18 F-FDG PET/CT characteristics of IASLC grade 3 invasive adenocarcinoma and the value of 18 F-FDG PET/CT for preoperative prediction: a new prognostication model.

OBJECTIVE: This study is performed to investigate the imaging characteristics of the International Association for the Study of Lung Cancer grade 3 invasive adenocarcinoma (IAC) on PET/CT and the value of PET/CT for preoperative predicting this tumor. MATERIALS AND METHODS: We retrospectively enrolled patients with IAC from August 2015 to September 2022. The clinical characteristics, serum tumor markers, and PET/CT features were analyzed. T test, Mann-Whitney U test, χ 2 test, Logistic regression analysis, and receiver operating characteristic analysis were used to predict grade 3 tumor and evaluate the prediction effectiveness. RESULTS: Grade 3 tumors had a significantly higher maximum standardized uptake value (SUV max ) and consolidation-tumor-ratio (CTR) ( P  < 0.001), while Grade 1 - 2 tumors were prone to present with air bronchogram sign or vacuole sign ( P  < 0.001). A stepwise logistic regression analysis revealed that smoking history, CEA, SUV max , air bronchogram sign or vacuole sign and CTR were useful predictors for Grade 3 tumors. The established prediction model based on the above 5 parameters generated a high AUC (0.869) and negative predictive value (0.919), respectively. CONCLUSION: Our study demonstrates that grade 3 IAC has a unique PET/CT imaging feature. The prognostication model established with smoking history, CEA, SUV max , air bronchogram sign or vacuole sign and CTR can effectively predict grade 3 tumors before the operation.

A proper protocol for routine 18F-FDG uEXPLORER total-body PET/CT scans.

BACKGROUND: Conventional clinical PET scanners typically have an axial field of view (AFOV) of 15-30 cm, resulting in limited coverage and relatively low photon detection efficiency. Taking advantage of the development of long-axial PET/CT, the uEXPLORER PET/CT scanner with an axial coverage of 194 cm increases the effective count rate by approximately 40 times compared to that of conventional PET scanners. Ordered subset expectation maximization (OSEM) is the most widely used iterative algorithm in PET. The major drawback of OSEM is that the iteration process must be stopped before convergence to avoid image degradation due to excessive noise. A new Bayesian penalized-likelihood iterative PET reconstruction, named HYPER iterative, was developed and is now available on the uEXPLORER total-body PET/CT, which incorporates a noise control component by using a penalty function in each iteration and finds the maximum likelihood solution through repeated iterations. To date, its impact on lesion visibility in patients with a full injected dose or half injected dose is unclear. The goal of this study was to determine a proper protocol for routine 18F-FDG uEXPLORER total-body PET/CT scans. RESULTS: The uEXPLORER total-body PET/CT images reconstructed using both OSEM and HYPER iterative algorithms of 20 tumour patients were retrospectively reviewed. The quality of the 5 min PET image was excellent (score 5) for all of the dose and reconstruction methods. Using the HYPER iterative method, the PET images reached excellent quality at 1 min with full-dose PET and at 2 min with half-dose PET. The PET image reached a similar excellent quality at 2 min with a full dose and at 3 min with a half dose using OSEM. The noise in the OSEM reconstruction was higher than that in the HYPER iterative. Compared to OSEM, the HYPER iterative had a slightly higher SUVmax and TBR of the lesions for large positive lesions (≥ 2 cm) (SUVmax: up to 9.03% higher in full dose and up to 12.52% higher in half dose; TBR: up to 8.69% higher in full dose and up to 23.39% higher in half dose). For small positive lesions (≤ 10 mm), the HYPER iterative had an obviously higher SUVmax and TBR of the lesions (SUVmax: up to 45.21% higher in full dose and up to 74.96% higher in half dose; TBR: up to 44.91% higher in full dose and up to 93.73% higher in half dose). CONCLUSIONS: A 1 min scan with a full dose and a 2 min scan with a half dose are optimal for clinical diagnosis using the HYPER iterative and 2 min and 3 min for OSEM. For quantification of the small lesions, HYPER iterative reconstruction is preferred.

Noninvasive imaging of FAP expression using positron emission tomography: A comparative evaluation of a [18F]-labeled glycopeptide-containing FAPI with [18F]FAPI-42.

PURPOSE: Research on fibroblast activating protein (FAP)-targeting inhibitor (FAPI) has become an important focus for cancer imaging and radiotherapy. Quinoline-based tracers [68 Ga]FAPI-04 and [18F]FAPI-42 have been widely used for positron emission tomography (PET) imaging of most tumors. However, there exist some limitations of these tracers with high uptake in biliary duct system and unstable uptake in pancreas, unsuitable for abdominal tumors PET imaging. Here we developed a [18F]-labeled glycopeptide-containing FAPI tracer (named [18F]FAPT) for PET imaging of FAP in cancers. METHODS: [18F]FAPT was synthesized manually and automatically. The competitive binding to FAP, cellular internalization, and efflux characteristics were examined in vitro using A549-FAP cells. Dynamic MicroPET and biodistribution studies of [18F]FAPT were then conducted in A549-FAP and U87MG xenograft tumor mouse models compared with [18F]FAPI-42. Five healthy volunteers and three patients with cancer underwent [18F]FAPT PET/CT. RESULTS: Preclinical and clinical studies showed specific binding of [18F]FAPT to FAP and favorable pharmacokinetic properties with better hydrophilicity, lower uptake in biliary duct system, higher tumor uptake and longer tumor retention compared with [18F]FAPI-42. The biodistribution of [18F]FAPT in healthy volunteers and patients with cancer displayed low uptake in most normal tissues except for pancreas, thyroid and salivary gland, which could contribute to high tumor-to-background ratios in most cancers. CONCLUSION: [18F]FAPT is better PET tracer than [18F]FAPI-42 for imaging of biliary duct system cancer, potentially providing a tool to examine FAP expression in most cancers with high tumor-to-background ratios.

Genomic Complexity Predicts Resistance to Endocrine Therapy and CDK4/6 Inhibition in Hormone Receptor-Positive (HR+)/HER2-Negative Metastatic Breast Cancer.

PURPOSE: Clinical biomarkers to identify patients unlikely to benefit from CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy (ET) are lacking. We implemented a comprehensive circulating tumor DNA (ctDNA) analysis to identify genomic features for predicting and monitoring treatment resistance. EXPERIMENTAL DESIGN: ctDNA was isolated from 216 plasma samples collected from 51 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) metastatic breast cancer (MBC) on a phase II trial of palbociclib combined with letrozole or fulvestrant (NCT03007979). Boosted whole-exome sequencing (WES) was performed at baseline and clinical progression to evaluate genomic alterations, mutational signatures, and blood tumor mutational burden (bTMB). Low-pass whole-genome sequencing was performed at baseline and serial timepoints to assess blood copy-number burden (bCNB). RESULTS: High bTMB and bCNB were associated with lack of clinical benefit and significantly shorter progression-free survival (PFS) compared with patients with low bTMB or low bCNB (all P < 0.05). Dominant APOBEC signatures were detected at baseline exclusively in cases with high bTMB (5/13, 38.5%) versus low bTMB (0/37, 0%; P = 0.0006). Alterations in ESR1 were enriched in samples with high bTMB (P = 0.0005). There was a high correlation between bTMB determined by WES and bTMB determined using a 600-gene panel (R = 0.98). During serial monitoring, an increase in bCNB score preceded radiographic progression in 12 of 18 (66.7%) patients. CONCLUSIONS: Genomic complexity detected by noninvasive profiling of bTMB and bCNB predicted poor outcomes in patients treated with ET and CDK4/6i and identified early disease progression before imaging. Novel treatment strategies including immunotherapy-based combinations should be investigated in this population.

Superiority of [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT to [18F]FDG PET/CT in delineating the primary tumor and peritoneal metastasis in initial gastric cancer.

OBJECTIVE: This study aimed to compare [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT with [18F]FDG PET/CT in the evaluation of initial gastric cancer. METHODS: We retrospectively compared [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT with [18F]FDG PET/CT in patients with initial gastric cancer from September 2020 to March 2021. Lesion detectability and the uptake of lesions quantified by the maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) were compared between the two modalities using the Wilcoxon signed-rank test, Mann-Whitney U test, and McNemar's chi-square test. RESULTS: A total of 61 patients (37 males, aged 23-81 years) were included, of which 22 underwent radical gastrectomy. For primary lesions, higher uptake of [68Ga]Ga-FAPI-04/[18F]FAPI-42 was observed compared to [18F]FDG (median SUVmax, 14.60 vs 4.35, p < 0.001), resulting in higher positive detection using [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT than [18F]FDG PET/CT (95.1% vs 73.8%, p < 0.001), particularly for tumors with signet-ring cell carcinoma (SRCC) (96.4% vs 57.1%, p < 0.001). [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT detected more positive lymph nodes than [18F]FDG PET/CT (637 vs 407). However, both modalities underestimated N staging compared to pathological N staging. [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT showed a higher sensitivity (92.3% vs 53.8%, p = 0.002) and peritoneal cancer index score (18 vs 3, p < 0.001) in peritoneum metastasis and other suspect metastases compared to [18F]FDG PET/CT. CONCLUSION: Our findings indicate that [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT outperformed [18F]FDG PET/CT in the evaluation of primary tumors with SRCC and peritoneum metastasis in initial gastric cancer. However, no clinically useful improvement was seen in N staging. KEY POINTS: • The uptake of [68Ga]Ga-FAPI-04/[18F]FAPI-42 in primary tumor and metastasis was intensely higher than that of [18F]FDG (p < 0.001) in 61 patients with initial gastric cancer. • [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT had a higher sensitivity detection in primary tumors (95.1% vs 73.8%, p < 0.001) and peritoneal metastases (92.3% vs 53.8%, p = 0.002) than [18F]FDG PET/CT. • [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT depicted more positive lymph nodes than [18F]FDG PET/CT (637 vs 407); however, both underestimated N staging compared to pathological N staging.

Synthesis and biological evaluation of Al[18F]-NOTA-IPB-PDL1P as a molecular probe for PET imaging of PD-L1 positive tumors.

PD-L1 is widely expressed in a variety of tumors, including NSCLC, melanoma, renal cell carcinoma, gastric cancer, hepatocellular as well as cutaneous and various leukemias, multiple myeloma and so on. Herein, we designed a novel peptide imaging agent (Al[18F]-NOTA-IPB-PDL1P) that specifically targets PD-L1 expressed in tumors. The overall radiochemical yield of Al[18F]-NOTA-IPB-PDL1P from 18F- was 10-15% (corrected radiochemical yield) within 20 min and the radiochemical purity of Al[18F]-NOTA-IPB-PDL1P was > 95% with a molar activity of 44.4-64.8 GBq/µmol. The lipophilicity logP value of Al[18F]-NOTA-IPB-PDL1P at pH 7.4 was -1.768 ±â€¯0.007 (n = 3). In the cellular uptake experiment, both HCT116 and PC3 cells dispalyed high uptake to Al[18F]-NOTA-IPB-PDL1P. The results of biodistribution showed that the uptake of Al[18F]-NOTA-IPB-PDL1P was high in kidneys, gall bladder and lung, and low in muscle and brain. In vivo micro PET studies, both HCT116 and PC3 tumors displayed high uptake for Al[18F]-NOTA-IPB-PDL1P, the tumor/muscle (T/M) radio was 2.93 and 3.57 respectively at 120 min. All the results indicate that Al[18F]-NOTA-IPB-PDL1P may have potential to be a PET imaging agent of tumors with high PD-L1 expression.

Plasma Cell-Free DNA Profiling of PTEN-PI3K-AKT Pathway Aberrations in Metastatic Castration-Resistant Prostate Cancer.

Tumor tissue from metastatic castration-resistant prostate cancer (mCRPC) harbors frequent copy number variations (CNVs) in the PTEN-PI3K-AKT pathway. However, identifying CNVs in plasma cell-free DNA (cfDNA) has proven to be challenging. With emerging data supporting Akt inhibition in PTEN-deficient mCRPC, we profiled PTEN-PI3K-AKT pathway aberrations in patients with mCRPC using a novel cfDNA assay optimized for CNV detection. METHODS: A next-generation sequencing-based cfDNA assay was used to profile 231 patients with mCRPC from two independent cohorts (Australian, n = 78; United States, n = 153). PTEN-PI3K-AKT pathway genomic aberrations were correlated with clinical outcomes, including progression-free survival and overall survival (OS). RESULTS: PTEN loss and PIK3CA gain were detected in 37% (85 of 231) and 17% (39 of 231) of patients, respectively. Poorer outcomes were observed in patients with PTEN-PI3K-AKT pathway aberrations, including those with dual PTEN loss and PIK3CA gain (hazard ratio 2.3, 95% CI 1.2 to 4.4). Cumulative CNV burden in the PTEN-PI3K-AKT and androgen receptor (AR) pathways was associated with significantly worse clinical outcomes (0 v 1 v ≥ 2 CNVs in Australian cohort: median OS 33.5 v 17.2 v 9.7 months, P < .001; 0 v 1 v ≥ 2 CNVs in US cohort: median OS 35.5 v 14.3 v 9.2 months, P < .001). Notably, 21% (31 of 146) of PTEN-neutral patients harbored alternative PTEN-PI3K-AKT pathway aberrations. CONCLUSION: PTEN-PI3K-AKT pathway CNVs were readily detected using our cfDNA assay, with the prevalence of PTEN loss comparable with tissue-based studies. Additional PTEN-PI3K-AKT pathway aberrations were found in one fifth of PTEN-neutral cases. Concurrent CNVs in the PTEN-PI3K-AKT and AR pathways portended poor survival, and identifying this high-risk patient subset for dual AR/Akt inhibition may optimize precision treatment with Akt inhibitors in mCRPC.

Combined Cell-free DNA and RNA Profiling of the Androgen Receptor: Clinical Utility of a Novel Multianalyte Liquid Biopsy Assay for Metastatic Prostate Cancer.

BACKGROUND: The androgen receptor (AR) remains a critical driver in metastatic castration-resistant prostate cancer (mCRPC). Profiling AR aberrations in both circulating DNA and RNA may identify key predictive and/or prognostic biomarkers in the context of contemporary systemic therapy. OBJECTIVE: To profile AR aberrations in circulating nucleic acids and correlate with clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: We prospectively enrolled 67 mCRPC patients commencing AR pathway inhibitors (ARPIs; n = 41) or taxane chemotherapy (n = 26). Using a first-in-class next-generation sequencing-based assay, we performed integrated cell-free DNA (cfDNA) and cell-free RNA (cfRNA) profiling from a single 10 ml blood tube. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between clinical outcomes and the following AR aberrations: copy number variation, splice variants (AR-V7 and AR-V9) and somatic mutations. RESULTS AND LIMITATIONS: Cell-free DNA and cfRNA were successfully sequenced in 67 (100%) and 59 (88%) patients, respectively. Thirty-six (54%) patients had one or more AR aberrations. AR gain and cumulative number of AR aberrations were independently associated with clinical/radiographic progression-free survival (PFS; hazard ratio [HR] 3.2, p = 0.01 and HR 3.0 for 0 vs ≥2, p = 0.04) and overall survival (HR 2.8, p = 0.04 and HR 2.9 for 0 vs ≥2, p = 0.03). Notably, concurrent AR gain and AR splice variant expression (AR gain/AR-V+) was associated with shorter prostate-specific antigen PFS on both ARPIs (HR 6.7, p = 0.009) and chemotherapy (HR 3.9, p = 0.04). Importantly, key findings were validated in an independent cohort of mCRPC patients (n = 40), including shorter OS in AR gain/AR-V+ disease (HR 3.3, p = 0.02). Limitations include sample size and follow-up period. CONCLUSIONS: We demonstrate the utility of a novel, multianalyte liquid biopsy assay capable of simultaneously detecting AR alterations in cfDNA and cfRNA. Concurrent profiling of cfDNA and cfRNA may provide vital insights into disease biology and resistance mechanisms in mCRPC. PATIENT SUMMARY: In this study of men with advanced prostate cancer, DNA and RNA abnormalities in the androgen receptor detected in blood were associated with poor outcomes on available drug treatments. This information could be used to better guide treatment of advanced prostate cancer.