An artificial intelligence-powered PD-L1 combined positive score (CPS) analyser in urothelial carcinoma alleviating interobserver and intersite variability.

AIMS: Immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) have shown promising clinical outcomes in urothelial carcinoma (UC). The combined positive score (CPS) quantifies PD-L1 22C3 expression in UC, but it can vary between pathologists due to the consideration of both immune and tumour cell positivity. METHODS AND RESULTS: An artificial intelligence (AI)-powered PD-L1 CPS analyser was developed using 1,275,907 cells and 6175.42 mm2 of tissue annotated by pathologists, extracted from 400 PD-L1 22C3-stained whole slide images of UC. We validated the AI model on 543 UC PD-L1 22C3 cases collected from three institutions. There were 446 cases (82.1%) where the CPS results (CPS ≥10 or <10) were in complete agreement between three pathologists, and 486 cases (89.5%) where the AI-powered CPS results matched the consensus of two or more pathologists. In the pathologist's assessment of the CPS, statistically significant differences were noted depending on the source hospital (P = 0.003). Three pathologists reevaluated discrepancy cases with AI-powered CPS results. After using the AI as a guide and revising, the complete agreement increased to 93.9%. The AI model contributed to improving the concordance between pathologists across various factors including hospital, specimen type, pathologic T stage, histologic subtypes, and dominant PD-L1-positive cell type. In the revised results, the evaluation discordance among slides from different hospitals was mitigated. CONCLUSION: This study suggests that AI models can help pathologists to reduce discrepancies between pathologists in quantifying immunohistochemistry including PD-L1 22C3 CPS, especially when evaluating data from different institutions, such as in a telepathology setting.

Discontinuation risk from adverse events: immunotherapy alone vs. combined with chemotherapy: a systematic review and network meta-analysis.

BACKGROUND: While immunotherapy combined with chemotherapy (Chemo-IO) is generally recognized for providing superior outcomes compared to monotherapy (mono-IO), it is associated with a higher incidence of treatment-related adverse events (TRAEs), which may lead to treatment discontinuation. In this study, we compared the rates of treatment discontinuation between mono-IO and Chemo-IO as first-line treatments for various solid tumors. METHODS: We systematically reviewed clinical trials from databases (PubMed, Embase, Cochrane Library, and an additional source) published from January 1, 2018, to July 10, 2023. We included phase III randomized controlled trials (RCTs) that utilized immunotherapy agents in at least one arm as first-line treatments for a variety of solid tumors. Data extraction followed the Preferred Reporting Items for Systematic Reviews (PRISMA) extension statement for network meta-analysis. A random effects model was used for the network meta-analysis, with the risk of bias assessed using the Cochrane risk-of-bias tool II. The primary outcomes encompassed treatment discontinuation rates due to TRAEs among patients who underwent immunotherapy, either alone or combined with chemotherapy, for various solid tumors. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated to compare between treatment groups. RESULTS: From 29 RCTs, a total of 21,677 patients and 5 types of treatment were analyzed. Compared to mono-IO, Chemo-IO showed a significantly higher rate of discontinuation due to TRAEs (RR 2.68, 95% CI 1.98-3.63). Subgroup analysis for non-small cell lung cancer (NSCLC) patients also exhibited a greater risk of discontinuation due to TRAEs with Chemo-IO compared to mono-IO (RR 2.93, 95% CI 1.67-5.14). Additional analyses evaluating discontinuation rates due to either treatment emergent adverse events (TEAEs) or AEs regardless of causality (any AEs) consistently revealed an elevated risk associated with Chemo-IO. CONCLUSIONS: Chemo-IO was associated with an elevated risk of treatment discontinuation not only due to TRAEs but also any AEs or TEAEs. Given that the treatment duration can impact clinical outcomes, a subset of patients might benefit more from mono-IO than combination therapy. Further research is imperative to identify and characterize this subset.

Artificial Intelligence-Powered Hematoxylin and Eosin Analyzer Reveals Distinct Immunologic and Mutational Profiles among Immune Phenotypes in Non-Small-Cell Lung Cancer.

The tumor microenvironment can be classified into three immune phenotypes: inflamed, immune excluded, and immune-desert. Immunotherapy efficacy has been shown to vary by phenotype; yet, the mechanisms are poorly understood and demand further investigation. This study unveils the mechanisms using an artificial intelligence-powered software called Lunit SCOPE. Artificial intelligence was used to classify 965 samples of non-small-cell lung carcinoma from The Cancer Genome Atlas into the three immune phenotypes. The immune and mutational profiles that shape each phenotype using xCell, gene set enrichment analysis with RNA-sequencing data, and cBioportal were described. In the inflamed subtype, which showed higher cytolytic score, the enriched pathways were generally associated with immune response and immune-related cell types were highly expressed. In the immune excluded subtype, enriched glycolysis, fatty acid, and cholesterol metabolism pathways were observed. The KRAS mutation, BRAF mutation, and MET splicing variant were mostly observed in the inflamed subtype. The two prominent mutations found in the immune excluded subtype were EGFR and PIK3CA mutations. This study is the first to report the distinct immunologic and mutational landscapes of immune phenotypes, and demonstrates the biological relevance of the classification. In light of these findings, the study offers insights into potential treatment options tailored to each immune phenotype.

Comprehensive Molecular Characterization of Adenocarcinoma of the Gastroesophageal Junction Between Esophageal and Gastric Adenocarcinomas.

OBJECTIVE: To investigate the molecular characteristics of AGEJ compared with EAC and gastric adenocarcinoma. SUMMARY OF BACKGROUND DATA: Classification of AGEJ based on differential molecular characteristics between EAC and gastric adenocarcinoma has been long-standing controversy but rarely conducted due to anatomical ambiguity and epidemiologic difference. METHODS: The molecular classification model with Bayesian compound covariate predictor was developed based on differential mRNA expression of EAC (N = 78) and GCFB (N = 102) from the Cancer Genome Atlas (TCGA) cohort. AGEJ/cardia (N = 48) in TCGA cohort and AGEJ/upper third GC (N = 46 pairs) in Seoul National University cohort were classified into the EAC-like or GCFB-like groups whose genomic, transcriptomic, and proteomic characteristics were compared. RESULTS: AGEJ in both cohorts was similarly classified as EAC-like (31.2%) or GCFB-like (68.8%) based on the 400-gene classifier. The GCFB-like group showed significantly activated phosphoinositide 3-kinase-AKT signaling with decreased expression of ERBB2. The EAC-like group presented significantly different alternative splicing including the skipped exon of RPS24, a significantly higher copy number amplification including ERBB2 amplification, and increased protein expression of ERBB2 and EGFR compared with GCFB-like group. High-throughput 3D drug test using independent cell lines revealed that the EAC-like group showed a significantly better response to lapatinib than the GCFB-like group (P = 0.015). CONCLUSIONS: AGEJ was the combined entity of the EAC-like and GCFB-like groups with consistently different molecular characteristics in both Seoul National University and TCGA cohorts. The EAC-like group with a high Bayesian compound covariate predictor score could be effectively targeted by dual inhibition of ERBB2 and EGFR.

Discovery of acquired molecular signature on immune checkpoint inhibitors in paired tumor tissues.

BACKGROUND: Immune checkpoint inhibitor (ICI) has an emerging role in several types of cancer. However, the mechanisms of acquired resistance (AR) to ICI have not been elucidated yet. To identify these mechanisms, we analyzed the pre- and post-ICI paired tumor samples in patients with AR. METHODS: Six patients with renal cell carcinoma, urothelial cell carcinoma, or head and neck cancer, who showed an initial response to ICI followed by progression and had available paired tissue samples, were retrospectively analyzed. Whole exome sequencing, RNA sequencing, and multiplex immunohistochemistry were performed on pre-treatment and resistant tumor samples. RESULTS: The median time to AR was 370 days (range, 210 to 739). Increased expression of alternative immune checkpoints including TIM3, LAG3, and PD-1 as well as increased CD8+ tumor-infiltrating lymphocytes were observed in post-treatment tumor than in pre-treatment tumor of a renal cell carcinoma patient. In contrast, CD8+ T cells and immunosuppressive markers were all decreased at AR in another patient with human papillomavirus-positive head and neck squamous cell carcinoma. This patient had an evident APOBEC-associated signature, and the tumor mutation burden increased at AR. Resistant tumor tissue of this patient harbored a missense mutation (E542K) in PIK3CA. No significant aberrations of antigen-presenting machinery or IFN-γ pathway were detected in any patient. CONCLUSIONS: Our study findings suggest that the observed increase in immunosuppressive markers after ICI might contribute to AR. Moreover, APOBEC-mediated PIK3CA mutagenesis might be an AR mechanism. To validate these mechanisms of AR, further studies with enough sample size are required.

Pan-cancer methylation analysis reveals an inverse correlation of tumor immunogenicity with methylation aberrancy.

Tumor immunogenicity is driven by various genomic and transcriptomic factors but the association with the overall status of methylation aberrancy is not well established. We analyzed The Cancer Genome Atlas pan-cancer database to investigate whether the overall methylation aberrancy links to the immune evasion of tumor. We created the definitions of hypermethylation burden, hypomethylation burden and methylation burden to establish the values that represent the degree of methylation aberrancy from human methylation 450 K array data. Both hypermethylation burden and hypomethylation burden significantly correlated with global methylation level as well as methylation subtypes defined in previous literatures. Then we evaluated whether methylation burden correlates with tumor immunogenicity and found that methylation burden showed a significant negative correlation with cytolytic activity score, which represent cytotoxic T cell activity, in pan-cancer (Spearman rho = - 0.37, p < 0.001) and 30 of 33 individual cancer types. Furthermore, this correlation was independent of mutation burden and chromosomal instability in multivariate regression analysis. We validated the findings in the external cohorts and outcomes of patients who were treated with immune checkpoint inhibitors, which showed that high methylation burden group had significantly poor progression-free survival (Hazard ratio 1.74, p = 0.038). Overall, the degree of methylation aberrancy negatively correlated with tumor immunogenicity. These findings emphasize the importance of methylation aberrancy for tumors to evade immune surveillance and warrant further development of methylation biomarker.

A phase I study of IMC-001, a PD-L1 blocker, in patients with metastatic or locally advanced solid tumors.

Introduction IMC-001 is a fully human IgG1 monoclonal antibody that binds to human PD-L1 (programmed death-ligand 1). This study evaluated the safety, pharmacokinetics, and pharmacodynamics of IMC-001 in patients with advanced solid tumors. Materials and Methods This open-labeled phase I study used a standard 3 + 3 dose-escalation design, with doses ranging from 2 to 20 mg/kg. IMC-001 was administered intravenously every 2 weeks until disease progression or unacceptable toxicity. The dose-limiting toxicity window was defined as 21 days from the first dose. Results Fifteen subjects were included in 5 dose-escalation cohorts. No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. The most common adverse events (AEs) were general weakness, decreased appetite, fever, and cough. No grade 4 or 5 treatment emergent AEs were reported during the study. One subject in the 2 mg/kg cohort showed grade 2 immune-induced thyroiditis and diabetes mellitus suspected to be related to IMC-001. Over the dose range of 2-20 mg/kg IMC-001, the AUC0-14d, AUC0-∞, and Cmax generally increased in a dose-proportional manner for each step of dose escalation. Of the 15 enrolled patients, 1 subject with rectal cancer showed a partial response, and the disease control rate was 33.3%. Conclusions IMC-001 demonstrated a favorable safety profile up to 20 mg/kg administered intravenously every 2 weeks and showed preliminary efficacy in patients with advanced solid tumors. Based on pharmacokinetic and pharmacodynamic data, 20 mg/kg was selected as the recommended phase II dose. Clinical trial identification NCT03644056 (date of registration: August 23, 2018).

Immunogenicity of Influenza Vaccination in Patients with Cancer Receiving Immune Checkpoint Inhibitors.

Among prospectively enrolled adult patients with cancer receiving immune checkpoint inhibitors (ICIs; n = 46) or cytotoxic agents (n = 90), seroprotection and seroconversion rates after seasonal quadrivalent influenza vaccinations were higher with ICI than with cytotoxic chemotherapy. These results support annual influenza vaccinations for cancer patients receiving ICIs. Clinical Trials Registration clinicaltrials.gov (NCT03590808).

Interleukin 1 Up-regulates MicroRNA 135b to Promote Inflammation-Associated Gastric Carcinogenesis in Mice.

BACKGROUND & AIMS: Gastritis is associated with development of stomach cancer, but little is known about changes in microRNA expression patterns during gastric inflammation. Specific changes in gene expression in epithelial cells are difficult to monitor because of the heterogeneity of the tissue. We investigated epithelial cell-specific changes in microRNA expression during gastric inflammation and gastritis-associated carcinogenesis in mice. METHODS: We used laser microdissection to enrich epithelial cells from K19-C2mE transgenic mice, which spontaneously develop gastritis-associated hyperplasia, and Gan mice, which express activated prostaglandin E2 and Wnt in the gastric mucosa and develop gastric tumors. We measured expression of epithelial cell-enriched microRNAs and used bioinformatics analyses to integrate data from different systems to identify inflammation-associated microRNAs. We validated our findings in gastric tissues from mice and evaluated protein functions in gastric cell lines (SNU-719, SNU-601, SNU-638, AGS, and GIF-14) and knockout mice. Organoids were cultured from gastric corpus tissues of wild-type and miR-135b-knockout C57BL/6 mice. We measured levels of microRNAs in pairs of gastric tumors and nontumor mucosa from 28 patients in Japan. RESULTS: We found microRNA 135b (miR-135B) to be the most overexpressed microRNA in gastric tissues from K19-C2mE and Gan mice: levels increased during the early stages of gastritis-associated carcinogenesis. Levels of miR-135B were also increased in gastric tumor tissues from gp130F/F mice and patients compared with nontumor tissues. In gastric organoids and immortalized cell lines, expression of miR-135B was induced by interleukin 1 signaling. K19-C2mE mice with disruption of Mir-135b developed hyperplastic lesions that were 50% smaller than mice without Mir-135b disruption and had significant reductions in cell proliferation. Expression of miR-135B in gastric cancer cell lines increased their colony formation, migration, and sphere formation. We identified FOXN3 and RECK messenger RNAs (mRNAs) as targets of miR-135B; their knockdown reduced migration of gastric cancer cell lines. Levels of FOXN3 and RECK mRNAs correlated inversely with levels of miR-135B in human gastric tumors and in inflamed mucosa from K19-C2mE mice. CONCLUSIONS: We found expression of miR-135B to be up-regulated by interleukin L1 signaling in gastric cancer cells and organoids. miR-135B promotes invasiveness and stem-cell features of gastric cancer cells in culture by reducing FOXN3 and RECK messenger RNAs. Levels of these messenger RNA targets, which encode tumor suppressor, are reduced in human gastric tumors.

Severe late dysphagia after multimodal treatment of stage III/IV laryngeal and hypopharyngeal cancer.

BACKGROUND: Long-term side effects after radiotherapy for organ preservation 'could deteriorate' the laryngeal function. This study intended to identify the incidence of severe late dysphagia following the multimodal treatment for stage III/IV laryngeal and hypopharyngeal cancer 'to evaluate the function of larynx'. METHODS: The medical records of patients successfully treated for laryngeal and hypopharyngeal cancer with a multimodal approach, including radiotherapy, were retrospectively analyzed. 'Functional larynx was defined as tolerable oral diet without severe late dysphagia or tracheostoma'. RESULTS: The study included 99 patients with a median follow-up period of 72 months. 'Tracheostomy during the follow-up period was required in only one patient due to aspiration pneumonia, and dysphagia is the main determinant for functional larynx'. The probability of maintaining functional larynx was 63% for 10 years, when the treatment was started with radiotherapy or concurrent chemoradiotherapy. In upfront surgery (operation first and adjuvant radiotherapy/concurrent chemoradiotherapy) group, 37% of patients required total laryngectomy as primary treatment and 43% of patients could maintain laryngeal function for 10 years. And severe late dysphagia in the latter group developed mainly after laryngeal preservation surgery. The patients aged ≥65 years showed significantly higher incidence of dysphagia. Severe late dysphagia was very rare in laryngeal cancer successfully cured with radiotherapy/concurrent chemoradiotherapy (1/25, 4%); however, it gradually increased over time in hypopharyngeal cancer patients showing a statistically significant difference from laryngeal cancer patients (P = 0.040). CONCLUSION: Severe late dysphagia occurred in 19.2% of patients treated for laryngeal and hypopharyngeal cancers, regardless of whether treatment started with radiotherapy/concurrent chemoradiotherapy or surgery.

Association between the exposure to anti-angiogenic agents and tumour immune microenvironment in advanced gastrointestinal stromal tumours.

BACKGROUND: Tumour immune microenvironment (TIME) of gastrointestinal stromal tumours (GISTs) is largely unknown. METHODS: A total of 81 surgical specimens from 67 patients with advanced GISTs were categorised into treatment groups: tyrosine kinase inhibitor (TKI)-naive, n = 20; imatinib-progressed and no exposure to sunitinib or regorafenib (IM-PD), n = 30; and imatinib-progressed and sunitinib and/or regorafenib-treated (IM-PD/SU-treated), n = 31. Multiplexed immunofluorescence staining and RNA sequencing were performed to define TIME. RESULTS: PD-L1 expression rate (>1%) of DOG-1+ tumour cells was 5.0, 6.7, and 29.0% in TKI-naive, IM-PD, and IM-PD/SU-treated group, respectively (p = 0.02). FoxP3 expression of CD3+ T cells and CD204+ CD68+ monocytes per DOG-1+ cells was significantly higher in IM-PD/SU-treated group compared to TKI-naive and IM-PD groups (p < 0.05). IM-PD/SU-treated group showed increased expression of PD-1 on CD3+ T cells (p = 0.03 vs TKI-naive; p = 0.003 vs IM-PD) and DOG-1+ tumour cells (p = 0.02 vs TKI-naive; p = 0.006 vs IM-PD), TIM-3 expression on CD3+ T cells (p = 0.01 vs TKI-naive; p = 0.002 vs IM-PD), and LAG3 expression on CD3+ T cells (p = 0.001 vs TKI-naive; p = 0.004 vs IM-PD). In the RNAseq analysis, TIGIT expression was significantly increased in IM-PD/SU-treated GISTs compared to IM-PD (p = 0.01). CONCLUSION: Immunosuppressive phenotype was predominant in tumours treated with anti-angiogenic agents compared to TKI-naive and IM-treated tumours.

Clinical observation of lymphopenia in patients with newly diagnosed glioblastoma.

PURPOSE: Lymphopenia in patients with glioblastoma (GBM) is related to treatment as well as disease progression. This retrospective study investigated the prevalence, influencing factors, recoverability, and clinical significance of lymphopenia in GBM patients treated with concomitant chemoradiotherapy (CCRT). PATIENTS AND METHODS: A total of 219 patients with newly diagnosed GBM who had received at least 3 cycles of adjuvant temozolomide (TMZ) followed by CCRT with TMZ were enrolled. Serial data on complete blood cell counts, including differential cell counts, were collected just before a new phase and before every treatment cycle of the regimen. Relationships between white blood cell (WBC) variable changes and treatment modalities as well as survival were analyzed. Lymphopenia was classified using the definition of the Common Terminology Criteria for Adverse Events version 5.0. RESULTS: A total of 92 patients (42.0%) showed decreased levels of lymphocytes (< 1500/µL) at baseline. The WBC count, absolute neutrophil count, lymphocyte count, and neutrophil-to-lymphocyte ratio were all significantly decreased after RT/TMZ treatment and did not recover during the adjuvant TMZ period. However, these metrics all began to recover 3 months after the last TMZ cycle, except for the lymphocyte count. The proportion of lymphopenia patients (< 1500 lymphocytes/µL) increased to 74.8% after RT/TMZ and remained steady at approximately 71.5% (range 63.7-75.3%) throughout the management period. Moreover, the number of patients with grade 3 lymphopenia (< 500 lymphocytes/µL) also increased significantly after treatment to reach 2.9% (from 0.9% at baseline). Statistically, 75.7% of lymphopenia patients were predicted to recover in a median time of 240.3 days (95% confidence interval ± 104.7 days) after TMZ withdrawal. There were no dose-dependent relationships between RT or TMZ and lymphopenia. Grade 3 (< 500 lymphocytes/µL) lymphopenia measured at 1 month after RT/TMZ predicted significantly reduced survival (13.0 months vs. 19.5 months, p = 0.011). CONCLUSION: Lymphopenia is a frequent event during GBM disease progression and treatment. Treatment-related lymphopenia is profound and prolonged and can be used as a prognostic factor for GBM patients.

BGJ398, A Pan-FGFR Inhibitor, Overcomes Paclitaxel Resistance in Urothelial Carcinoma with FGFR1 Overexpression.

Paclitaxel (PTX) is commonly used to treat urothelial carcinoma (UC) after platinum-based chemotherapy has failed. However, single-agent taxane therapy is not sufficient to inhibit tumor progression and drug resistance in advanced UC. Epithelial-to-mesenchymal transition (EMT) induced by fibroblast growth factor receptor (FGFR)1 signaling has been proposed as a mechanism of PTX resistance, but it is unclear whether this can be overcome by FGFR1 inhibition. The present study investigated whether FGFR1 overexpression contributes to PTX resistance and whether FGFR inhibition can enhance PTX efficacy in UC. The effects of PTX combined with the FGFR inhibitor BGJ398 were evaluated in UC cell lines by flow cytometry; Western blot analysis; cell viability, migration, and colony forming assays; and RNA interference. PTX+BGJ398 induced cell cycle arrest and apoptosis in UC cells with mesenchymal characteristics was accompanied by downregulation of cyclin D1 protein and upregulation of gamma-histone 2A family member X and cleaved poly(ADP-ribose) polymerase. Additionally, PTX+BGJ398 synergistically suppressed UC cell migration and colony formation via regulation of EMT-associated factors, while FGFR1 knockdown enhanced the antitumor effect of PTX. These findings provide a basis for development of effective strategies for overcoming PTX resistance in UC through inhibition of FGFR1 signaling.

Prognostic implication of antitumor immunity measured by the neutrophil-lymphocyte ratio and serum cytokines and angiogenic factors in gastric cancer.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is associated with a poor prognosis in many cancers but the biological mechanisms involved are unknown. Since cytokines and angiogenic factors (CAFs) are reflected by various immune responses, we analyzed the association between the NLR and CAFs and their prognostic implications in gastric cancer (GC). METHODS: Of 745 GC patients who were enrolled in NLR analysis, 70 underwent NLR and CAF association analyses. Pretreatment serum levels of 52 CAFs were measured by means of multiplex bead immunoassays and enzyme-linked immunosorbent assays. Linear regression analysis and survival analysis of the NLR with each CAF were performed. RESULTS: Metastatic organ numbers and carbohydrate antigen 19-9 levels were significantly higher in patients with a high NLR [greater than 2.42 (median): P = 0.047 and P < 0.001 respectively]. The overall survival was significantly worse in the high NLR group (17.8 months vs 11.2 months, P < 0.001). In CAF analysis, osteopontin (R 2 = 0.337, P < 0.001) and interleukin-6 (R 2 = 0.141, P = 0.001) were significantly associated with the NLR. Stromal-cell-derived factor 1 (SDF-1) was a significant poor prognostic factor independently of the NLR. Consideration of both the NLR and SDF-1 divided patient groups with different overall survival (both low, 21.0 months; either high, 15.8 months; both high, 8.2 months). CONCLUSION: The NLR is a significant poor prognostic factor in advanced GC. The NLR is mainly associated with osteopontin and interleukin-6. Besides the NLR, SDF-1 is an independent poor prognostic factor in GC. Consideration of both the NLR and SDF-1 might give insights into antitumor immunity in GC.

Signature of cytokines and angiogenic factors (CAFs) defines a clinically distinct subgroup of gastric cancer.

BACKGROUND: Little is known about cytokine and angiogenic factors (CAFs) in gastric cancer (GC) in terms of tumor classification and prognostic value. Here, we aimed to correlate CAF signature with overall survival (OS) in GC. METHODS: We measured pretreatment serum levels of 52 kinds of CAFs in 68 GC patients who were treated with fluoropyrimidine and platinum combination chemotherapy using multiplex bead immunoassays and enzyme-linked immunosorbent assay. We evaluated correlations between CAF levels and pathological features and OS. RESULTS: Three distinct patient groups were identified: one with high levels of proangiogenic factors, another with high levels of proinflammatory factors, and the other with high levels of both factors. Eleven CAFs [interleukin (IL)-2 receptor-alpha, growth-regulated alpha protein, hepatocyte growth factor, macrophage colony-stimulating factor, stromal cell-derived factor, IL-6, IL-8, IL-10, interferon-gamma, vascular endothelial growth factor, and osteopontin] were independently correlated with poor OS. Clustering analysis of these 11 CAFs revealed distinct high and low 11-CAF signature groups. High 11-CAF signature was associated with shorter OS (10.1 vs. 17.9 months, p = 0.026) along with poor performance status, and the presence of signet ring cell components in multivariate analysis of OS (HR 1.76, p = 0.029). The patients' traditional clinicopathological characteristics were not significantly different between the high and low 11-CAF signature groups. CONCLUSION: Serum CAF profiling differentiated GC patient groups. A high 11-CAF signature could identify GC patients with a poor prognosis when treated with standard chemotherapy who need urgent new treatment strategies.

Predictive and prognostic value of PET/CT imaging post-chemoradiotherapy and clinical decision-making consequences in locally advanced head & neck squamous cell carcinoma: a retrospective study.

BACKGROUND: The accuracy of (18)F-fluorodeoxygluocose positron emission tomography/computed tomography (PET/CT) in predicting immediate failure after radical chemoradiotherapy (CRT) for HNSCC is poorly characterized at present. The purpose of this study was to examine PET/CT as a predictive and prognostic gauge of immediate failure after CRT and determine the impact of these studies on clinical decision making in terms of salvage surgery. METHODS: Medical records of 78 consecutive patients receiving radical CRT for locally advanced HNSCC were reviewed, analyzing PET/CTs done before and 3 months after CRT. Immediate failure was defined as residual disease or locoregional and/or systemic relapse within 6 months after CRT. RESULTS: Maximum standard uptake value (SUV) of post CRT PET/CT (postSUVmax) was found optimal for predicting immediate failure at a cutpoint of 4.4. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were 90.0%, 83.8%, 98.3%, and 45.0%, respectively. Of 78 patients studied, postSUVmax ≥ 4.4 prevailed in 20 (25.6%), with postSUVmax <4.4 in 58 (74.4%). At postSUVmax ≥ 4.4 (vs. postSUVmax <4.4) OS was poorer by comparison (3-year OS: 56.9 vs. 87.7%; P = 0.005), as was progression-free survival (3-year PFS: 42.9 vs. 81.1%; P < 0.001). At postSUVmax ≥ 4.4, OS with and without immediate salvage surgery did not differ significantly (3-year OS: 60.0 vs. 55.6%; Log-rank P = 0.913). CONCLUSION: Post CRT PET/CT imaging has prognostic value in terms of OS and PFS and is useful in predicting immediate therapeutic failure, given its high NPV. However, OS was not significantly altered by early salvage surgery done on the basis of post CRT PET/CT findings.

Metabolic landscape of advanced gastric cancer according to HER2 and its prognostic implications.

BACKGROUND: In advanced gastric cancer (AGC), HER2 is a validated therapeutic target. However, the metabolic landscape of AGC based on HER2 status has not been reported. Furthermore, the prognostic value of HER2 in AGC is under debate. The purpose of this study was to determine the metabolic landscape and prognosis on the basis of HER2 status in AGC. METHODS: We analyzed 866 AGC patients treated with palliative chemotherapy and whose HER2 status was evaluated. HER2 positivity was defined as HER2 IHC 3+ or HER2/CEP17 ratio ≥2. Among them, 363 patients were evaluated with (18)F FDG-PET before chemotherapy. We analyzed mSUV (maximal standardized uptake value) according to HER2 status and clinical outcomes. RESULTS: Among 866 patients, 225 (26.0 %) had HER2+ GC. The mSUV of HER2+ GC was significantly higher than that of HER2- GC (12.6 vs. 8.7, p < 0.001). Increased HER2 IHC positivity was correlated with increased mSUV (IHC-: 8.1, IHC 1+: 8.2, 2+: 11.4, 3+: 13.2, p < 0.001). Excluding HER2+ patients who received HER2-targeting agents, OS of patients was not different by HER2 status (12.5 vs. 11.9 months, p = 0.688). However, according to tumor metabolism, patients with higher mSUV showed worse OS regardless of HER2 positivity (mSUV < 12.8:14.8, ≥12.8:8.6 months, p < 0.001). CONCLUSION: Tumor metabolism of AGC adversely influenced OS under treatment with cytotoxic chemotherapy. Tumor metabolism was higher in HER2+ AGC than HER2-. However, HER2 was not a prognostic factor in patients who received chemotherapy without HER2-targeting agents.

Weight loss at the first month of palliative chemotherapy predicts survival outcomes in patients with advanced gastric cancer.

BACKGROUND: Weight loss during chemotherapy is a significant prognostic factor for poor survival in patients with advanced gastric cancer (AGC). However, in most studies, weight loss was measured at the end of chemotherapy, limiting its clinical use. In this study, we evaluated whether weight loss during the first month of chemotherapy could predict survival outcomes in patients with AGC. METHODS: We analyzed 719 patients with metastatic or recurrent AGC who were receiving palliative chemotherapy. We calculated the initial body mass index (BMIi), percent weight loss after 1 month of chemotherapy (ΔW 1m), percent weight loss after last administration of chemotherapy (ΔW end), and average weight loss per month during chemotherapy (ΔW/m). We correlated these data with overall survival (OS) by receiver-operating characteristic (ROC) curves and Kaplan-Meier curves, and performed a subgroup analysis using Cox regression. RESULTS: The probabilities of longer OS had stronger correlations with ΔW/m and ΔW 1m than with ΔW end or BMIi. A significant positive correlation between ΔW 1m and ΔW/m (r (2) = 0.591, p < 0.001) was observed. Median OS of patients with ΔW 1m more than 3 % was significantly shorter than in patients with less weight loss (OS: 9.7 vs. 16.3 months, p < 0.001). Subgroup analysis revealed that ΔW 1m accompanied poor survival irrespective of other clinical characteristics. CONCLUSION: Weight loss at the very first month of palliative chemotherapy could predict unfavorable survival outcomes in AGC.

Prediction of immunotherapy response using mutations to cancer protein assemblies.

While immune checkpoint inhibitors have revolutionized cancer therapy, many patients exhibit poor outcomes. Here, we show immunotherapy responses in bladder and non-small cell lung cancers are effectively predicted by factoring tumor mutation burden (TMB) into burdens on specific protein assemblies. This approach identifies 13 protein assemblies for which the assembly-level mutation burden (AMB) predicts treatment outcomes, which can be combined to powerfully separate responders from nonresponders in multiple cohorts (e.g., 76% versus 37% bladder cancer 1-year survival). These results are corroborated by (i) engineered disruptions in the predictive assemblies, which modulate immunotherapy response in mice, and (ii) histochemistry showing that predicted responders have elevated inflammation. The 13 assemblies have diverse roles in DNA damage checkpoints, oxidative stress, or Janus kinase/signal transducers and activators of transcription signaling and include unexpected genes (e.g., PIK3CG and FOXP1) for which mutation affects treatment response. This study provides a roadmap for using tumor cell biology to factor mutational effects on immune response.

Clinical Validation of Artificial Intelligence-Powered PD-L1 Tumor Proportion Score Interpretation for Immune Checkpoint Inhibitor Response Prediction in Non-Small Cell Lung Cancer.

PURPOSE: Evaluation of PD-L1 tumor proportion score (TPS) by pathologists has been very impactful but is limited by factors such as intraobserver/interobserver bias and intratumor heterogeneity. We developed an artificial intelligence (AI)-powered analyzer to assess TPS for the prediction of immune checkpoint inhibitor (ICI) response in advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The AI analyzer was trained with 393,565 tumor cells annotated by board-certified pathologists for PD-L1 expression in 802 whole-slide images (WSIs) stained by 22C3 pharmDx immunohistochemistry. The clinical performance of the analyzer was validated in an external cohort of 430 WSIs from patients with NSCLC. Three pathologists performed annotations of this external cohort, and their consensus TPS was compared with AI-based TPS. RESULTS: In comparing PD-L1 TPS assessed by AI analyzer and by pathologists, a significant positive correlation was observed (Spearman coefficient = 0.925; P < .001). The concordance of TPS between AI analyzer and pathologists according to TPS ≥50%, 1%-49%, and <1% was 85.7%, 89.3%, and 52.4%, respectively. In median progression-free survival (PFS), AI-based TPS predicted prognosis in the TPS 1%-49% or TPS <1% group better than the pathologist's reading, with the TPS ≥50% group as a reference (hazard ratio [HR], 1.49 [95% CI, 1.19 to 1.86] v HR, 1.36 [95% CI, 1.08 to 1.71] for TPS 1%-49% group, and HR, 2.38 [95% CI, 1.69 to 3.35] v HR, 1.62 [95% CI, 1.23 to 2.13] for TPS <1% group). CONCLUSION: PD-L1 TPS assessed by AI analyzer correlates with that of pathologists, with clinical performance also being comparable when referenced to PFS. The AI model can accurately predict tumor response and PFS of ICI in advanced NSCLC via assessment of PD-L1 TPS.