity of HER2 status and spatial heterogeneity of 18F-FDG uptake could predict the treatment outcome of pyrotinib in patients with HER2-positive MBC, which provide practically applicable methods to assess tumor heterogeneity and guidance for treatment decisions.

Zanubrutinib ameliorates lipopolysaccharide-induced acute lung injury via regulating macrophage polarization.

Acute lung injury (ALI) is a disease characterized by pulmonary diffusion dysfunction and its exacerbation stage is acute respiratory distress syndrome (ARDS), which may develop to multiple organ failure and seriously threatens human health. ALI has high mortality rates and few effective treatments, thus effective protection measures for ALI are becoming increasingly important. Macrophages play a key regulatory role in the pathogenesis of ALI, and the degree of macrophage polarization is closely related to the severity and prognosis of ALI. In this study, we evaluated the effects of Zanubrutinib (ZB), a BTK small molecule inhibitor approved by the FDA for the treatment of cell lymphoma, on macrophage polarization and acute lung injury. In the in vivo study, we constructed a mouse model of Lipopolysaccharide (LPS)-induced acute lung injury and found that ZB could improve the acute injury of mouse lungs by inhibiting the secretion of proinflammatory factors and promoting the secretion of anti-inflammatory factors, reduce the number of inflammatory cells in alveolar lavage fluid, and then alleviate the inflammatory response. In vivo and in vitro studies have shown that ZB could inhibit the M1 macrophage polarization and promote the M2 macrophage polarization. Subsequent mechanistic studies revealed that ZB could inhibit the macrophage M1 polarization via targeting BTK activation and inhibiting JAK2/STAT1 and TLR4/MyD88/NF-κB signaling pathways, and promote the macrophage M2 polarization by promoting the activation of STAT6 and PI3K / Akt signaling pathways. In summary, ZB has shown therapeutic effect in LPS-induced acute lung injury in mice, which provides a potential candidate drug to treat acute lung injury.

Evaluation of tumour heterogeneity by 18F-fluoroestradiol PET as a predictive measure in breast cancer patients receiving palbociclib combined with endocrine treatment.

BACKGROUND: Predictive biomarkers are needed to identify oestrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER + /HER2-) metastatic breast cancer (MBC) patients who would likely benefit from cyclin-dependent kinase 4 and 6 inhibitors combined with endocrine therapy. Therefore, we performed an exploratory study to evaluate the tumour heterogeneity parameters based on 16α-18F-fluoro-17ß-oestradiol (18F-FES)-PET imaging as a potential marker to predict progression-free survival (PFS) in MBC patients receiving palbociclib combined with endocrine therapy. METHODS: Fifty-six ER + MBC patients underwent 18F-FES-PET/CT before the initiation of palbociclib. 18F-FES uptake was quantified and expressed as the standardized uptake value (SUV). Interlesional heterogeneity was qualitatively identified according to the presence or absence of 18F-FES-negative lesions. Intralesional heterogeneity was measured by the SUV-based heterogeneity index (HI = SUVmax/SUVmean). Association with survival was evaluated using the Cox proportional hazards model. RESULTS: A total of 551 metastatic lesions were found in 56 patients: 507 lesions were identified as 18F-FES-positive, 38 lesions were distributed across 10 patients without 18F-FES uptake, and the remaining 6 were liver lesions. Forty-three patients obtained a clinical benefit, and 13 developed progressive disease (PD) within 24 weeks. Nine out of 10 patients with an 18F-FES-negative site developed PD, and the median PFS was only 2.4 months. Among 46 patients with only 18F-FES-positive lesions, only four patients had PD, and the median PFS was 23.6 months. There were statistically significant differences between the two groups (P < 0.001). For the subgroup of patients with only 18F-FES-positive lesions, low FES-HI patients experienced substantially longer PFS times than those with high FES-HI (26.5 months vs. 16.5 months, P = 0.004). CONCLUSIONS: 18F-FES-PET may provide a promising method for identifying and selecting candidate ER + /HER2- MBC patients who would most likely benefit from palbociclib combined with endocrine treatment and could serve as a predictive marker for treatment response. Trial registration NCT04992156, Date of registration: August 5, 2021 (retrospectively registered).

Chemotherapy Shows a Better Efficacy Than Endocrine Therapy in Metastatic Breast Cancer Patients with a Heterogeneous Estrogen Receptor Expression Assessed by 18F-FES PET.

Background: The heterogeneity of estrogen receptor (ER) expression has long been a challenge for the diagnosis and treatment strategy of metastatic breast cancer (MBC). A novel convenient method of ER detection using 18F-fluoroestradiol positron emission tomography/computed tomography (18F-FES PET/CT) offers a chance to screen and analyze MBC patients with ER uncertainty. Methods: MBC patients who received 18F-FES PET/CT were screened and patients with both FES positive (FES+) and negative (FES-) lesions were enrolled in this study. Progression-free survival (PFS) was estimated using the Kaplan−Meier method and was compared using the log-rank test. Results: A total of 635 patients were screened and 75 of 635 (11.8%) patients showed ER uncertainty; 51 patients received further treatment and were enrolled in this study. Among them, 20 (39.2%) patients received chemotherapy (CT), 21 (41.2%) patients received endocrine-based therapy (ET), and 10 (19.6%) patients received combined therapy (CT + ET). CT showed a better progression-free survival (PFS) compared with ET (mPFS 7.1 vs. 4.6 months, HR 0.44, 95% CI 0.20−0.93, p = 0.03). CT + ET did not improve PFS compared with either CT or ET alone (mPFS 4.4 months, p > 0.2). All three treatment options were well tolerated. Conclusions: 18F-FES PET/CT could identify patients with ER heterogeneity. Patients with bone metastasis are more likely to have ER heterogeneity. Patients with ER heterogeneity showed better sensitivity to CT rather than ET. Combined therapy of CT + ET did not improve the treatment outcome.