Favorable Prognosis In Patients Research Articles

FGFR2 fusion/rearrangement is associated with favorable prognosis and immunoactivation in patients with intrahepatic cholangiocarcinoma.

Increasing evidence highlights that fibroblast growth factor receptor 2 (FGFR2) fusion/rearrangement shows important therapeutic value for patients with intrahepatic cholangiocarcinoma (ICC). This study aims to explore the association of FGFR2 status with the prognosis and immune cell infiltration profiles of patients with ICC. A total of 226 ICC tissue samples from patients who received surgery at the Department of Liver Surgery at Zhongshan Hospital, Fudan University, were collected retrospectively and assigned to a primary cohort (n = 152) and validation cohort (n = 74) group. Fluorescence in situ hybridization was performed to determine FGFR2 status. Multiplex immunofluorescence (mIF) staining and immunohistochemistry were performed to identify immune cells. Thirty-two (14.2%) ICC tissues presented with FGFR2 fusion/rearrangement. FGFR2 fusion/rearrangement was associated with low levels of carcinoembryonic antigen (CEA, P = .026) and gamma glutamyl transferase (γ-GGT, P = .003), low TNM (P = .012), CNLC (P = .008) staging as well as low tumor cell differentiation (P = .016). Multivariate COX regression analyses revealed that FGFR2 fusion/rearrangement was an independent protective factor for both overall survival (OS) and relapse-free survival in patients with ICC. Furthermore, correlation analysis revealed that an FGFR2 fusion/rearrangement was associated with low levels of Tregs and N2 neutrophils and high levels of N1 neutrophils infiltrating into tumors but not with CD8+ T-cell or macrophage tumor infiltration. FGFR2 fusion/rearrangement may exert a profound impact on the prognosis of ICC patients and reprogram the tumor microenvironment to be an immune-activated state. FGFR2 status may be used for ICC prognostic stratification and as an immunotherapeutic target in patients with ICC.

VEGFA locus amplification potentially predicts a favorable prognosis in gastric adenocarcinoma

Gastric adenocarcinoma harbors a range of genetic and epigenetic alterations, including alterations in DNA copy number. However, the key genes that promote the development and progression of gastric adenocarcinoma remain unknown.To identify the key genes amplified in gastric adenocarcinoma, we performed array comparative genomic hybridization on formalin-fixed paraffin-embedded samples of surgically resected gastric adenocarcinoma. We detected a relatively wide genomic region of gain containing the vascular endothelial growth factor A (VEGFA) gene locus on chromosome 6p. VEGFA locus amplification in gastric adenocarcinoma was validated by fluorescence in situ hybridization. To assess the frequency of VEGFA locus amplification in gastric adenocarcinoma, we conducted multiplex ligation-dependent probe amplification (MLPA) assays using homemade probes designed to target the VEGFA gene locus. Eleven of 54 (20 %) gastric adenocarcinomas with MLPA values above 1.3 were defined as having VEGFA locus amplification. Next, we investigated the effect of VEGFA locus amplification on the clinicopathological characteristics of gastric adenocarcinomas and patient survival. VEGFA locus amplification demonstrated a significantly close relationship with pathological intestinal type and lower rates of venous invasion Furthermore, a Kaplan-Meier analysis showed that patients with VEGFA locus amplification had significantly better overall survival than those without amplification (p = 0.038), particularly in the long-term follow-up period. In conclusion, VEGFA locus amplification can predict modest aggressiveness and good outcomes, suggesting the possibility that it may predict a favorable prognosis in patients with gastric adenocarcinoma.

Lymph node metastasis burden identifies head and neck squamous cell carcinoma patients benefiting from adjuvant chemoradiation: a propensity score-matching

IntroductionTo examine the influence of adjuvant chemoradiation therapy (CRT) on survival, stratified by varying numbers and level involved of metastatic lymph nodes in patients with head and neck squamous cell carcinoma (HNSCC). MethodsPatients who underwent surgery for metastatic, negative margin HNSCC without extranodal extension were retrospectively enrolled and divided into two groups based on adjuvant therapy received: radiotherapy (RT) and CRT. The impact of RT versus CRT, stratified by the number of positive lymph nodes and the level involved, on Disease-Free Survival (DFS) and Overall Survival (OS) was analyzed. ResultsFollowing propensity score matching, a total of 580 patients were included. The burden and level of lymph node metastasis were independent predictors of poorer survival. Among patients with no more than two positive lymph nodes or involvement of levels I-III, the addition of chemotherapy to RT did not demonstrate a significant improvement in prognosis. However, in patients with three or more positive lymph nodes, CRT showed improved DFS and OS compared to RT. In patients with involvement of levels IV-V, the addition of chemotherapy to RT resulted in a significant 24% reduction in the risk of recurrence and a 20% decrease in the risk of death. ConclusionIncorporation of adjuvant chemoradiation can lead to a favorable prognosis in patients with metastatic HNSCC. This impact was notable in cases where there were three or more positive lymph nodes or involvement of levels IV-V.

Immune landscape of renal cell carcinoma with metastasis to the pancreas

IntroductionClear cell Renal Cell Carcinoma (ccRCC) has a poor prognosis once metastatic. However, certain metastatic sites have been reported to have a different impact on the patient prognosis. For example, patients with pancreatic metastases have a much more favorable prognosis than those with metastases to other organs. The biological basis for this observation remains poorly understood. The aim of this study was to characterize the immune landscape of pancreatic metastases and the corresponding primary tumors in order to identify possible immunological features that correlate with disease biology. Patients and MethodsA detailed assessment of immune cell populations was performed using a total of 1,700 microscopic images from ccRCCs from 11 patients, their corresponding pancreatic metastases and ccRCCs from 10 patients without pancreatic metastases. Tumor specimens were stained for CD45, CD8, CD163 and FOXP3 and the densities of the respective immune cells were assessed semiquantitatively in the intratumoral and extratumoral compartment. Multispectral imaging was performed in selected tumors. ResultsWe found that pancreatic metastases show the lowest intratumoral infiltration with CD8+ cytotoxic T lymphocytes of all tumor specimens analyzed. The frequency of CD8+ lymphocytes was on 1.9 fold lower in pancreatic metastases (median density 8.3 cells per field of view [FOV] = 1.23 mm2) when compared to the corresponding primary tumor (15.6 cells per FOV, P = 0.0002) and more than 3-fold lower when compared to ccRCCs without pancreatic metastases (27.2 cells per FOV, P = 0.0012). There was also a significantly reduced intratumoral infiltration with immunosuppressive FOXP3+ lymphocytes in pancreatic metastases (2.6 cells per FOV, P = 0.009) and corresponding primary tumors (2 cells per FOV, P = 0.028) when compared to ccRCCs without pancreatic metastases (5.6 cells per FOV). ConclusionsIn this proof-of-concept study, we show that pancreatic metastases of ccRCC present with unique immunological features including a low intratumoral density of CD8+ and FOXP3+ lymphocytes. The low counts of CD8+ and FOXP3+ lymphocytes may reflect less aggressive features of ccRCC with pancreatic metastasis that may result in a more favorable patient prognosis.

Assessment of prognostic factors in pediatric adrenocortical tumors: the modified pediatric S-GRAS score in an international multicenter cohort-a work from the ENSAT-PACT working group.

Pediatric adrenocortical carcinoma (pACC) is rare, and prognostic stratification remains challenging. We aimed to confirm the prognostic value of the previously published pediatric scoring system (pS-GRAS) in an international multicenter cohort. Analysis of pS-GRAS items of pACC from 6 countries in collaboration of ENSAT-PACT, GPOH-MET, and IC-PACT. We received patient data of the pS-GRAS items including survival information from 9 centers. PS-GRAS score was calculated as a sum of tumor stage (1 = 0; 2-3 = 1; 4 = 2 points), grade (Ki67 index: 0%-9% = 0; 10%-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX/R1/R2 = 1 point), age (<4 years = 0; ≥4 years = 1 point), and hormone production (androgen production = 0; glucocorticoid-/mixed-/no-hormone production = 1 point) generating 8 scores and 4 groups (1: 0-2, 2: 3-4, 3: 5, 4: 6-7). Primary endpoint was overall survival (OS). We included 268 patients with median age of 4 years. The analysis of the pS-GRAS score showed a significantly favorable prognosis in patients with a lower scoring compared to higher scoring groups (5-year OS: Group 1 98%; group 2 87% [hazard ratio {HR} of death 3.6, 95% CI of HR 1.6-8.2]; group 3 43% [HR of death 2.8, 95% CI 1.9-4.4]; group 4: OS 18% [HR of death 2.1, 95% CI 1.7-2.7]). In the multivariable analysis, age (HR of death 3.5, 95% CI 1.8-7.0), resection status (HR of death 5.5, 95% CI 2.7-11.1), tumor stage (HR of death 1.9, 95% CI of HR 1.2-3.0), and Ki67 index (HR of death 1.7, 95% CI 1.2-2.4) remained strong independent outcome predictors. Especially infants < 4 years showed more often low-risk constellations with a better OS for all tumor stages. In an international multicenter study, we confirmed that the pS-GRAS score is strongly associated with overall survival among patients with pACC. Age, resection status, stage, and Ki67 index are important parameters for risk stratification.

GATA binding protein 2 mediated ankyrin repeat domain containing 26 high expression in myeloid-derived cell lines.

Thrombocytopenia 2, an autosomal dominant inherited disease characterized by moderate thrombocytopenia, predisposition to myeloid malignancies and normal platelet size and function, can be caused by 5'-untranslated region (UTR) point mutations in ankyrin repeat domain containing 26 (ANKRD26). Runt related transcription factor 1 (RUNX1) and friend leukemia integration 1 (FLI1) have been identified as negative regulators of ANKRD26. However, the positive regulators of ANKRD26 are still unknown. To prove the positive regulatory effect of GATA binding protein 2 (GATA2) on ANKRD26 transcription. Human induced pluripotent stem cells derived from bone marrow (hiPSC-BM) and urothelium (hiPSC-U) were used to examine the ANKRD26 expression pattern in the early stage of differentiation. Then, transcriptome sequencing of these iPSCs and three public transcription factor (TF) databases (Cistrome DB, animal TFDB and ENCODE) were used to identify potential TF candidates for ANKRD26. Furthermore, overexpression and dual-luciferase reporter experiments were used to verify the regulatory effect of the candidate TFs on ANKRD26. Moreover, using the GENT2 platform, we analyzed the relationship between ANKRD26 expression and overall survival in cancer patients. In hiPSC-BMs and hiPSC-Us, we found that the transcription levels of ANKRD26 varied in the absence of RUNX1 and FLI1. We sequenced hiPSC-BM and hiPSC-U and identified 68 candidate TFs for ANKRD26. Together with three public TF databases, we found that GATA2 was the only candidate gene that could positively regulate ANKRD26. Using dual-luciferase reporter experiments, we showed that GATA2 directly binds to the 5'-UTR of ANKRD26 and promotes its transcription. There are two identified binding sites of GATA2 that are located 2 kb upstream of the TSS of ANKRD26. In addition, we discovered that high ANKRD26 expression is always related to a more favorable prognosis in breast and lung cancer patients. We first discovered that the transcription factor GATA2 plays a positive role in ANKRD26 transcription and identified its precise binding sites at the promoter region, and we revealed the importance of ANKRD26 in many tissue-derived cancers.

IFNγ at the early stage induced after cryo-thermal therapy maintains CD4+ Th1-prone differentiation, leading to long-term antitumor immunity.

Recently, more and more research illustrated the importance of inducing CD4+ T helper type (Th)-1 dominant immunity for the success of tumor immunotherapy. Our prior studies revealed the crucial role of CD4+ Th1 cells in orchestrating systemic and durable antitumor immunity, which contributes to the satisfactory outcomes of the novel cryo-thermal therapy in the B16F10 tumor model. However, the mechanism for maintaining the cryo-thermal therapy-mediated durable CD4+ Th1-dominant response remains uncovered. Additionally, cryo-thermal-induced early-stage CD4+ Th1-dominant T cell response showed a correlation with the favorable prognosis in patients with colorectal cancer liver metastasis (CRCLM). We hypothesized that CD4+ Th1-dominant differentiation induced during the early stage post cryo-thermal therapy would affect the balance of CD4+ subsets at the late phase. To understand the role of interferon (IFN)-γ, the major effector of Th1 subsets, in maintaining long-term CD4+ Th1-prone polarization, B16F10 melanoma model was established in this study and a monoclonal antibody was used at the early stage post cryo-thermal therapy for interferon (IFN)-γ signaling blockade, and the influence on the phenotypic and functional change of immune cells was evaluated. IFNγ at the early stage after cryo-thermal therapy maintained long-lasting CD4+ Th1-prone immunity by directly controlling Th17, Tfh, and Tregs polarization, leading to the hyperactivation of Myeloid-derived suppressor cells (MDSCs) represented by abundant interleukin (IL)-1β generation, and thereby further amplifying Th1 response. Our finding emphasized the key role of early-phase IFNγ abundance post cryo-thermal therapy, which could be a biomarker for better prognosis after cryo-thermal therapy.

Biomarkers for prognosis of meningioma patients: A systematic review and meta-analysis.

Meningioma is the most common primary brain tumor and many studies have evaluated numerous biomarkers for their prognostic value, often with inconsistent results. Currently, no reliable biomarkers are available to predict the survival, recurrence, and progression of meningioma patients in clinical practice. This study aims to evaluate the prognostic value of immunohistochemistry-based (IHC) biomarkers of meningioma patients. A systematic literature search was conducted up to November 2023 on PubMed, CENTRAL, CINAHL Plus, and Scopus databases. Two authors independently reviewed the identified relevant studies, extracted data, and assessed the risk of bias of the studies included. Meta-analyses were performed with the hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS), recurrence-free survival (RFS), and progression-free survival (PFS). The risk of bias in the included studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool. A total of 100 studies with 16,745 patients were included in this review. As the promising markers to predict OS of meningioma patients, Ki-67/MIB-1 (HR = 1.03, 95%CI 1.02 to 1.05) was identified to associate with poor prognosis of the patients. Overexpression of cyclin A (HR = 4.91, 95%CI 1.38 to 17.44), topoisomerase II α (TOP2A) (HR = 4.90, 95%CI 2.96 to 8.12), p53 (HR = 2.40, 95%CI 1.73 to 3.34), vascular endothelial growth factor (VEGF) (HR = 1.61, 95%CI 1.36 to 1.90), and Ki-67 (HR = 1.33, 95%CI 1.21 to 1.46), were identified also as unfavorable prognostic biomarkers for poor RFS of meningioma patients. Conversely, positive progesterone receptor (PR) and p21 staining were associated with longer RFS and are considered biomarkers of favorable prognosis of meningioma patients (HR = 0.60, 95% CI 0.41 to 0.88 and HR = 1.89, 95%CI 1.11 to 3.20). Additionally, high expression of Ki-67 was identified as a prognosis biomarker for poor PFS of meningioma patients (HR = 1.02, 95%CI 1.00 to 1.04). Although only in single studies, KPNA2, CDK6, Cox-2, MCM7 and PCNA are proposed as additional markers with high expression that are related with poor prognosis of meningioma patients. In conclusion, the results of the meta-analysis demonstrated that PR, cyclin A, TOP2A, p21, p53, VEGF and Ki-67 are either positively or negatively associated with survival of meningioma patients and might be useful biomarkers to assess the prognosis.

Estrogen induces LCAT to maintain cholesterol homeostasis and suppress hepatocellular carcinoma development.

Hepatocellular carcinoma (HCC) is an aggressive disease that occurs predominantly in men. Estrogen elicits protective effects against HCC development. Elucidation of the estrogen-regulated biological processes that suppress HCC could lead to improved prevention and treatment strategies. Here, we performed transcriptomic analyses on mouse and human liver cancer and identified LCAT as the most highly estrogen-upregulated gene and a biomarker of favorable prognosis. LCAT upregulation inhibited HCC in vitro and in vivo and mediated estrogen-induced suppression of HCC in an ESR1-dependent manner. LCAT facilitated high-density lipoprotein cholesterol (HDL-C) production and uptake via the LDLR and SCARB1 pathways. Consistently, high HDL-C levels corresponded to a favorable prognosis in HCC patients. The enhanced HDL-C absorption induced by LCAT impaired SREBP2 maturation, which ultimately suppressed cholesterol biosynthesis and dampened HCC cell proliferation. HDL-C alone inhibited HCC growth comparably to the cholesterol-lowering drug lovastatin, and SREBF2 overexpression abolished the inhibitory activity of LCAT. Clinical observations and cross-analyses of multiple databases confirmed the correlation of elevated LCAT and HDL-C levels to reduced cholesterol synthesis and improved HCC patient prognosis. Furthermore, LCAT deficiency mimicked whereas LCAT overexpression abrogated the tumor growth promoting effects of ovariectomy in HCC-bearing female mice. Most importantly, HDL-C and LCAT delayed the development of subcutaneous tumors in nude mice, and HDL-C synergized with lenvatinib to eradicate orthotopic liver tumors. Collectively, this study reveals that estrogen upregulates LCAT to maintain cholesterol homeostasis and dampen hepatocarcinogenesis. LCAT and HDL-C represent potential prognostic and therapeutic biomarkers for targeting cholesterol homeostasis as a strategy for treating HCC.

Abstract PO2-06-04: Prospective study on eribulin efficacy in advanced and metastatic breast cancer: changes in TGF-β compared to other standard chemotherapy agents (KBCSG-TR 2018, POTENTIAL)

Abstract Introduction Eribulin (E) has been demonstrated to improve overall survival (OS) compared to standard chemotherapies in pivotal phase III clinical trials (studies 301 and 305), although there was no difference in progression-free survival. These findings suggest that E might have a mechanism for OS improvement different from the common anti-tumor effect. Several studies reported that E inhibits epithelial-mesenchymal transition and the suppression of TGF-β plays a central role. Data on the relationship between the E-induced serial change in TGF-β and the improvement in OS remains insufficient. Therefore, we conducted this prospective observational study of patients treated with E while undergoing sequential TGF-β testing. This study also enrolled patients who received chemotherapy other than E as a control. Methods Patients with HER2-negative recurrent/metastatic breast cancer (MBC) were prospectively enrolled from 23 breast cancer centers in Japan, if they had not previously used E, had received two or fewer prior chemotherapy regimens, and were scheduled to start either E, capecitabine, S-1 or paclitaxel (± bevacizumab) between September 2020 and February 2022. The target sample sizes were 150 and 50 patients scheduled to receive E (Cohort E) and other drugs (Cohort Others), respectively. We collected blood samples for TGF-β testing at baseline, at two or three weeks (week 2/3), and at four or five weeks (week 4/5) from the beginning. The observation period was until February 2023. The primary endpoint was to evaluate the relationship between changes in TGF-β and clinical response, including OS and time to treatment failure (TTF). Results A total of 202 of the 203 enrolled patients were included in the analysis (1 patient declined consent). The median age was 60.0 (interquartile range, 52.0-69.0) years and ECOG performance status was 0 or 1 in all patients. Among 152 patients in Cohort E and 50 patients in Cohort Others, 37 patients (24.3%) and 12 patients (24.0%) had hormonal receptor-negative breast cancer, and 29 patients (19.1%) and 30 patients (60.0%) had no prior chemotherapy for MBC, respectively. Visceral metastasis totaled 115 (75.7%) in Cohort E and 46 (92.0%) in Cohort Others. In OS analysis of 199 patients, the median OS was 24.5 months (95% CI, 17.3-NA) for no prior chemotherapy, and 17.7 months for one or two prior chemotherapy (median follow-up 14.5 months). In Cohort E and Cohort Others, 139 and 45 patients, respectively, had paired samples for TGF-β testing at baseline and week 2/3. The proportion of patients with a percent change at week 2/3 from baseline in TGF-β (ΔTGF-β) of less than zero (decreased TGF-β) was 46.8% in Cohort E and 33.3% in Cohort Others, indicating a 13.4% (-2.6% – 29.5%) higher trend in Cohort E. Based on the time-dependent receiver operating characteristic (ROC) curves at 6 months for TTF, the threshold of ΔTGF-β was determined to be 27%. For the low ΔTGF-β group (&amp;lt; 27%) and the high ΔTGF-β group (≥27%), OS rates at median follow-up (14.5 months) were 70.6% and 54.3% (p=0.085) in Cohort E and 68.9% and 58.2% (p=0.585) in Cohort Others, respectively, suggesting a relationship between low ΔTGF-β and a favorable prognosis only in Cohort E. Conclusions The current study showed the trend in the higher frequency of decreased TGF-β, as well as the important relationship between decreased TGF-β and a favorable prognosis in patients treated with E compared with those receiving other chemotherapies. As the next step, further biomarker analyses including cytokines and chemokines, and immunological analyses are planned. Citation Format: Takahiro Nakayama, Tersuhiro Yoshinami, Fumie Fujisawa, Minako Nishio, Takashi Yamanaka, Toshinari Yamashita, Chiya Oshiro, Ayaka Izui, Nobumoto Tomioka, Hideki Maeda, Masafumi Shimoda, Kenzo Shimazu, Michiko Tsuneizumi, Ryoichi Matsunuma, Hiroko Bando, Aya Ueda, Hiroyuki Yasojima, Kumiko Okada, Kenichi Inoue, Yuichiro Kai, Katsuhide Yoshidome, Hidetoshi Kawaguchi, Masayuki Nagahashi, Kazuteru Oshima, Shinichiro Kashiwagi, Tsutomu Iwasa, Kanae Taruno, Shigeru Tsuyuki, Fumine Tsukamoto, Takashi Morimoto, Nobuyoshi Kittaka, Toru Higuchi, Yoichi Naito, Ryotaro Saita, Hiroyoshi Nishikawa, Daisuke Sugiyama, Yasuo Miyoshi, Yohei Uchida, Tomomi Yamada, Norikazu Masuda. Prospective study on eribulin efficacy in advanced and metastatic breast cancer: changes in TGF-β compared to other standard chemotherapy agents (KBCSG-TR 2018, POTENTIAL) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-04.

Cuproptosis-related gene LIPT1 as a prognostic indicator in non-small cell lung cancer: Functional involvement and regulation of ATOX1 expression.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths, necessitating a deeper understanding of novel cell death pathways like cuproptosis. This study explored the relevance of cuproptosis-related genes in NSCLC and their potential prognostic significance. We analyzed the expression of 16 cuproptosis-related genes in 1017 NSCLC tumors and 578 Genotype-Tissue Expression (GTEx) normal samples from The Cancer Genome Atlas (TCGA) to identify significant genes. A risk model and prognostic nomogram were employed to identify the pivotal prognostic gene. Further in vitro experiments were conducted to investigate the functions of the identified genes in NSCLC cell lines. LIPT1, a gene for lipoate-protein ligase 1 enzyme, emerged as the central prognostic gene with decreased expression in NSCLC. Importantly, elevated LIPT1 levels were associated with a favorable prognosis for NSCLC patients. Overexpression of LIPT1 inhibited cell growth and enhanced apoptosis in NSCLC. We confirmed that LIPT1 downregulates the copper chaperone gene antioxidant 1 (ATOX1), thereby impeding NSCLC progression. Our study identified LIPT1 as a valuable prognostic biomarker in NSCLC as it elucidates its tumor-inhibitory role through the modulation of ATOX1. These findings offered insights into the potential therapeutic targeting of LIPT1 in NSCLC, contributing to a deeper understanding of this deadly disease.

Intraoperative hypothermia in patients with laparoscopic surgery: Influencing factors and prevention strategies

BackgroundEffective body temperature management is crucial for the favorable prognosis of patients undergoing surgery. The purpose of this study is to explore the risk factors of intraoperative hypothermia and to develop a risk prediction model to provide basis for clinical treatment. MethodsPatients who underwent laparoscopic surgery in a tertiary hospital in China from February 1, 2023 to January 31, 2024 were included. The body temperature characteristics of patients in hypothermia group and non-hypothermia group were collected and evaluated. Univariate and Logistic regression analysis were used to evaluate the influencing factors. Based on the regression coefficients of risk factors, a risk prediction model of hypothermia was established. The model was assessed by Hosmer's Lemeshow (H- L) test and receiver working characteristic (ROC) curve. ResultsIn 216 patients undergoing laparoscopic surgery, the incidence of hypothermia was 52.78 %. BMI≤23 kg/m2(OR = 2.061, 95%CI: 1.413–3.263), basal body temperature≤36.1 °C (OR = 3.715, 95%CI: 3.011–4.335), operating room temperature≤22 °C (OR = 2.481, 95%CI: 1.906–3.014), length of surgery≥120 min (OR = 2.228, 95%CI: 1.925–2.981) were the risk factors of hypothermia in patients undergoing laparoscopic surgery (all P < 0.05). The P value of H-L test was 0.098, the area under ROC curve and 95%CI were 0.806 (0.746–0.869). The sensitivity and specificity of the model in this study were good. ConclusionsPatients undergoing laparoscopic surgery are at a high risk of developing hypothermia, a condition influenced by a multitude of factors. This model is designed to be integrated into clinical practice, enabling healthcare providers to identify patients with a higher risk and to implement targeted preventive measures.

High keratin 15 expression reflects favorable prognosis in early cervical cancer patients.

Keratin 15 (KRT15) exhibits inconsistent prognostic roles in different cancers, and its prognostic value in early cervical cancer patients who receive tumor resection remains unknown. This study aimed to assess the relationship of KRT15 expression with prognosis in these patients. Totally, 147 early cervical cancer patients who received tumor resection were reviewed in this retrospective study. KRT15 was detected in formalin-fixed paraffin-embedded tumor tissue by immunohistochemistry (IHC). KRT15 IHC scores were computed by multiplying the percentage of positively stained cells (scored as 0-4) and corresponding staining intensity (scored as 0-3), ranging from 0 to 12. Elevated KRT15 IHC score was linked with moderate to well differentiation (P = 0.005), tumor size ≤ 4cm (P = 0.017), and International Federation of Gynecology and Obstetrics (FIGO) stage Ia/Ib (P < 0.001). KRT15 IHC score was inversely associated with adjuvant radiotherapy (P = 0.025) and adjuvant chemotherapy (P = 0.016). KRT15 IHC score ≥ 1 was linked with increased disease-free survival (DFS) (P = 0.003) and overall survival (OS) (P = 0.049). Meanwhile, KRT15 IHC score ≥ 1 independently predicted increased DFS (hazard ratio = 0.213, P = 0.017), but not OS (P > 0.05). KRT15 IHC score ≥ 3 and KRT15 IHC score ≥ 6 could not predict DFS or OS (all P > 0.05). By subgroup analyses, KRT15 IHC score ≥ 1 forecasted favorable DFS in patients with age > 45years, human papillomavirus-positive, squamous carcinoma, and tumor size ≤ 4cm (all P < 0.05). KRT15 IHC score ≥ 1 and KRT15 IHC score ≥ 3 predicted ascended DFS in patients without adjuvant radiotherapy or adjuvant chemotherapy (all P < 0.05). High KRT15 expression reflects favorable tumor features and longer survival in early cervical cancer patients who receive tumor resection.

Patterns of Chromosomal Instability and Clonal Heterogeneity in Luminal B Breast Cancer: A Pilot Study.

Chromosomal instability (CIN), defined by variations in the number or structure of chromosomes from cell to cell, is recognized as a distinctive characteristic of cancer associated with the ability of tumors to adapt to challenging environments. CIN has been recognized as a source of genetic variation that leads to clonal heterogeneity (CH). Recent findings suggest a potential association between CIN and CH with the prognosis of BC patients, particularly in tumors expressing the epidermal growth factor receptor 2 (HER2+). In fact, information on the role of CIN in other BC subtypes, including luminal B BC, is limited. Additionally, it remains unknown whether CIN in luminal B BC tumors, above a specific threshold, could have a detrimental effect on the growth of human tumors or whether low or intermediate CIN levels could be linked to a more favorable BC patient prognosis when contrasted with elevated levels. Clarifying these relationships could have a substantial impact on risk stratification and the development of future therapeutic strategies aimed at targeting CIN in BC. This study aimed to assess CIN and CH in tumor tissue samples from ten patients with luminal B BC and compare them with established clinicopathological parameters. The results of this study reveal that luminal B BC patients exhibit intermediate CIN and stable aneuploidy, both of which correlate with lymphovascular invasion. Our results also provide valuable preliminary data that could contribute to the understanding of the implications of CIN and CH in risk stratification and the development of future therapeutic strategies in BC.

Clinical prognostic significance of xeroderma pigmentosum group C and IFN‑γ in non‑small cell lung cancer.

Lung cancer is the most common cancer in the world due to its high incidence and recurrence. Genetic instability is one of the main factors leading to its occurrence, development and poor prognosis. Decreased xeroderma pigmentosum group C (XPC) expression notably enhances the stem cell properties of lung cancer cells and increases their proliferation and migration. Additionally, patients with lung cancer and low XPC expression had a poor prognosis. The purpose of the present study was to analyze the effect of XPC and IFN-γ on the clinical prognosis of patients with non-small cell lung cancer (NSCLC). Lung adenocarcinoma specimens were collected from a total of 140 patients with NSCLC. Additionally, from these 140 patients, 48 paracarcinoma tissue specimens were also collected, which were later used to construct tissue microarrays. The expression of XPC and IFN-γ in cancer tissues and in paraneoplastic tissues was detected using immunohistochemistry. The prognosis and overall survival of patients were determined through telephone follow-up. The results showed a positive correlation between expression of XPC and IFN-γ in NSCLC. Additionally, high expression of both markers was associated with a favorable prognosis in patients with NSCLC. The aforementioned findings suggest that the expression of XPC and IFN-γ has prognostic value in clinical practice and is expected to become a marker for clinical application.

Oncological outcomes after a pathological complete response following total neoadjuvant therapy or chemoradiotherapy for high-risk locally advanced rectal cancer in the RAPIDO trial

BackgroundA pathological complete response (pCR) following chemoradiation (CRT) or short-course radiotherapy (scRT) leads to a favourable prognosis in patients with rectal cancer. Total neo-adjuvant therapy (TNT) doubles the pCR rate, but it is unknown whether oncological outcomes remain favourable and whether the same characteristics are associated with pCR as after CRT. MethodsComparison between patients with pCR in the RAPIDO trial in the experimental [EXP] (scRT, chemotherapy, surgery, as TNT) and standard-of-care treatment [STD] (CRT, surgery, postoperative chemotherapy depending on hospital policy) groups. Primary and secondary outcomes were time-to-recurrence (TTR), overall survival (OS) and association between patient, tumour, and treatment characteristics and pCR. ResultsAmong patients with a resection within six months after preoperative treatment, 120/423 (28%) [EXP] and 57/398 (14%) [STD] achieved a pCR. Following pCR, 5-year cumulative TTR and OS rates in the EXP and STD arms were 8% vs. 7% (hazard ratio 1.04, 95%CI 0.32–3.38) and 94% vs. 93% (hazard ratio 1.41, 95%CI 0.51–3.92), respectively. Besides the EXP treatment (odds ratio 2.70, 95%CI 1.83–3.97), pre-treatment carcinoembryonic antigen (CEA) <5, pre-treatment tumour size <40 mm and cT2 were associated with pCR. Distance from the anal verge was the only characteristic with a statistically significant difference in association with pCR between the EXP and STD treatment (Pinteraction=0.042). pCR rates did not increase with prolonged treatment time. ConclusionsThe doubled pCR rate of TNT compared to CRT results in similar oncological outcomes. Characteristics associated with pCR are the EXP treatment, normal CEA, and small tumour size.

RBM10 C761Y mutation induced oncogenic ASPM isoforms and regulated β-catenin signaling in cholangiocarcinoma

BackgroundCholangiocarcinoma (CCA) comprises a heterogeneous group of biliary tract cancer. Our previous CCA mutation pattern study focused on genes in the post-transcription modification process, among which the alternative splicing factor RBM10 captured our attention. However, the roles of RBM10 wild type and mutations in CCA remain unclear.MethodsRBM10 mutation spectrum in CCA was clarified using our initial data and other CCA genomic datasets from domestic and international sources. Real-time PCR and tissue microarray were used to detect RBM10 clinical association. Function assays were conducted to investigate the effects of RBM10 wild type and mutations on CCA. RNA sequencing was to investigate the changes in alternative splicing events in the mutation group compared to the wild-type group. Minigene splicing reporter and interaction assays were performed to elucidate the mechanism of mutation influence on alternative splicing events.ResultsRBM10 mutations were more common in Chinese CCA populations and exhibited more protein truncation variants. RBM10 exerted a tumor suppressive effect in CCA and correlated with favorable prognosis of CCA patients. The overexpression of wild-type RBM10 enhanced the ASPM exon18 exon skipping event interacting with SRSF2. The C761Y mutation in the C2H2-type zinc finger domain impaired its interaction with SRSF2, resulting in a loss-of-function mutation. Elevated ASPM203 stabilized DVL2 and enhanced β-catenin signaling, which promoted CCA progression.ConclusionsOur results showed that RBM10C761Y-modulated ASPM203 promoted CCA progression in a Wnt/β-catenin signaling-dependent manner. This study may enhance the understanding of the regulatory mechanisms that link mutation-altering splicing variants to CCA.

Relationship between pathohistological characteristics of the tumor and distant metastasis of differentiated thyroid cancer

Papillary thyroid cancer has the most favorable prognosis for patients. According to the recommendations of the National Comprehensive Cancer Network (NCCN), organ‑sparing surgery can be performed for such patients without radioactive iodine therapy (RIT). However, some factors, for example, vascular invasion, multifocality, the presence of regional metastases, etc. increase stratification risks for the patient and give the reason to perform more voluminous surgical interventions and conduct RIT. With differentiated thyroid cancer (DTC), the 5‑year and 10‑year overall survival rates reach 100% and 96%, respectively.&#x0D; Objective — to investigate the relationship between the pathohistological characteristics of the DTC tumor and distant metastasis.&#x0D; Materials and methods. The study involved 522 patients aged 4 to 79 years (the mean age 40.2±0.6 years) after previous thyroid cancer surgery and RIT. Patients were divided into two groups depending on the presence of distant metastases: 28 (5.4%) with distant metastases and 494 (94.6%) patients without distant metastases.&#x0D; Results. Using the data of pathohistological findings, both groups were compared according to the following criteria: pathomorphological DTC subtype, vascular invasion, other extraordinary invasion, multifocality, the size of the primary tumor, the size of the largest focus and the total size of foci for multifocal cancers, the number and maximum size of metastases in the central and lateral lymphatic collectors of the neck.&#x0D; Conclusions. No significant relationship has been found between the pathomorphological subtype of differentiated thyroid cancer, the presence of vascular and extra‑organ invasion, and the presence of distant metastases, but a relationship was found with multifocality. In the group of patients with distant metastases, a larger size of the primary focus, and a larger size and number of regional metastases were determined.&#x0D;

Abstract 5205: Beyond boundaries: ADRB3, a novel prognostic marker in pediatric neuroblastoma

Abstract Introduction: Neuroblastoma (NB) is a pediatric tumor arising from immature nerve cells originating from neural crest cells. This malignancy is characterized by a remarkably early onset, with only 10% of cases occurring beyond 5 years of age. According to the INRG classification, ~50% of patients are classified as low risk (L1/L2). Despite advances in treatment, around 20% of these experienced a relapse within 5 years with a mere 10% survival rate. Methods: We investigated the role of the adrenoceptor beta-3 (ADRB3) as a prognostic factor for NB. The samples provided by IRCCS Meyer Children’s Hospital allowed us to measure cytofluorimetric level expression of ADRB3 in tissue biopsies from 43 NBs, in the circulating tumor cells (CTCs) and in the bone marrow cells (BMCs) at onset and at the end of treatment. Further, to study the role of ADRB3 in NB, we used CRISPR-Cas9 to knock down ADRB3 expression in mice model. Results: Results indicate that ADRB3 levels in biopsy at the onset are significantly higher (Wilcoxon test, p = 0.026) in patients with negative outcome than those who achieved complete remission. The R package survival was used to perform Survival curve analysis to further assess the impact of ADRB3 at the onset in biopsy tissues. Results confirmed a significant separation (p = 0.031) between survival curves of patients with high levels and those with low levels, reinforcing its importance as a prognostic factor. Moreover, the same results were found in survival curves (p = 0.038) in low-risk patients, corroborating the importance of ADRB3 levels to discriminate between unfavorable or favorable prognosis. Moreover, post-chemotherapeutic treatment analysis, in both residual CTCs and BMCs, indicated statistically differences in ADRB3 levels between fully recovered patients and deceased. Survival curves, stratified by ADRB3 levels in CTCs post-chemotherapy, a favorable prognosis for patients with low levels (p = 0.0001). Finally, the expression analysis showed that ADRB3 levels in NB cells led to increment of processes associated with the cellular migration and metastasization and in metabolism. Conclusion: Our findings suggest that ADRB3 is a significant prognostic factor for NB. Patients with high ADRB3 expression in biopsy at the onset and after the treatment have a higher risk of unfavorable outcome, even for low-risk patients. In conclusion, our results challenge current classification and prognostic paradigms, highlighting ADRB3's crucial role in NB, contributing to refine risk stratification and unveil a new potential target for liquid biopsy of detecting, analyzing and monitoring CTCs. Citation Format: Gianluca Mattei, Cristina Banella, Francesco Carrozzo, Amada Pasha, Annalisa Tondo, Claudio Favre, Maura Calvani. Beyond boundaries: ADRB3, a novel prognostic marker in pediatric neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5205.

Abstract 2520: CD133 expression is associated with less DNA repair, better response to chemotherapy, and survival in ER-positive/ER-negative breast cancer

Abstract Introduction: Cancer stem cells (CSC) constitute only 0.1-1% of all the cells in a bulk tumor, yet they play a crucial role in treatment resistance and relapses. Its role in breast cancer (BC) has been studied but a consensus remains elusive. We focused on gene expression of a CSC marker CD133 and studied its clinical significance in ER-positive/HER2-negative (ER+/HER2-) BC, the most prevalent subtype. We utilized multiple independent large patient cohorts of gene expression and clinical variables for transcriptome analysis. Methods: A total of 2969 patients from The Cancer Genome Atlas (TCGA, n=1065) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n=1904) BC cohorts, as well as BC patients who underwent neoadjuvant chemotherapy (NAC; GSE25066, GSE20194, GSE32646 cohorts) were analyzed. Results: By analyzing SCP1039 and SCP1106 single-cell sequencing cohorts, we found that epithelial cells were the predominant source of CD133 gene expression in the tumor microenvironment. High expression of CD133 in ER+/HER2- BC correlated with elevated gene expressions of the other CSC markers; CD24, NOTCH1, DLL1, and ALDH1A1 (all p&amp;lt;0.001), and significantly enriched WNT/β-Catenin, Hedgehog, and Notch signaling (all FDR&amp;lt;0.25), which are all known pathways related with CSC in TCGA and validated in METABRIC cohort. Consistent with CSC phenotype, CD133-high BC was negatively enriched with Hallmark cell proliferation-related gene sets, such as E2F Targets, G2M Checkpoint, MYC Targets V1, Ki67 gene expression and proliferation score (FDR&amp;lt;0.25 and p&amp;lt;0.001, respectively) in both cohorts. CD133-high BC was negatively associated with DNA repair genes, such as BRCA1, E2F7 in both cohorts (all p&amp;lt;0.001). In agreement, CD133-high BC was associated with less homologous recombination deficiency, lower silent and non-silent mutation rates. Surprisingly, CD133-high BC exhibited a proinflammatory microenvironment, as represented by higher cytolytic activity in the METABRIC and higher lymphocyte infiltrations, TGF-beta response, and TCR richness in TCGA (both p&amp;lt;0.001), but less Th1 cells, M1 macrophages and dendritic cell infiltrations consistently in both cohorts. It also enriched signaling pathways related to inflammation and immune responses such as inflammatory response, allograft rejection, TNF-alpha, IL-6, TGF-beta signaling, and complement signaling (all FDR&amp;lt;0.25). CD133-high tumors had better pathological complete response after NAC in GSE25066 cohort and improved Disease-Free Survival and Overall Survival in both TCGA and METABRIC cohorts (all p&amp;lt;0.05). Conclusion: CD133-high ER+/HER2- BC is associated with CSC phenotype, reduced cell proliferation, and impaired DNA repair, but enhanced inflammation, potentially explaining the better response to NAC and favorable patient prognosis. Citation Format: Takumi Sato, Masanori Oshi, Jing Lee, Arya M. Roy, Kohei Chida, Itaru Endo, Masato Obayashi, Kazuaki Takabe. CD133 expression is associated with less DNA repair, better response to chemotherapy, and survival in ER-positive/ER-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2520.