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.

Multi-task deep learning-based radiomic nomogram for prognostic prediction in locoregionally advanced nasopharyngeal carcinoma.

PURPOSE: Prognostic prediction is crucial to guide individual treatment for locoregionally advanced nasopharyngeal carcinoma (LA-NPC) patients. Recently, multi-task deep learning was explored for joint prognostic prediction and tumor segmentation in various cancers, resulting in promising performance. This study aims to evaluate the clinical value of multi-task deep learning for prognostic prediction in LA-NPC patients. METHODS: A total of 886 LA-NPC patients acquired from two medical centers were enrolled including clinical data, [18F]FDG PET/CT images, and follow-up of progression-free survival (PFS). We adopted a deep multi-task survival model (DeepMTS) to jointly perform prognostic prediction (DeepMTS-Score) and tumor segmentation from FDG-PET/CT images. The DeepMTS-derived segmentation masks were leveraged to extract handcrafted radiomics features, which were also used for prognostic prediction (AutoRadio-Score). Finally, we developed a multi-task deep learning-based radiomic (MTDLR) nomogram by integrating DeepMTS-Score, AutoRadio-Score, and clinical data. Harrell's concordance indices (C-index) and time-independent receiver operating characteristic (ROC) analysis were used to evaluate the discriminative ability of the proposed MTDLR nomogram. For patient stratification, the PFS rates of high- and low-risk patients were calculated using Kaplan-Meier method and compared with the observed PFS probability. RESULTS: Our MTDLR nomogram achieved C-index of 0.818 (95% confidence interval (CI): 0.785-0.851), 0.752 (95% CI: 0.638-0.865), and 0.717 (95% CI: 0.641-0.793) and area under curve (AUC) of 0.859 (95% CI: 0.822-0.895), 0.769 (95% CI: 0.642-0.896), and 0.730 (95% CI: 0.634-0.826) in the training, internal validation, and external validation cohorts, which showed a statistically significant improvement over conventional radiomic nomograms. Our nomogram also divided patients into significantly different high- and low-risk groups. CONCLUSION: Our study demonstrated that MTDLR nomogram can perform reliable and accurate prognostic prediction in LA-NPC patients, and also enabled better patient stratification, which could facilitate personalized treatment planning.

PET imaging of PARP expression using 68Ga-labelled inhibitors.

PURPOSE: Imaging the PARP expression using 18F probes has been approved in clinical trials. Nevertheless, hepatobiliary clearance of both 18F probes hindered their application in monitoring abdominal lesions. Our novel 68Ga-labelled probes aim for fewer abdominal signals while ensuring PARP targeting by optimizing the pharmacokinetic properties of radioactive probes. METHODS: Three radioactive probes targeted PARP were designed, synthesized, and evaluated based on the PARP inhibitor Olaparib. These 68Ga-labelled radiotracers were assessed in vitro and in vivo. RESULTS: Precursors that did not lose binding affinity for PARP were designed, synthesized, and then labelled with 68Ga in high radiochemical purity (> 97%). The 68Ga-labelled radiotracers were stable. Due to the increased expression of PARP-1 in SK-OV-3 cells, the uptake of the three radiotracers by SK-OV-3 cells was significantly greater than that by A549 cells. PET/CT imaging of the SK-OV-3 models indicated that the tumor uptake of 68Ga-DOTA-Olaparib (0.5 h: 2.83 ± 0.55%ID/g; 1 h: 2.37 ± 0.64%ID/g) was significantly higher than that of the other 68Ga-labelled radiotracers. There was a significant difference in the T/M (tumor-to-muscle) ratios between the unblocked and blocked groups as calculated from the PET/CT images (4.07 ± 1.01 vs. 1.79 ± 0.45, P = 0.0238 < 0.05). Tumor autoradiography revealed high accumulation in tumor tissues, further confirming the above data. PARP-1 expression in the tumor was confirmed by immunochemistry. CONCLUSION: As the first 68Ga-labelled PARP inhibitor, 68Ga-DOTA-Olaparib displayed high stability and quick PARP imaging in a tumor model. This compound is thus a promising imaging agent that can be used in a personalized PARP inhibitor treatment regimen.

Head-to-head evaluation of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT in recurrent soft tissue sarcoma.

PURPOSE: We aimed to evaluate the value of [68 Ga]Ga-DOTA-FAPI-04 PET/CT for the diagnosis of recurrent soft tissue sarcoma (STS), compared with [18F]FDG PET/CT. METHODS: A total of 45 patients (21 females and 24 males; median age, 46 years; range, 18-71 years) with 13 subtypes of STS underwent [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT examination within 1 week for assessment local relapse or distant metastasis. Positive lesions on PET/CT images were verified by biopsy or 3-month follow-up. Wilcoxon matched-pairs signed-rank test was used to compare the semiquantitative values (SUVmax and TBR) of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 in tumor lesions, and McNemar test was applied to test for differences of both tracers. RESULTS: Among the 45 patients, 282 local relapses and distant metastases were identified. Compared to [18F]FDG, [68 Ga]Ga-DOTA-FAPI-04 PET/CT detected more lesions (275 vs. 186) and outperformed in sensitivity, specificity, PPV, NPV, and accuracy for the diagnosis of recurrent lesions (P < 0.001). [68 Ga]Ga-DOTA-FAPI-04 demonstrated significantly higher values of SUVmax and TBR than [18F]FDG PET/CT in liposarcoma (P = 0.011 and P < 0.001, respectively), malignant solitary fibrous tumor (MSFT) (P < 0.001 and P < 0.001, respectively), and interdigitating dendritic cell sarcoma (IDCS) (P < 0.001and P < 0.001, respectively). While mean SUVmax and TBR presented favorable uptake of [18F]FDG over [68 Ga]Ga-DOTA-FAPI-04 in undifferentiated pleomorphic sarcoma (UPS) (P = 0.003 and P < 0.001, respectively) and rhabdomyosarcoma (RMS) (P < 0.001 and P < 0.001, respectively). CONCLUSION: [68 Ga]Ga-DOTA-FAPI-04 PET/CT is a promising new imaging modality for recurrent surveillance of STS, and compares favorably with [18F]FDG for identifying recurrent lesions of liposarcoma, MSFT, and IDCS.

A core-shell Au@Cu2-xSe heterogeneous metal nanocomposite for photoacoustic and computed tomography dual-imaging-guided photothermal boosted chemodynamic therapy.

Chemodynamic therapy (CDT) has aroused extensive attention for conquering cancers because of its high specificity and low invasiveness. Quick generation of hydroxyl radicals (·OH) during CDT could induce more irreparable damage to cancer cells. The generation rate of ·OH could be magnified via the selection of suitable nanocatalysts or under the assistance of exogenous thermal energy from photothermal therapy (PTT). Here, we construct a kind of monodisperse core-shell Au@Cu2-xSe heterogeneous metal nanoparticles (NPs) for PTT boosted CDT synergistic therapy. Due to the localized surface plasmon resonance (LSPR) coupling effect in the core-shell structure, the photothermal conversion efficiency of Au@Cu2-xSe NPs is up to 56.6%. The in situ generated heat from photothermal can then accelerate the Fenton-like reaction at Cu+ sites to produce abundant ·OH, which will induce apoptotic cell death by attacking DNA, contributing to a heat-boosted CDT. Both in vitro and in vivo results showed that after this synergistic therapy, tumors could be remarkably suppressed. Guided by photoacoustic (PA) and computed tomography (CT) imaging, the therapeutic effects were more specified. Our results revealed that PA and CT dual-imaging-guided PTT boosted CDT synergistic therapy based on core-shell Au@Cu2-xSe NPs is an effective cancer treatment strategy.

A pH-responsive photoacoustic imaging probe for tumor pH imaging in vivo based on polyaniline-bovine serum albumin.

Precise pH detection in tumors can guide the design of pH-responsive drugs and theranostic agents to improve treatment efficacy. However, most reported pH-responsive probes are fluorescent probes, for which in vivo application is limited by low probe penetration depth. In this study, a pH-responsive polyaniline-bovine serum albumin (BSA) probe was constructed for precise pH detection in tumors using photoacoustic imaging. The probe can be used to generate high-resolution images of deep biological tissues. The photoacoustic signal of the polyaniline-BSA probe exhibits a clear linear relationship with pH in the range of 5-6.8 both in vitro and in vivo, indicating that the probe is ideal for precise pH detection in most tumors. The polyaniline-BSA probe also exhibits satisfactory biocompatibility, low toxicity, fast response, and good reversibility. This work provides a useful in vivo pH detection probe for developing pH-responsive drugs and theranostic agents.

Establishment and validation of a nomogram with intratumoral heterogeneity derived from 18F-FDG PET/CT for predicting individual conditional risk of 5-year recurrence before initial treatment of nasopharyngeal carcinoma.

BACKGROUND: Intratumoral heterogeneity has an enormous effect on patient treatment and outcome. The purpose of the current study was to establish and validate a nomogram with intratumoral heterogeneity derived from 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for prognosis of 5-Year progression-free survival (PFS) of patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 171 NPC patients who underwent pretreatment 18F-FDG PET/CT were retrospectively enrolled. Data was randomly divided into training cohort (n = 101) and validation cohort (n = 70). The clinicopathologic parameters and the following PET parameters were analyzed: maximum and mean standardized uptake value (SUVmax, SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), and heterogeneity index (HI, SUVmax/SUVmean) for primary tumor and maximal neck lymph node. Cox analyses were performed on PFS in the training cohort. A prognostic nomogram based on this model was developed and validated. RESULTS: For the primary tumor, MTV-2.5, TLG-2.5, MTV-70%, and TLG-70% were significantly correlated with PFS. For the maximal neck lymph node, short diameter and HI were significantly correlated with PFS. Among the clinicopathologic parameters, M stage was a significant prognostic factor for recurrence. In multivariate analysis, M stage (P = 0.006), TLG-T-70% (P = 0.002), and HI-N (P = 0.018) were independent predictors. Based on this prognostic model, a nomogram was generated. The C-index of this model was 0.74 (95% CI: 0.63-0.85). For the cross validation, the C-index for the model was 0.73 (95% CI: 0.62-0.83) with the validation cohort. Patients with a risk score of ≥111 had poorer survival outcomes than those with a risk score of 0-76 and 77-110. CONCLUSIONS: Intratumoral heterogeneity derived from 18F-FDG PET/CT could predict long-term outcome in patients with primary NPC. A combination of PET parameters and the TNM stage enables better stratification of patients into subgroups with different PFS rates.

Ellagic acid-Fe nanoscale coordination polymer with higher longitudinal relaxivity for dual-modality T1-weighted magnetic resonance and photoacoustic tumor imaging.

Dual-modality contrast agents for T1-weighted magnetic resonance imaging (MRI) and photoacoustic imaging have attracted substantial attention as they combine the advantages of unlimited penetration depth and high sensitivity. However, most of the reported agents are Gd-based materials that exhibit nephrotoxicity, and few studies have focused on Fe-based materials owing to their lower relaxivity. This work describes the development of an ellagic acid (EA)-Fe nanoscale coordination polymer with high longitudinal relaxivity and strong near-infrared absorption for dual-modality T1-weighted MRI and photoacoustic imaging. The longitudinal relaxivity (r1) of the prepared EA-Fe@BSA nanoparticles was 2.54 mM-1 s-1, an increase of 185% compared with previously reported gallic acid-Fe nanoparticles. Furthermore, in vitro and in vivo experiments demonstrate that the EA-Fe@BSA NPs are an excellent T1-weighted MRI and photoacoustic dual-modality contrast agent with the advantages of convenient synthesis and low toxicity, exhibiting great potential for clinical use in tumor imaging.

Bovine serum albumin-templated nanoplatform for magnetic resonance imaging-guided chemodynamic therapy.

BACKGROUND: Nanotechnology in medicine has greatly expanded the therapeutic strategy that may be explored for cancer treatment by exploiting the specific tumor microenvironment such as mild acidity, high glutathione (GSH) concentration and overproduced hydrogen peroxide (H2O2). Among them, tumor microenvironment responsive chemodynamic therapy (CDT) utilized the Fenton or Fenton-like reaction to produce excess hydroxyl radical (·OH) for the destruction of tumor cells. However, the produced ·OH is easily depleted by the excess GSH in tumors, which would undoubtedly impair the CDT's efficiency. To overcome this obstacle and enhance the treatment efficiency, we design the nanoplatforms for magnetic resonance imaging (MRI)-guided CDT. RESULTS: In this study, we applied the bovine serum albumin (BSA)-templated CuS:Gd nanoparticles (CuS:Gd NPs) for MRI-guided CDT. The Cu2+ in the CuS:Gd NPs could be reduced to Cu+ by GSH in tumors, which further reacted with H2O2 and triggered Fenton-like reaction to simultaneously generate abundant ·OH and deplete GSH for tumor enhanced CDT. Besides, the Gd3+ in CuS:Gd NPs endowed them with excellent MRI capability, which could be used to locate the tumor site and monitor the therapy process preliminarily. CONCLUSIONS: The designed nanoplatforms offer a major step forward in CDT for effective treatment of tumors guided by MRI.

High specific activity is not optimal: 18 F-fluoroestradio positron emission tomography-computed tomography results in a breast cancer xenograft.

The purpose of the preliminary study was to investigate whether high specific activity (SA) of 18 F-fluoroestradiol was optimal in breast cancer diagnosis. Imaging at variable SA was conducted in a ZR-75-1 xenograft model of estrogen-receptor positive human breast cancer in 6 mice. The region of interest was manually drawn, and the percent of injected dose per gram of the tumor and muscle in the regions of interest were recorded. Tumor-to-muscle ratio (T/M) was calculated and compared in each group with different SAs. In addition, the correlation between blood estradiol and sex hormone-binding globulin and the value of T/M were also analyzed. The value of T/M increased initially with the rise of SA and it reached the peak at SA of 1.6 Ci/µmol. After that, the value fell down sharply and remained stable from SA of 3.1 Ci/µmol. The value of T/M was highest at SA of 1.6 Ci/µmol (P < .001). Additionally, the blood levels of estradiol and sex hormone-binding globulin showed no correlation with the value of T/M (P > .05). High SA of 18 F-fluoroestradiol leads to low T/M results in breast cancer xenograft models. We should control SA in a reasonable range to obtain high-quality images.

Dexamethasone enhances programmed cell death 1 (PD-1) expression during T cell activation: an insight into the optimum application of glucocorticoids in anti-cancer therapy.

BACKGROUND: Programmed cell death 1 (PD-1) is a key cell-surface receptor of CD28 superfamily that triggers inhibitory pathways to attenuate T-cell responses and promote T-cell tolerance. As a crucial role in tumor immunity, PD-1 has been a focus of studies in anti-cancer therapy. It has been approved that tumors could exploit PD-1-dependent immune suppression for immune evasion. Considering the wide use of glucocorticoids (GCs) in anti-cancer therapy and their immunosuppressive effects, we explored whether GCs could influence the expression of PD-1. RESULTS: In our study, we used dexamethasone (DEX) as a model glucocorticoid and demonstrated that DEX could enhance PD-1 expression in a dose-dependent manner. The effects were completely inhibited by the glucocorticoid receptor (GR) antagonist mifepristone (RU486), indicating that the effect of DEX on PD-1 is mediated through GR. We further found the sensitivity to DEX-induced upregulation of PD-1 expression had a significant difference between different T cell subsets, with memory T cells more susceptible to this effect. We also showed that DEX could suppress T cell functions via inhibition of cytokines production such as IL-2, IFN-γ, TNF-α and induction of apoptosis of T cells. CONCLUSION: Our findings suggest a novel way by which DEX suppress the function of activated T lymphocytes by enhancing expression of PD-1 and provide an insight into the optimum clinical application of GCs.

Differentiation of cancer of unknown primary and lymphoma in head and neck metastatic poorly differentiated cancer using 18 F-FDG PET/CT tumor metabolic heterogeneity index.

OBJECTIVE: To explore the value of 18 F-FDG PET/CT tumor metabolic heterogeneity index (HI) and establish and validate a nomogram model for distinguishing head and neck cancer of unknown primary (HNCUP) from lymphoma with head and neck metastatic poorly differentiated cancer. METHODS: This retrospective analysis was conducted on 1242 patients with cervical metastatic poorly differentiated cancer. 108 patients, who were clinically and pathologically confirmed as HNCUP or lymphoma, were finally enrolled. Two independent sample t-tests and χ 2 test were used to compare the clinical and imaging features. Binary logistic regression was used to screen for independent predictive factors. RESULTS: Among the 108 patients), 65 patients were diagnosed with HNCUP and 43 were lymphoma. Gender ( P  = 0.001), SUV max ( P  < 0.001), SUV mean ( P  < 0.001), TLG ( P  = 0.012), and HI ( P  < 0.001) had statistical significance in distinguishing HNCUP and lymphoma. Female ( OR  = 4.546, P  = 0.003) and patients with HI ≥ 2.37 ( OR  = 3.461, P  = 0.047) were more likely to be diagnosed as lymphoma. CONCLUSION: For patients with cervical metastatic poorly differentiated cancer, gender and HI were independent predictors of pathological type. For such patients, clinical attention should be paid to avoid misdiagnosing lymphoma as HNCUP, which may delay treatment.

Janus ACSP Nanoparticle for Synergistic Chemodynamic Therapy and Radiosensitization.

Protective autophagy and DNA damage repair lead to tumor radio-resistance. Some hypoxic tumors exhibit a low radiation energy absorption coefficient in radiation therapy. High doses of X-rays may lead to side effects in the surrounding normal tissues. In order to overcome the radio-resistance and improve the efficacy of radiotherapy based on the characteristics of the tumor microenvironment, the development of radiosensitizers has attracted much attention. In this study, a Janus ACSP nanoparticle (NP) was developed for chemodynamic therapy and radiosensitization. The reactive oxygen species generated by the Fenton-like reaction regulated the distribution of cell cycles from a radioresistant phase to a radio-sensitive phase. The high-Z element, Au, enhanced the production of hydroxyl radicals (•OH) under X-ray radiation, promoting DNA damage and cell apoptosis. The NP delayed DNA damage repair by interfering with certain proteins involved in the DNA repair signaling pathway. In vivo experiments demonstrated that the combination of the copper-ion-based Fenton-like reaction and low-dose X-ray radiation enhanced the effectiveness of radiotherapy, providing a novel approach for synergistic chemodynamic and radiosensitization therapy. This study provides valuable insights and strategies for the development and application of NPs in cancer treatment.

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.

COVID-19 and retinal layer thickness: A bidirectional Mendelian randomization study.

BACKGROUND: Observational studies have reported that COVID-19 is associated with alterations in retinal layer thickness, including changes in the ganglion cell inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL). However, the causal relationships remain unknown. Therefore, we assessed the direction and strength of the causal relationship between COVID-19 and GCIPL and RNFL thicknesses using a bidirectional two-sample Mendelian randomization (MR) design. METHODS: Data were obtained from a large-scale COVID-19 Host Genetics Initiative (Nsample = 6,512,887), GCIPL dataset (Ncase = 31,434), and RNFL dataset (Ncase = 31,434). The inverse-variance weighted (IVW) method is the primary approach used to estimate causal effects. MR Egger, weighted median, weighted mode, MR Egger (bootstrap), and penalized weighted median methods were applied. Sensitivity analyses were implemented with RadialMR, MRPRESSO, MR-Egger regression, Cochran's Q statistic, leave-one-out analysis, and the funnel plot. RESULTS: Forward MR analysis revealed that genetically identified COVID-19 susceptibility significantly increased the risk of GCIPL thickness (OR = 2.428, 95 % confidence interval [CI]:1.493-3.947, PIVW = 3.579 × 10-4) and RNFL thickness (OR = 1.735, 95 % CI:1.198-2.513, PIVW = 3.580 × 10-3) after Bonferroni correction. Reverse MR analysis did not indicate a significant causal association between GCIPL and RNFL thicknesses and COVID-19 phenotypes. No significant horizontal pleiotropy was found in the sensitivity analysis. CONCLUSIONS: The host genetic liability to COVID-19 susceptibility was causally associated with increased GCIPL and RNFL thicknesses. Documenting this association increases our understanding of the pathophysiological mechanisms underlying COVID -19 susceptibility in retinopathy.

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.

Single-cell profiling of the microenvironment in human bone metastatic renal cell carcinoma.

Bone metastasis is of common occurrence in renal cell carcinoma with poor prognosis, but no optimal treatment approach has been established for bone metastatic renal cell carcinoma. To explore the potential therapeutic targets for bone metastatic renal cell carcinoma, we profile single cell transcriptomes of 6 primary renal cell carcinoma and 9 bone metastatic renal cell carcinoma. We also include scRNA-seq data of early-stage renal cell carcinoma, late-stage renal cell carcinoma, normal kidneys and healthy bone marrow samples in the study to better understand the bone metastasis niche. The molecular properties and dynamic changes of major cell lineages in bone metastatic environment of renal cell carcinoma are characterized. Bone metastatic renal cell carcinoma is associated with multifaceted immune deficiency together with cancer-associated fibroblasts, specifically appearance of macrophages exhibiting malignant and pro-angiogenic features. We also reveal the dominance of immune inhibitory T cells in the bone metastatic renal cell carcinoma which can be partially restored by the treatment. Trajectory analysis showes that myeloid-derived suppressor cells are progenitors of macrophages in the bone metastatic renal cell carcinoma while monocytes are their progenitors in primary tumors and healthy bone marrows. Additionally, the infiltration of immune inhibitory CD47+ T cells is observed in bone metastatic tumors, which may be a result of reduced phagocytosis by SIRPA-expressing macrophages in the bone microenvironment. Together, our results provide a systematic view of various cell types in bone metastatic renal cell carcinoma and suggest avenues for therapeutic solutions.

In situ forming oxygen/ROS-responsive niche-like hydrogel enabling gelation-triggered chemotherapy and inhibition of metastasis.

Though the development of the diverse hypoxia-activated prodrugs (HAPs) has made great progresses in the last several decades, current cancer therapy based on HAPs still suffers many obstacles, e.g., poor therapeutic outcome owing to hard deep reaching to hypoxic region, and the occurrence of metastasis due to hypoxia. Inspired by engineered niches, a novel functional chitosan polymer (CS-FTP) is synthesized for construction of a hydrogel-based bio-niche (CS-FTP-gel) in aiming at remodeling tumor hypoxic microenvironment. The CS-FTP polymers are crosslinked to form a niche-like hydrogel via enzyme-mediated oxygen-consumable dimerization after injected into tumor, in which a HAP (i.e., AQ4N) could be physically encapsulated, resulting in enhanced tumor hypoxia to facilitate AQ4N-AQ4 toxic transformation for maximizing efficacy of chemotherapy. Furthermore, Pazopanib (PAZ) conjugated onto the CS backbone via ROS-sensitive linker undergoes a stimuli-responsive release behavior to promote antiangiogenesis for tumor starvation, eventually contributing to the inhibition of lung metastasis and synergistic action with AQ4N-based chemotherapy for an orthotopic 4T1 breast tumor model. This study provides a promising strategy for hypoxia-based chemotherapy and demonstrates an encouraging clinical potential for multifunctional hydrogel applicable for antitumor treatment.

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.

Prediction of 5-year progression-free survival in advanced nasopharyngeal carcinoma with pretreatment PET/CT using multi-modality deep learning-based radiomics.

Objective: Deep learning-based radiomics (DLR) has achieved great success in medical image analysis and has been considered a replacement for conventional radiomics that relies on handcrafted features. In this study, we aimed to explore the capability of DLR for the prediction of 5-year progression-free survival (PFS) in advanced nasopharyngeal carcinoma (NPC) using pretreatment PET/CT images. Methods: A total of 257 patients (170/87 patients in internal/external cohorts) with advanced NPC (TNM stage III or IVa) were enrolled. We developed an end-to-end multi-modality DLR model, in which a 3D convolutional neural network was optimized to extract deep features from pretreatment PET/CT images and predict the probability of 5-year PFS. The TNM stage, as a high-level clinical feature, could be integrated into our DLR model to further improve the prognostic performance. For a comparison between conventional radiomics and DLR, 1,456 handcrafted features were extracted, and optimal conventional radiomics methods were selected from 54 cross-combinations of six feature selection methods and nine classification methods. In addition, risk group stratification was performed with clinical signature, conventional radiomics signature, and DLR signature. Results: Our multi-modality DLR model using both PET and CT achieved higher prognostic performance (area under the receiver operating characteristic curve (AUC) = 0.842 ± 0.034 and 0.823 ± 0.012 for the internal and external cohorts) than the optimal conventional radiomics method (AUC = 0.796 ± 0.033 and 0.782 ± 0.012). Furthermore, the multi-modality DLR model outperformed single-modality DLR models using only PET (AUC = 0.818 ± 0.029 and 0.796 ± 0.009) or only CT (AUC = 0.657 ± 0.055 and 0.645 ± 0.021). For risk group stratification, the conventional radiomics signature and DLR signature enabled significant difference between the high- and low-risk patient groups in both the internal and external cohorts (p < 0.001), while the clinical signature failed in the external cohort (p = 0.177). Conclusion: Our study identified potential prognostic tools for survival prediction in advanced NPC, which suggests that DLR could provide complementary values to the current TNM staging.