Rational Design and Comparison of Novel 99mTc-Labeled FAPI Dimers for Visualization of Multiple Tumor Types.

Recognizing the significance of SPECT in nuclear medicine and the pivotal role of fibroblast activation protein (FAP) in cancer diagnosis and therapy, this study focuses on the development of 99mTc-labeled dimeric HF2 with high tumor uptake and image contrast. The dimeric HF2 was synthesized and radiolabeled with 99mTc in one pot using various coligands (tricine, TPPTS, EDDA, and TPPMS) to yield [99mTc]Tc-TPPTS-HF2, [99mTc]Tc-EDDA-HF2, and [99mTc]Tc-TPPMS-HF2 dimers. SPECT imaging results indicated that [99mTc]Tc-TPPTS-HF2 exhibited higher tumor uptake and tumor-to-normal tissue (T/NT) ratio than [99mTc]Tc-EDDA-HF2 and [99mTc]Tc-TPPMS-HF2. Notably, [99mTc]Tc-TPPTS-HF2 exhibited remarkable tumor accumulation and retention in HT-1080-FAP and U87-MG tumor-bearing mice, thereby surpassing the monomeric [99mTc]Tc-TPPTS-HF. Moreover, [99mTc]Tc-TPPTS-HF2 achieved acceptable T/NT ratios in the hepatocellular carcinoma patient-derived xenograft (HCC-PDX) model, which provided identifiable contrast and imaging quality. In conclusion, this study presents proof-of-concept research on 99mTc-labeled FAP inhibitor dimers for the visualization of multiple tumor types. Among these candidate compounds, [99mTc]Tc-TPPTS-HF2 showed excellent clinical potential, thereby enriching the SPECT tracer toolbox.

68Ga-Labeled TMTP1 Modified with d-Amino Acid for Positron Emission Tomography Diagnosis of Highly Metastatic Hepatocellular Carcinoma.

TMTP1 (NVVRQ) has been proven to selectively target various highly metastatic tumor cells. Nonetheless, existing TMTP1 probes encounter challenges such as rapid blood clearance, limited tumor uptake, and inadequate suitability for therapeutic interventions. To overcome these constraints, we designed and synthesized eight peptide probes, employing innovative chemical modification strategies involving d-amino acid modification and retro-inverso isomerization. Notably, [68Ga]TV2 exhibited particularly impressive performance, displaying an 88.88, 76.90, and 90.32% improvement in uptake at 15, 30, and 60 min, respectively, while maintaining a high target-to-nontarget ratio. Further research has demonstrated that [68Ga]TV2 also exhibits remarkable diagnostic potential for detecting in situ microtumors in the liver. The results suggest that through the implementation of innovative chemical modification strategies, we successfully developed a peptide precursor, NOTA-G-NVvRQ, with specific affinity for highly metastatic tumors, enhanced in vivo pharmacokinetic profile, and heightened stability in vivo, rendering it well suited for prospective investigations in combination therapy studies.

Patient Versus Physician Perspective in the Management of Chronic Myeloid Leukemia During Treatment with Tyrosine Kinase Inhibitors.

INTRODUCTION: Chronic myeloid leukemia (CML) is a chronic disease with treatment-free remission (TFR) increasingly regarded as a feasible goal of treatment. However, various factors may influence adherence to international guidelines for CML management. This study aimed to compare the reporting of care between patients with CML and their treating doctors. METHODS: Parallel patient and physician online surveys were conducted between September 22, 2021, and March 15, 2022, which focused on the perceptions of 1882 adult patients with CML and 305 physicians regarding tyrosine kinase inhibitor (TKI) treatment options, monitoring and toxicities, TFR, and challenges faced. RESULTS: Among the enrolled patients, 69.9% received first-line imatinib treatment, 18.6% received nilotinib, and 4.7% received dasatinib. Among the patients treated with imatinib, 36.7% switched to other TKIs due to imatinib resistance/intolerance (71.1%), exploration of more potent TKIs to achieve TFR (8.9%), and treating physicians' recommendation (14.0%), with a median duration of initial treatment of 14 months [interquartile range (IQR) 6-36]. Most (91.8%) physicians agreed that the breakpoint cluster region-Abelson 1 (BCR::ABL1) transcript level should be assessed every 3 months, but only 42.7% of individuals committed to 3-monthly testing and only 17.8% strictly followed their treating physicians' recommendation. Half of the patients aimed for TFR; however, just 45.2% of physicians considered TFR as one of the top three goals for their patients. The major concern in obtaining TFR was patients' adherence. Fatigue was often distressing for patients with TKIs, while physicians were more concerned about platelet and neutrophil counts. A total of 12% and 20.8% of patients reported moderate/severe anxiety and depression, respectively, while only 53.7% of physicians had concerns about their patients' mental health. During the coronavirus disease 2019 (COVID-19) pandemic, 69.2% of patients reported a reduction in their income. Among these patients, 61.8% maintained their current treatment, while 7.3% switched to cheaper alternatives or discontinued treatment, with over 80% of these patients belonging to the low-income group. CONCLUSIONS: Overcoming challenges in patient-physician communication and treatment access is key to improving disease management and quality of life, especially for patients with low income. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05092048.

In Vivo Comparative Study of Radioiodinated Folate Receptor Targeting Albumin Probes for Atherosclerosis Plaque Imaging.

The objective of this study is to compare a series of albumin-based folate radiotracers for the potential imaging of folate receptor (FR) positive macrophages in advanced atherosclerotic plaques. Diversified radioiodinated FR-targeting albumin-binding probes ([131I]IBAbHF, [131I]IBNHF, and [131I]HF) were developed through various strategies. Among the three radiotracers, [131I]IBAbHF and [131I]IBNHF showed excellent in vitro stability (>98%) in saline and PBS 7.4 for 24 h. Also, good stability of [131I]IBNHF in mouse serum albumin was monitored using an HSA ELISA kit. The experiments in Raw264.7 macrophages activated by ox-LDL confirmed the specificity of tracers for FR-ß. Biodistribution studies of radiotracers were performed to verify the prolonged blood half-life. Prolonged blood half-lives of [131I]IBAbHF, [131I]HF, and [131I]IBNHF were 17.26 ± 4.29, 6.33 ± 2.64, and 5.50 ± 1.26 h, respectively. SPECT-CT imaging of ApoE-/- mice at different stages was performed to evaluate the progression and monitor the prognosis of AS. Evident [131I]IBNHF uptake in atherosclerotic lesions could be observed along with a low background signal. In summary, we demonstrated a proof-of-concept of albumin-based radioligands for FR-targeting atherosclerosis imaging and found that different incorporation of radioiodinated groups resulted in different pharmacokinetic properties. Among these candidate compounds, [131I]IBNHF would be a satisfactory radiotracer for SPECT imaging of atherosclerosis.

Autologous followed by allogeneic versus tandem-autologous transplantation in high-risk, newly diagnosed multiple myeloma: a systematic review and meta-analysis.

OBJECTIVES: High-risk multiple myeloma (HRMM) is associated with poor survival, despite many advances in antimyeloma strategies. Autologous followed by allogeneic stem cell transplantation (auto-allo-SCT) has yielded controversial results compared to tandem autologous stem cell transplantation (auto-SCT) in patients with HRMM. We conducted this meta-analysis to compare the efficacy and safety of auto-allo-SCT and tandem-auto-SCT in patients with HRMM. METHODS: Embase, Cochrane Library, and PubMed databases were searched until March 2023. Prospective or retrospective studies comparing the effects of auto-allo-SCT and tandem-auto-SCT were included. Hazard ratios (HRs) and 95% confidence intervals (CIs) for time-to-event outcomes, and odds ratios (ORs) and 95%CIs for dichotomous outcomes were pooled using random-effects models. RESULTS: Three studies involving 491 patients were included. Despite auto-allo-SCT seemed to be associated with improvements in progression-free survival (PFS) (HR [95%CI], 0.71 [0.51-1.00]) and complete response (CR) (OR [95%CI], 3.16 [1.67-5.99]), and reduced relapse/progression rates (47% vs. 55%) in comparison with tandem-auto-SCT, no marked improvement in overall survival (OS). In comparison to tandem-auto-SCT, patients assigned to auto-allo-SCT exhibited a higher risk of transplant-related mortality (TRM) (11.9% vs. 4.1%) and non-relapse mortality (NRM) (12.3% vs. 3.1%). CONCLUSION: Auto-allo-SCT seemed to be associated with improvements in PFS and CR when compared to tandem-auto-SCT in patients with HRMM, but it did not lead to a significant improvement in OS. Furthermore, patients in the auto-allo-SCT group were at a higher risk of developing TRM and NRM. Auto-allo-SCT transplantation should not be routinely incorporated into HRMM therapy but rather should be considered investigational.

Longitudinal MicroSPECT Imaging of Systemic Sclerosis Model Mice with [99mTc]Tc-HYNFA via Folate Receptor Targeting.

Noninvasive single-photon emission computed tomography (SPECT) imaging with [99mTc]Tc-HYNFA via folate receptor (FR) targeting was proposed to assess the inflammation and therapeutic effect of systemic sclerosis (SSc) in model mice. The radiochemical yield and purity of [99mTc]Tc-HYNFA were over 95%, with a specific activity of about 9.36 ± 0.17 MBq/nmol. At the end of induction, the uptake ratios of bleomycin-injected regions on the back-to-muscle (R/M) and lung-to-muscle (L/M) derived from SPECT images were 7.27 ± 0.50 and 4.25 ± 0.15, respectively. The radioactivity uptakes could be blocked by excessive folic acid (FA), and R/M and L/M obviously decreased to 2.78 ± 0.57 and 2.51 ± 0.79, respectively. R/M (2.22 ± 0.71) and L/M (1.62 ± 0.28) decreased very close to those of the control mice group (R/M = 1.99 ± 0.36, L/M = 1.50 ± 0.14) when macrophages had been depleted in advance. After being treated with cyclophosphamide (CTX) or methotrexate (MTX), R/M and L/M decreased to 3.58 ± 0.52 and 2.03 ± 0.32 (CTX treatment) or 2.48 ± 0.64 and 1.83 ± 0.06 (MTX treatment). R/M and L/M were highly correlated with pathological changes. The trend of hydroxyproline content in lungs at the later non-inflammatory phase of each group was similar to the uptake values of the lung in the 4th week from the beginning of induction. [99mTc]Tc-HYNFA had an ideal uptake in SSc lesions. R/M and L/M had a high consistency with pathological changes. SPECT imaging-targeted FR could monitor the therapeutic effect of CTX and MTX. It is expected to be an effective means to evaluate SSc.

Efficacy and toxicity of carfilzomib- or bortezomib-based regimens for treatment of transplant-ineligible patients with newly diagnosed multiple myeloma: A meta-analysis.

BACKGROUND: Multiple myeloma is a clonal disorder of malignant plasma cells that comprises approximately 10% of hematologic malignancies. The aim of this study was to investigate the efficacy and toxicity of carfilzomib- or bortezomib-based regimens for treatment of transplant-ineligible patients with newly diagnosed multiple myeloma by performing a meta-analysis of randomized controlled trials (RCTs). METHODS: Data mining was conducted in March 2022 across PubMed, EMBASE and ClinicalTrials.gov. All published RCTs which assessed efficacy and toxicity of carfilzomib-based regimens treatment for transplant-ineligible patients with newly diagnosed multiple myeloma when compared with a bortezomib-based regimens were included. RESULTS: Our meta-analysis showed that the overall response rate (ORR) (Odds ratio = 1.33, 95% CI 1.05-1.69, P = .02) was significantly higher in the carfilzomib-based regimens group than in the bortezomib-based regimens group. However, the difference in ORR did not translate into improvements in progression-free survival (PFS), overall survival (OS) and complete response rate (CRR). Adverse events of grade 3 or worse that occurred with a higher incidence in the carfilzomib-based regimens group compared with the bortezomib-based regimens group were dyspnea, hypertension, acute kidney injury, and heart failure. CONCLUSIONS: The carfilzomib-based regimens did not improve PFS, OS and CRR compared with the bortezomib-based regimens in transplant-ineligible patients with newly diagnosed multiple myeloma, and they showed higher toxicity.

Novel Radiolabeled TMTP1 for Long-Acting Hepatocellular Carcinoma Therapeutics.

Currently, the 5-year survival rate for patients with advanced hepatocellular carcinoma (HCC) is very low. Therefore, there is an urgent need to find new strategies for the treatment of HCC. TMTP1 (NVVRQ) is a tumor-homing peptide that has been shown to target a range of highly metastatic tumor cells. In this study, a novel radiotherapeutic probe, [177Lu]Lu-DOTA-EB-TMTP1, was synthesized and used to explore the antitumor efficacy in an HCC tumor model. The albumin-binding TMTP1 radioligand was achieved with >98% radiochemical purity. Long tumor retention property of [177Lu]Lu-DOTA-EB-TMTP1 was exhibited in single photon emission computed tomography (SPECT) imaging and biodistribution study. The [177Lu]Lu-DOTA-EB-TMTP1 showed significant accumulation in the SMMC-7721 HCC tumor with an uptake value of 9.67 ± 1.27 %ID/g at 8 h and a T/M ratio of 6.4. In radiotherapy studies, 30 days after injection of [177Lu]Lu-DOTA-EB-TMTP1, the tumor inhibition rate reached 93.2 ± 0.10 and 94.9 ± 0.04% in the 18.5 and 29.6 MBq high-dose groups, respectively. These preclinical data suggest that [177Lu]Lu-DOTA-EB-TMTP1 may be an effective treatment option for HCC and should be further evaluated in human trials.

PD-L1-Targeted Radionuclide Therapy Combined with αPD-L1 Antibody Immunotherapy Synergistically Improves the Antitumor Effect.

Immune checkpoint blockers (ICBs) targeting programmed death receptor 1 (PD-1) ligand 1 (PD-L1) for immunotherapy have radically reformed oncology. It is of great significance to enhance the response rate of ICB in cancer patients. Here, a radioiodinated anti-PD-L1 antibody (131I-αPD-L1) was developed for PD-L1-targeted single-photon emission computed tomography (SPECT) imaging and αPD-L1 immunotherapy. Flow cytometry and immunofluorescence staining were performed to identify PD-L1 upregulation in a time- and dose-dependent manner after being induced by 131I-αPD-L1. ImmunoSPECT imaging and biodistributions of 131I-αPD-L1 in CT26, MC38, 4T1, and B16F10 tumor models were conducted to visualize the high tumor uptake and low background signal. Compared to monotherapy alone, concurrent administration of αPD-L1 mAb and 131I-αPD-L1 revealed improved tumor control in murine tumor models. The combination of 11.1 MBq of 131I-αPD-L1 and 200 µg of αPD-L1 mAb resulted in significant tumor growth delay and prolonged survival. This radioligand synergized immunotherapy strategy holds great potential for cancer management.

A Paradigm of Cancer Immunotherapy Based on 2-[18F]FDG and Anti-PD-L1 mAb Combination to Enhance the Antitumor Effect.

PURPOSE: Efforts have been devoted to select eligible candidates for PD-1/PD-L1 immune checkpoint blocker (ICB) immunotherapy. Here, we have a serendipitous finding of positron emission tomography (PET) imaging tracer 2-[18F]FDG as a potential immunomodulator. Therefore, we hypothesize that 2-[18F]FDG could induce PD-L1 expression change and create an immune-favorable microenvironment for tumor immunotherapy. EXPERIMENTAL DESIGN: We designed a series of assays to verify PD-L1 upregulation, and tested immunotherapy regimens based on 2-[18F]FDG and anti-PD-L1 mAb, as monotherapy and in combination, in fully immunocompetent mice of MC38 and CT26 models. PD-L1 expression and tumor microenvironment (TME) changes were analyzed by Western blot, transcriptomics study, and flow-cytometric analysis. RESULTS: PD-L1 was upregulated in a time- and dose-dependent manner after being induced by 2-[18F]FDG. The activation of NF-κB/IRF3 pathway and STAT1/3-IRF1 pathway play crucial parts in modulating PD-L1 expression after DNA damage and repair. Improved αPD-L1 mAb utilization rate and significant tumor growth delay were observed when the personalized therapeutic alliance of 2-[18F]FDG stimulation and ICB was used. In addition, combination of 2-[18F]FDG with αPD-L1 mAb could reprogram a TME from "cold" to "hot," to make low immunoactivity tumors sensitive to ICB therapy. CONCLUSIONS: In summary, this promising paradigm has the potential to expand the traditional tumor theranostics. 2-[18F]FDG-based ICB immunotherapy is highly significant in enhancing antitumor effect. A research of 2-[18F]FDG-based ICB immunotherapy has been proposed to enhance the antitumor effect.

Radioiodinated Ethinylestradiol Derivatives for Estrogen Receptor Targeting Breast Cancer Imaging.

Two novel PEGylated ethinylestradiol (PEG = poly(ethylene glycol)) estrogen receptor (ER) targeting probes [131I]EITE and [131I]MITE were synthesized and evaluated. Both probes had a nanomolar binding affinity to the ER receptor (36.47 nM for [131I]EITE and 61.83 nM for [131I]MITE). They showed high uptake in ER-positive MCF-7 cells and tumors, which could be significantly blocked by a coinjection of excess estradiol. Their ER specificities were further demonstrated by the low uptake in ER-negative MDA-MB-231 cells and tumors. The maximum tumor-to-muscle (T/M) ratios reach to 6.59 for [131I]EITE at 1 h postinjection (p.i.) and to 3.69 for [131I]MITE at 2 h p.i. in MCF-7 tumors. Among these two probes, [131I]EITE showed a faster tumor accumulation and a higher T/M ratio indicating it could be a better candidate for the potential diagnosis of ER-positive breast cancers.

A radioiodinated FR-ß-targeted tracer with improved pharmacokinetics through modification with an albumin binder for imaging of macrophages in AS and NAFL.

PURPOSE: The formation of advanced plaques, which is characterized by the uninterrupted aggregation of macrophages with high expression of folate receptor-ß (FR-ß), is observed in several concomitant metabolic syndromes. The objective of this study was to develop a novel FR-ß-targeted single-photon emission computed tomography (SPECT) radiotracer and validate its application to the noninvasive detection of atherosclerosis (AS) plaque and non-alcoholic fatty liver (NAFL). METHODS: Two radioiodinated probes, [131I]IPBF and [131I]IBF, were developed, and cell uptake studies were used to identify their specific targets for activated macrophages. Biodistribution in normal mice was performed to obtain the pharmacokinetic information of the probes. Apolipoprotein E knockout (ApoE-/-) mice with atherosclerotic aortas were induced by a high-fat and high-cholesterol (HFHC) diet. To investigate the affinity of radiotracers to FR-ß, Kd values were determined using in vitro assays. In addition, the assessments of the aorta in the ApoE-/- mice at different stages were performed using in vivo SPECT/CT imaging, and the findings were compared by histology. RESULTS: Both [131I]IPBF and [131I]IBF were synthesized with > 95% radiochemical purity and up to 3 MBq/nmol molar activity. In vitro assay of [131I]IPBF showed a moderate binding affinity to plasma proteins and specific uptake in activated macrophages. The prolonged blood elimination half-life (t1/2z) of [131I]IPBF (8.14 h) was observed in a pharmacokinetic study of normal mice, which was significantly longer than that of [131I]IBF (t1/2z = 2.95 h). As expected, the Kd values of [131I]IPBF and [131I]IBF in the Raw 264.7 cells were 43.94 ± 9.83 nM and 61.69 ± 15.19 nM, respectively. SPECT imaging with [131I]IPBF showed a high uptake in advanced plaques and NAFL. Radioactivity in excised aortas examined by ex vivo autoradiography further confirmed the specific uptake of [131I]IPBF in high-risk AS plaques. CONCLUSIONS: In summary, we reported a proof-of-concept study of an albumin-binding folate derivative for macrophage imaging. The FR-ß-targeted probe, [131I]IPBF, significantly prolongs the plasma elimination half-life and has the potential for the monitoring of AS plaques and concomitant fatty liver.

Integrated analysis of hub gene expression in multiple myeloma.

PURPOSE: To explore the expression and clinical significance of factors associated with multiple myeloma (MM) and identify new diagnostic markers. METHODS: Two gene expression array data sets (GSE6477 and GSE5900) were downloaded and differentially expressed genes (DEGs) in bone marrow from patients with MM and healthy donors analyzed. Kyoto Encyclopedia of Genes and Genomes pathway enrichment and Gene Ontology annotation of DEGs was conducted and a protein-protein interaction network generated. Plasma and bone marrow samples from patients with MM were analyzed for cytokine expression by ELISA and correlations between cytokine levels and clinical indicators evaluated. RESULTS: Of 908 DEGs, 416 were up-regulated and 492 down-regulated. Further, 161 proteins pairs and 21 nodes were detected, and eight hub genes (CXCL2, CXCL8, CXCL12, ELANE, LCN2, CX3CL1, CCL13, and CCL27) screened out. Expression levels of CXCL8, CXCL2, CXCL12, LCN2, and CCL13 were low in CD138+ plasma cells, and expression levels of the eight cytokines differed significantly in peripheral blood plasma from patients with MM and healthy controls. ROC curve analysis determined optimal diagnostic thresholds determined for: CCL27 (189 ng/mL), CXCL2 (313 ng/L), CX3CL1 (132 ng/L), CCL13 (235 pg/mL), CXCL8 (884 ng/L), ELANE (50 µg/L), LCN2 (8 µg/L), and CXCL12 (2525 pg/mL). CONCLUSIONS: CX3CL1, CCL13, CXCL8, and CXCL12 levels were positively correlated with those of hemoglobin and ß2 microglobulin (ß2-MG); CCL27 and CXCL2 with ß2-MG; and CCL13 and ELANE with white blood cell count and age, respectively. CCL27, CXCL2, and ß2-MG levels were associated with MM incidence.

Radioiodinated 4-(p-Iodophenyl) Butanoic Acid-Modified Estradiol Derivative for ER Targeting SPECT Imaging.

Overexpression of estrogen receptors (ERs) is one of the important characteristics of most breast cancers. We aim to develop a new type of ER-specific radioiodine-labeled estrogen derivative ([131I]IPBA-EE), which was modified with an albumin-specific ligand 4-(p-iodophenyl) butyric acid (IPBA) to improve the metabolic stability and enhance the ER-targeting ability of estrogen. [131I]IPBA-EE can effectively bind to albumin in vitro, and its dissociation constant (Kd = 0.31 µM) is similar to IPBA (Kd = 0.30 µM). The uptake of [131I]IPBA-EE in ER-positive MCF-7 cells (41.81 ± 3.41%) was significantly higher than that in ER-negative MDA-MB-231 cells (8.78 ± 2.37%, ***P < 0.0005) and could be significantly blocked (3.92 ± 0.35%, ***P < 0.0005). The uptakes of [131I]IPBA-EE in rat uterus and ovaries were 5.66 ± 0.34% ID/g and 5.71 ± 2.77% ID/g, respectively, at 1 h p.i., and these uptakes could be blocked by estradiol (uterus: 2.81 ± 0.41% ID/g, *P < 0.05; ovarian: 3.02 ± 0.08% ID/g, *P < 0.05). SPECT/CT imaging showed that ER-positive MCF-7 tumor uptake of [131I]IPBA-EE reached to 6.07 ± 0.20% ID/g at 7 h p.i., which was significantly higher than that of ER-negative MDA-MB-231 tumor (0.87 ± 0.08% ID/g, **P < 0.005) and could be blocked obviously with fulvestrant (1.65 ± 1.56% ID/g, *P < 0.05). In conclusion, a novel radioiodinated estradiol derivative, [131I]IPBA-EE with albumin-binding property and good metabolic stability, was developed to image the ER in breast cancer. This promising ER-targeted probe has the potential to warrant further preclinical investigations.

Integrative Analysis of Gene Expression Through One-Class Logistic Regression Machine Learning Identifies Stemness Features in Multiple Myeloma.

Tumor progression includes the obtainment of progenitor and stem cell-like features and the gradual loss of a differentiated phenotype. Stemness was defined as the potential for differentiation and self-renewal from the cell of origin. Previous studies have confirmed the effective application of stemness in a number of malignancies. However, the mechanisms underlying the growth and maintenance of multiple myeloma (MM) stem cells remain unclear. We calculated the stemness index for samples of MM by utilizing a novel one-class logistic regression (OCLR) machine learning algorithm and found that mRNA expression-based stemness index (mRNAsi) was an independent prognostic factor of MM. Based on the same cutoff value, mRNAsi could stratify MM patients into low and high groups with different outcomes. We identified 127 stemness-related signatures using weighted gene co-expression network analysis (WGCNA) and differential expression analysis. Functional annotation and pathway enrichment analysis indicated that these genes were mainly involved in the cell cycle, cell differentiation, and DNA replication and repair. Using the molecular complex detection (MCODE) algorithm, we identified 34 pivotal signatures. Meanwhile, we conducted unsupervised clustering and classified the MM cohorts into three MM stemness (MMS) clusters with distinct prognoses. Samples in MMS-cluster3 possessed the highest stemness fractions and the worst prognosis. Additionally, we applied the ESTIMATE algorithm to infer differential immune infiltration among the three MMS clusters. The immune core and stromal score were significantly lower in MMS-cluster3 than in the other clusters, supporting the negative relation between stemness and anticancer immunity. Finally, we proposed a prognostic nomogram that allows for individualized assessment of the 3- and 5-year overall survival (OS) probabilities among patients with MM. Our study comprehensively assessed the MM stemness index based on large cohorts and built a 34-gene based classifier for predicting prognosis and potential strategies for stemness treatment.

Development and Preclinical Evaluation of Radiolabeled Covalent G12C-Specific Inhibitors for Direct Imaging of the Oncogenic KRAS Mutant.

Although KRAS has been an important target for many cancers, direct inhibition of oncogenic RAS remains challenging. Until recently, covalent KRAS G12C-specific inhibitors have been developed and progressed to the clinics. Nevertheless, not all patients benefit from these covalent inhibitors. At present, identification of candidates for this treatment requires tissue biopsies and gene sequencing, which are invasive, time-consuming, and could be of insufficient quality and limited predictive value owing to tumor heterogeneity. The use of noninvasive molecular imaging techniques such as PET and SPECT for spying KRAS G12C mutation in tumors provide a promising strategy for circumventing these hurdles. In the present study, based on the covalent G12C-specific inhibitor ARS-1620, we sought to develop radiolabeled small molecules for direct imaging of the KRAS mutation status in tumors. [131I]I-ARS-1620 and [18F]F-ARS-1620 were successfully prepared with high radiochemical yield, radiochemical purity, and molar activity. In vitro and in vivo studies have demonstrated the affinity, specificity, and capacity of [131I]I-ARS-1620 for direct imaging of the oncogenic KRAS G12C mutant. This initial attempt allows us to directly screen the KRAS G12C mutant for the first time in vivo.

Syntheses and Preliminary Evaluation of Dual Target PET Probe [18F]-NOTA-Gly3- E (2PEG4-RGD-WH701) for PET Imaging of Breast Cancer.

PURPOSE: Tumor Necrosis Factor Receptor 1 (TNFR1) and integrin αvß3 receptor are overexpressed in breast cancer. We hypothesized that a peptide ligand recognizing both receptors in a single receptor-binding probe would be advantageous. Here, we developed a novel 18F-labeled fusion peptide probe [18F]-NOTA-Gly3- E(2PEG4-RGD-WH701) targeting dual receptors (TNFR1 and αvß3) and evaluated the diagnostic efficacy of this radioactive probe in both MDA-MB-231 and MCF-7 xenograft models in mice. METHODS: The NOTA-conjugated RGD-WH701 analog was radiolabeled with 18F using NOTA-AlF chelation method. We used two PEG4 molecules and Glutamic acid (Glu) to covalently link c(RGDyK) with WH701. Gly3 was also added to further improve the water solubility and pharmacokinetic properties of the probe. The expression of TNFR1 and Integrin αvß3 in MCF-7 and MDA-MB-231 cells was detected by western blot analysis and immunofluorescence staining. The tumor-targeting characteristics of [18F]-NOTA-Gly3-E(2PEG4-RGDWH701) were assessed in nude mice bearing MDA-MB-231 and MCF-7 xenografts. RESULTS: HPLC analysis of the product NOTA-G3-E (2P4-RGD-WH701) revealed a purity >95%. The yield after attenuation correction was approximately 33.5%±2.8% (n=5), and the radiochemical purity was above 95%. The MDA-MB-231 tumor uptake of [18F]-NOTA-Gly3-E(2PEG4-RGD-WH701) was 1.14±0.14%ID/g, as measured by PET at 40min postinjection (p.i.). In comparison, the tumor uptake of [18F]-NOTA-RGD and [18F]- NOTA-WH701 in MDA-MB-231 xenografts was 0.96±0.13%ID/g and 0.93±0.28%ID/g, respectively. The MCF-7 tumor uptake of [18F]-NOTA-Gly3-E(2PEG4-RGD-WH701) was 1.22±0.11%ID/g, as measured by PET at 40min postinjection (p.i.). In comparison, the tumor uptake of [18F]-NOTA-RGD and [18F]-NOTA-WH701 in MCF-7 xenografts was 0.99±0.18%ID/g and 0.57±0.08%ID/g, respectively. CONCLUSION: [18F]AlF-NOTA-Gly3-E(2PEG4-RGD-WH701) was successfully synthesized and labeled with 18F. The results from the microPET/CT and biodistribution studies of [18F]AlF-NOTA-Gly3-E(2PEG4-RGDWH701) showed that the tracer could specifically target TNFR1 and integrin αvß3 receptors.

Synthesis and Application of a Long-Circulating Radiolabeled Peptide for Targeting of Osteosarcoma.

PURPOSE: The small peptide TMTP1 (NVVRQ) has been proved to target a series of highly metastatic tumor cells. The aim of this study was to develop a new agent based on TMTP1 conjugated with Evans blue (EB), to increase tumor uptake and modify the pharmacokinetic characteristics of the resulting radiolabeled agent. PROCEDURES: DOTA-EB-TMTP1 was prepared through conventional solid-phase peptide synthesis chemistry. Then, it was successfully labeled with Cu-64 to obtain [64Cu]DOTA-EB-TMTP1. The tumor targeting properties were evaluated in vivo using 143B xenografts. RESULTS: DOTA-EB-TMTP1 was successfully labeled with Cu-64 in a yield of 87.3 ± 5.2 %. In a small animal positron emission tomography/X-ray computed tomography (PET/CT) study in osteosarcoma 143B xenograft mice, [64Cu]DOTA-EB-TMTP1 was found to rapidly accumulate in the tumor tissue. The tumor uptake increased over time and reached a plateau of 6.50 ± 0.88 % ID/g 8 h after tail vein injection. The radioactivity remained in the tumor tissue 48 h postinjection with a negligible decrease. CONCLUSIONS: Overall, the introduction of the EB motif to TMTP1 significantly changed its pharmacokinetics in vivo, and this strategy fulfills the purpose of prolonging the blood circulation and enhancing the tumor uptake. [64Cu]DOTA-EB-TMTP1 is a promising agent for osteosarcoma targeting. Moreover, our study highlights that DOTA-EB-TMTP1 is a good candidate for labeling with different radionuclides for potential theranostic applications.

Efficacy and safety of lenalidomide for the treatment of acute myeloid leukemia: a systematic review and meta-analysis.

BACKGROUND: Lenalidomide is effective for the treatment of low-risk myelodysplastic syndromes with deletion 5q abnormalities. However, whether lenalidomide leads to a significant improvement in treatment response and overall survival (OS) in cases of acute myeloid leukemia (AML) remains controversial. A systematic review and a meta-analysis were performed to evaluate the efficacy and safety of lenalidomide in the treatment of AML. METHODS: Clinical studies were identified from the Cochrane Central Register of Controlled Trials, PubMed, Embase, and ClinicalTrials.gov. Efficacy outcomes included overall response rate (ORR), complete remission (CR), and OS. Safety was evaluated based on the incidence of grade 3 and 4 treatment-related adverse events (AEs). RESULTS: Eleven studies were included in our meta-analysis; collectively these studies featured 407 AML patients. Pooled estimates for overall ORR and CR were 31% (95% CI: 26%-36%) and 21% (95% CI: 16%-27%), respectively. Thrombocytopenia, anemia, neutropenia, and infection were the most common grade 3 and 4 AEs. CONCLUSION: Lenalidomide may have some clinical activity in AML, but the population that would benefit from lenalidomide and incorporating lenalidomide into combination drug strategies need to be better defined.