Value of 68Ga-FAPI-04 and 18F-FDG PET/CT in Early Prediction of Pathologic Response to Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer.

This prospective study investigated whether PET parameters from 18F-FDG and 68Ga-fibroblast activation protein inhibitor (FAPI)-04 PET/CT can predict a pathologic response to neoadjuvant chemotherapy (NAC) early in patients with locally advanced gastric cancer (LAGC). Methods: The study included 28 patients with LAGC who underwent 18F-FDG PET/CT and 68Ga-FAPI-04 PET/CT at baseline and after 1 cycle of NAC. PET parameters including SUV and tumor-to-background ratio (TBR), as well as the change rate of SUV and TBR, were recorded. Patients were classified as major or minor pathologic responders according to postoperative pathology findings. We compared the PET parameters between the 2 pathologic response groups and different treatment regimens and analyzed their predictive performance for tumor pathologic response. Results: Major pathologic responders had significantly lower 68Ga-FAPI change rates (percentage SUVmax [%SUVmax], percentage SUVpeak [%SUVpeak], and percentage TBR [%TBR]) than minor pathologic responders. Among the PET parameters, 68Ga-FAPI %SUVmax (area under the curve, 0.856; P = 0.009), %SUVpeak (area under the curve, 0.811; P = 0.022), and %TBR (area under the curve, 0.864; P = 0.007) were significant parameters for early prediction of pathologic response to NAC in LAGC; they had the same predictive accuracy of 89.29%, with the thresholds of decrease to at least 52.43%, 60.46%, and 52.96%, respectively. In addition, 68Ga-FAPI %SUVmax and %TBR showed significant differences between the different treatment regimens. Conclusion: In this preliminary study, 68Ga-FAPI-04 PET change rate parameters were preferable to 18F-FDG in predicting pathologic response to NAC at an early stage in LAGC. 68Ga-FAPI %SUVmax and %TBR may be better predictors of therapeutic response between different treatment regimens. These findings may help optimize the treatment for patients with LAGC.

Intrinsic RIG-I restrains STAT5 activation to modulate antitumor activity of CD8+ T cells.

Antitumor activity of CD8+ T cells is potentially restrained by a variety of negative regulatory pathways that are triggered in the tumor microenvironment, yet, the exact mechanisms remain incompletely defined. Here, we report that intrinsic RIG-I in CD8+ T cells represents such a factor, as evidenced by observations that the tumor-restricting effect of endogenous or adoptively transferred CD8+ T cells was enhanced by intrinsic Rig-I deficiency or inhibition, with the increased accumulation, survival, and cytotoxicity of tumor-infiltrating CD8+ T cells. Mechanistically, T cell activation-induced RIG-I upregulation restrained STAT5 activation via competitive sequestering of HSP90. In accordance with this, the frequency of RIG-I+ tumor-infiltrating CD8+ T cells in human colon cancer positively correlated with attenuated survival and effector signatures of CD8+ T cells as well as poor prognosis. Collectively, these results implicate RIG-I as a potentially druggable factor for improving CD8+ T cell-based tumor immunotherapy.

Utility of [68Ga]FAPI-04 and [18F]FDG dual-tracer PET/CT in the initial evaluation of gastric cancer.

OBJECTIVES: We aimed to investigate the role of [68Ga]FAPI-04 and [18F]FDG dual-tracer PET/CT for the initial assessment of gastric cancer and to explore the factors associated with their uptake. METHODS: This study enrolled 62 patients with histopathologically confirmed gastric cancer. We compared the diagnostic performance of [68Ga]FAPI-04, [18F]FDG, and combined dual-tracer PET/CT. The standardized uptake value (SUV) and tumor-to-background ratio (TBR) were also measured, and the factors that influence tracer uptake were analyzed. RESULTS: [68Ga]FAPI-04 PET/CT detected more primary lesions (90.3% vs 77.4%, p = 0.008) and peritoneal metastases (91.7% vs 41.7%, p = 0.031) and demonstrated higher SUVmax and TBR values (p < 0.001) of primary lesions compared to [18F]FDG PET/CT. Dual-tracer PET/CT significantly improved the diagnostic sensitivity for the detection of distant metastases, compared with stand-alone [18F]FDG (97.1% vs 73.5%, p = 0.008) or [68Ga]FAPI-04 (97.1% vs 76.5%, p = 0.016) PET/CT. Subsequently, treatment strategies were changed in nine patients following [68Ga]FAPI-04 and [18F]FDG dual-tracer PET/CT. Nevertheless, [68Ga]FAPI-04 uptake was primarily influenced by the size and invasion depth of the tumor. Both [68Ga]FAPI-04 and [18F]FDG PET/CT showed limited sensitivity for detecting early gastric cancer (EGC) (37.5% vs 25.0%, p > 0.05). CONCLUSIONS: In this initial study, [68Ga]FAPI-04 and [18F]FDG dual-tracer PET/CT were complementary and improved sensitivity for the detection of distant metastases pre-treatment in gastric cancer and could improve treatment stratification in the future. [68Ga]FAPI-04 had limited efficacy in detecting EGC. KEY POINTS: • [68Ga]FAPI-04 and [18F]FDG dual-tracer PET/CT are complementary to each other for improving diagnostic sensitivity in the initial evaluation of distant metastases from gastric cancer. • [68Ga]FAPI-04 PET/CT showed limited sensitivity in detecting EGC. • Need for further validation in a larger multi-centre prospective study.

Molecular evolutionary process of advanced gastric cancer during sequential chemotherapy detected by circulating tumor DNA.

BACKGROUND: Efficacy of conventional sequential chemotherapy paradigm for advanced gastric cancer (AGC) patients has largely plateaued. Dynamic molecular changes during and after sequential chemotherapy have not been fully delineated. We aimed to profile the molecular evolutionary process of AGC patients during sequential chemotherapy by next generation sequencing (NGS) of plasma circulating tumor DNA (ctDNA). METHODS: A total of 30 chemo-naïve patients who were diagnosed with unresectable advanced or metastatic stomach adenocarcinoma were enrolled. All patients received sequential chemotherapy regimens following the clinical guideline. One hundred and eight serial peripheral blood samples were collected at baseline, radiographical assessment and disease progression. Plasma ctDNA was isolated and a customized NGS panel was used to detect the genomic features of ctDNA including single nucleotide variants (SNVs) and gene-level copy number variations (CNVs). KEGG pathway enrichment analysis was performed. RESULTS: Platinum-based combination chemotherapy was administrated as first-line regimen. Objective response rate was 50% (15/30). Patients with higher baseline values of copy number instability (CNI), CNVs and variant allel frequency (VAF) were more sensitive to platinum-based first-line regimens. Tumor mutation burden (TMB), CNI and CNV burden at partial response and stable disease were significantly lower than those at baseline, where at progressive disease they recovered to baseline levels. Dynamic change of TMB (ΔTMB) was correlated with progression-free survival of first-line treatment. Fluctuating changes of SNVs and gene-level CNVs could be observed during sequential chemotherapy. Under the pressure of conventional chemotherapy, the number of novel gene-level CNVs were found to be higher than that of novel SNVs. Such novel molecular alterations could be enriched into multiple common oncologic signaling pathways, including EGFR tyrosine kinase inhibitor resistance and platinum drug resistance pathways, where their distributions were found to be highly heterogenous among patients. The impact of subsequent regimens, including paclitaxel-based and irinotecan-based regimens, on the molecular changes driven by first-line therapy was subtle. CONCLUSION: Baseline and dynamic changes of genomic features of ctDNA could be biomarkers for predicting response of platinum-based first-line chemotherapy in AGC patients. After treatment with standard chemotherapy regimens, convergent oncologic pathway enrichment was identified, which is yet characterized by inter-patient heterogenous gene-level CNVs.

Camrelizumab and metronomic capecitabine for patients with treatment-refractory solid tumors (McCREST trial).

This is an open-label, single-center, multi-cohort phase Ib trial, which consists of three cohorts, including cohort 1 (HER2 negative gastric or gastric esophageal junction adenocarcinoma), cohort 2 (esophageal squamous cell carcinoma and head and neck squamous cell carcinoma) and cohort 3 (hepato-biliary-pancreatic and non-stomach non-esophagi gastrointestinal carcinoma). All eligible patients will be treated by camrelizumab (200 mg, every 2 weeks) and capecitabine (500 mg, twice a day, per os). The primary end point is the safety profiles of camrelizumab plus metronomic capecitabine according to CTCAE v5.0. The secondary end points are progression free survival, overall survival, objective response rate, disease control rate and duration of response. Planned enrollment is 20 subjects for each cohort. Total duration of this trial is expected to be 2 years.

Immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors have been used to treat gastrointestinal cancer patients in clinical practices. Combination with other drugs can improve the efficacy of ICIs. Metronomic chemotherapy using low dose and high frequency of cytotoxic drugs has multi-targeted anti-tumor effects and can be a potential partner of ICIs. In this study, the authors assess the safety and efficacy of a combination of a PD-1 inhibitor (camrelizumab) and an oral chemotherapy drug (capecitabine with metronomic dose) in patients with metastatic treatment-refractory solid tumors.

The efficacy of pyrotinib-based therapy in lapatinib-resistant metastatic HER2-positive breast cancer.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer tends to metastasize and is associated with poor prognosis. Anti-HER2 treatment combined with chemotherapy or endocrine therapy is often used for HER2-positive metastatic breast cancer (MBC). For later lines of therapy in HER2-positive MBC, there is no standard treatment. We investigated the efficacy of pyrotinib, a new irreversible tyrosine kinase inhibitor (TKI) targeting epidermal growth factor receptor, HER2, and HER4, in lapatinib-resistant HER2-positive MBC patients. METHODS: This is a retrospective observational study including lapatinib-resistant HER2-positive MBC patients who received pyrotinib-based treatment. We used the Kaplan-Meier method for the survival analyses. RESULTS: A total of 31 patients were included. Concurrent treatments included cytotoxic chemotherapy (29 patients, 93.6%), endocrine therapy (1 patient, 3.2%), and another targeted therapy (1 patient, 3.2%). The objective response rate (ORR) was 25.8% and the median progression-free survival in the study population was 4.5 months (95% CI: 3.1-5.9 months). The treatment-related adverse events (AEs) included diarrhea, neutropenia, vomiting, fatigue, and thrombocytopenia. Dose reduction to 320 mg was conducted in 19.4% of all cases due to severe AEs. CONCLUSIONS: Pyrotinib-based treatment was effective and generally well tolerated in lapatinib-resistant HER2-positive MBC for later line treatment.

LncRNA HCP5 Participates in the Tregs Functions in Allergic Rhinitis and Drives Airway Mucosal Inflammatory Response in the Nasal Epithelial Cells.

Allergic rhinitis (AR) is an allergic disease characterized as (immunoglobulin, IgE)-mediated type I hypersensitivity disorder. Regulatory T cells (Tregs) play a crucial role in AR. In the present study, we aimed to investigate the mechanism of how Tregs are regulated by long noncoding RNA HCP5 and the regulatory role of HCP5 in IL-13-induced inflammatory response in nasal epithelial cells (NECs) from AR patients. Peripheral blood mononuclear cells (PBMCs) and NECs were obtained from collected blood samples and nasal epithelial tissues. CD4+ T cells and Tregs were purified using certain cell isolation kits from PBMCs and Tregs were also differentiated from CD4+ T cells using recombinant human IL-2 and TGF-ß. The expression levels of HCP5, miR-16, ATXN2L, GM-CSF, eotaxin, and MUC5AC were detected by real-time PCR and western blot. The concentrations of inflammatory cytokines were detected by enzyme-linked immunosorbent assay (ELISA). The interaction among HCP5, miR-16, and ATXN2L were verified by dual-luciferase reporter assay. lncRNA HCP5 expression dramatically downregulated in PBMCs, CD4+ T cells, Tregs, and nasal tissues of AR patients, as well as in IL-13-treated NECs. HCP5 promoted Tregs differentiation and proliferation via targeting miR-16/ATXN2L axis. Additionally, HCP5 inhibited IL-13-induced GM-CSF, eotaxin, and MUC5AC production in NECs. HCP5 sponged miR-16 and negatively regulated its expression, and miR-16 targeted ATXN2L and inhibition of miR-16 suppressed IL-13-induced GM-CSF, eotaxin, and MUC5AC expression. HCP5/miR-16/ATXN2L axis mediated Tregs proliferation and functions in AR. Besides, the regulation of IL-13-induced dysfunction of NECs by lncRNA HCP5 depended on miR-16/ATXN2L in the inflammatory response of AR.

The kynurenine derivative 3-HAA sensitizes hepatocellular carcinoma to sorafenib by upregulating phosphatases.

Objectives: Sorafenib is the only FDA-approved first-line target drug for HCC patients. However, sorafenib merely confers 3-5 months of survival benefit with less than 30% of HCC patients sensitive to sorafenib therapy. Thus, it's necessary to develop a sensitizer for hepatocellular carcinoma (HCC) to sorafenib. Methods: The principal component analysis, gene ontology, and KEGG analysis are utilized following RNA-sequencing. The mass spectrometry analysis following immunoprecipitation is performed to discover the phosphatase targets. Most importantly, both the cell line-derived xenograft (CDX) and the patient-derived xenograft (PDX) mouse model are used to determine the effect of 3-HAA on sorafenib-resistant HCC in vivo. Results: In nude mice carrying HCC xenograft, tumor growth is inhibited by sorafenib or 3-HAA alone. When used in combination, the treatment particularly prevents the xenograft from growing. Combined treatment also suppresses the growth of sorafenib-resistant (≥30mg/kg) PDXs. In a set of mechanistic experiments, we find enhanced AKT activation and decreased apoptotic cells in de novo and acquired sorafenib-resistant HCC cells and tissues. 3-HAA decreases AKT phosphorylation and increases the apoptosis of HCC in both cultured cells and mouse xenografts by upregulation of phosphatases PPP1R15A/DUSP6. PPP1R15A/PPP1α directly reduces Akt phosphorylation while DUSP6 decreases Akt activity through inhibiting PDK1. The AKT activator abolishes 3-HAA inhibition of HCC growth in vitro and in mice. Conclusion: This study demonstrates that 3-HAA sensitizes HCC cells to sorafenib by upregulation of phosphatases, suggesting it as a promising molecule for HCC therapy.

Modified surface measurement method to determine catheter tip position of totally implantable venous access port through right subclavian vein.

BACKGROUND: Optimal catheter tip position of a totally implantable venous access port (TIVAP) is important to maintain its function and to avoid severe complications. In this study, we aimed to assess the reliability of a modified surface measurement method to determine optimal tip position of a TIVAP catheter inserted through the right subclavian vein. METHODS: Clinical and radiologic information of 105 patients who underwent TIVAP implantation through the right subclavian vein was collected retrospectively. The length of the implanted catheter was determined by a modified surface measurement method, as follows. The distance from the puncture point (point A) to the middle point of the sternal notch (point B), then from the middle point of the sternal notch (point B) to the middle point of Louis angle (point C) was added up. The equation for the catheter length is given by catheter length (cm) = AB + BC + 3. Postprocedure plain chest radiography (CXR) and enhanced chest computed tomography (CT) were used to check the catheter tip position and to calculate optimal position rate. Distance from the carina to the catheter tip and the length of the vertebral body unit were measured on both CXR and CT. Distances from carina to caval-atrial junction (CAJ) and from catheter tip to CAJ were measured on CT. RESULTS: Mean length of the implanted catheter of all patients was 17.0 ± 0.7 cm (male vs female, 17.3 ± 0.5 cm vs 16.7 ± 0.7 cm; P < .001). On CXR, a catheter tip located within 2.4 vertebral body units below the carina was identified as the optimal position, and the optimal position rate was 97.1% (102/105 cases). On CT, two definitions of optimal position were used: within 2 cm above or below the CAJ and within 2 cm above or at the CAJ; the optimal position rate was 92.4% (97/105 cases) and 78.1% (82/105 cases), respectively. Median follow-up time was 9.4 months. During the follow-up, no severe cardiac complication was recorded. CONCLUSIONS: The modified surface measurement had high reliability in determining the optimal catheter length to accurately place the tip in the superior vena cava near the CAJ.

Performance of 18F-FDG PET/CT Radiomics for Predicting EGFR Mutation Status in Patients With Non-Small Cell Lung Cancer.

OBJECTIVE: To assess the performance of pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) radiomics features for predicting EGFR mutation status in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We enrolled total 173 patients with histologically proven NSCLC who underwent preoperative 18F-FDG PET/CT. Tumor tissues of all patients were tested for EGFR mutation status. A PET/CT radiomics prediction model was established through multi-step feature selection. The predictive performances of radiomics model, clinical features and conventional PET-derived semi-quantitative parameters were compared using receiver operating curves (ROCs) analysis. RESULTS: Four CT and two PET radiomics features were finally selected to build the PET/CT radiomics model. Compared with area under the ROC curve (AUC) equal to 0.664, 0.683 and 0.662 for clinical features, maximum standardized uptake values (SUVmax) and total lesion glycolysis (TLG), the PET/CT radiomics model showed better performance to discriminate between EGFR positive and negative mutations with the AUC of 0.769 and the accuracy of 67.06% after 10-fold cross-validation. The combined model, based on the PET/CT radiomics and clinical feature (gender) further improved the AUC to 0.827 and the accuracy to 75.29%. Only one PET radiomics feature demonstrated significant but low predictive ability (AUC = 0.661) for differentiating 19 Del from 21 L858R mutation subtypes. CONCLUSIONS: EGFR mutations status in patients with NSCLC could be well predicted by the combined model based on 18F-FDG PET/CT radiomics and clinical feature, providing an alternative useful method for the selection of targeted therapy.

Cancer-associated fibroblasts enhance tumor 18F-FDG uptake and contribute to the intratumor heterogeneity of PET-CT.

Purpose: Elevated glucose uptake is a hallmark of cancer. Fluorodeoxyglucose (FDG) uptake was believed to indicate the aggressiveness of tumors and the standardized uptake value (SUV) is a well-known measurement for FDG uptake in positron emission tomography-computed tomography (PET/CT). However, the SUV is variable due to the heterogeneity of tumors. Methods: 126 patients with colorectal cancer underwent 18F-FDG PET/CT scanning before surgery between Jan 2011 and April 2016. Cancer-associated fibroblast (CAF) densities were calculated with the inForm Advanced image analysis software and were comparatively analyzed between patients with high and low maximum SUV (SUVmax-high and SUVmax-low). Glucose uptake was evaluated in induced and isolated CAFs and CAF-cocultured colon cancer HCT116 cells. Moreover, micro-PET/CT was performed on xenografted tumors and autoradiography was performed in the AOM/DSS induced colon cancer model. Results: CAFs were glycolytic, evidenced by glucose uptake and upregulated HK2 expression. Compared to non-activated fibroblasts (NAFs), CAFs were more dependent on glucose and sensitive to a glycolysis inhibitor. CAFs increased the SUVmax in xenograft tumors and spontaneous colon cancers. Moreover, multivariate analysis revealed that the SUVmax was only associated with tumor size among conventional parameters in colon cancer patients (126 cases, p = 0.009). Besides tumor size, the CAF density was the critical factor associated with SUVmax and outcome, which was 2.27 ± 0.74 and 1.68 ± 0.45 in the SUVmax-high and the SUVmax-low groups, respectively (p = 0.014). Conclusion: CAFs promote tumor progression and increase SUVmax of 18F-FDG, suggesting CAFs lead to the intratumor heterogeneity of the SUV and the SUVmax is a prognostic marker for cancer patients.

Prognostic value of clinicopathological characteristics in patients with pancreatic cancer.

BACKGROUND: The purpose of this study was to analyze the effects of all clinical characteristics on the overall survival time, in order to provide a basis for determining the prognostic factor of patients with pancreatic cancer. METHODS: A total of 103 pancreatic cancer patients were admitted to the Department of Radiotherapy and Chemotherapy of the Ruijin Hospital, Shanghai Jiaotong University School of Medicine, between January 2002 and December 2012. There were 68 men and 35 women; the median age was 62 years. Diagnoses of pancreatic cancer in all patients were confirmed by histopathology, cytology, or clinical diagnosis. The Kaplan-Meier method was performed to calculate the overall survival rate. The log-rank method was used to examine the univariate analysis. The Cox regression model was performed for multivariate analysis. RESULTS: The median survival time was 293 days, the 1-, 2-, and 3-year survival rates were 27.18%, 5.83%, and 1.94%, respectively. Cox regression analysis revealed that age (P=0.015), Karnofsky performance status (PS) (P=0.002), surgical types (P<0.001), and platelet counts (P<0.001) were independent prognostic factors affecting the overall survival of patients with pancreatic cancer. CONCLUSIONS: Pancreatic cancer had a poor prognosis, the general physical condition, age, the availability of radical surgery, and platelet counts were factors influencing the overall survival of patients with pancreatic cancer.

[Effect of allergy on outcomes after endoscopic sinus surgery in patients with chronic rhinosinusitis].

OBJECTIVE: To explore correlation of allergy and outcomes after endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis. METHOD: Before ESS, 115 cases were arranged to detect allergic serum relative index: the concentration of serum TIgE, specific IgE semi-quantitative test and the concentration of serum ECP; to survey QOL status: VAS, SNOT-20 and SF-36; as well as inquire medical record, Lund-Mackay CT system scoring, clinical classification of chronic rhinosinusitis. After ESS (>1 year), 74 cases were followed up. The subjective and objective assessment were achieved by means of VAS, SNOT-20, SF-36 and Lund-Kennedy endoscopic scores. RESULT: The improvements of VAS scores of the cases with increased serum TIgE were significantly lower than those without increased serum TIgE (P<0.05). In cases of II, III types, the objective outcomes of the cases with increased serum TIgE were significantly worse than those without increased serum TIgE (P<0.05). The objective outcomes of the cases with positive allergen (> or = 3) were significantly worse than those with positive allergen (<3) (P<0.05). The objective outcomes of the cases with strong positive allergen were significantly worse than those without strong positive allergen (P<0.05). VAS scores and SNOT-20 scores after endoscopic sinus surgery of the cases with strong positive allergen were significantly worse than those without strong positive allergen (P<0.05). The concentration of serum ECP of the invalid cases was significantly higher than effective cases (P<0.05). The concentration of serum ECP was positive correlated with Lund-Kennedy endoscopic scores (r=0.49, P<0.05). In cases of II, III types, the objective outcomes of the cases with increased serum ECP were significantly worse than those without increased serum ECP (P<0.05), VAS scores and SNOT-20 scores after endoscopic sinus surgery of the cases with increased serum ECP were significantly worse than those without incre- ased serum ECP (P<0.05), the improvements of VAS scores of the cases with increased serum ECP were significantly lower than those without increased serum ECP (P<0.05). CONCLUSION: Those allergic serum relative indexes make some negative effect on subjective and objective outcomes. Especially, in cases with polyps, the increase of serum TIgE and serum ECP has more negative effect. Our results might help to choose immunotherapy to combine with endoscopic sinus surgery for those selected patients to improve the outcomes of chronic rhinosinusitis.