Prognostic Factor For Overall Survival Research Articles

Long-Term Outcomes of the Treatment for Gastric Tube Cancer After Esophagectomy for Esophageal Cancer.

The long-term outcomes of gastric tube cancer (GTC) are unclear. This study therefore aimed to clarify clinicopathologic features and the long-term outcomes of patients with GTC. The 25 patients who were diagnosed with GTC between April 2003 and December 2022 at our hospital were eligible for inclusion in this retrospective study, and this included 27 lesions. We retrospectively evaluated clinicopathologic factors based on hospital records. In our cohort, 88% of incidences of GTC were located in the middle or lower gastric tube. As the treatment of GTC, we used endoscopic submucosal dissection, gastrectomy, chemoradiotherapy, chemotherapy, and best supportive care for 16 (59%), 6 (22%), 1 (4%), 1 (4%), and 3 (11%) lesions, respectively. Perforation after endoscopic submucosal dissection was observed in 6 of the 16 lesions. Partial gastric tube resection was performed for 3 patients and total gastric tube resection was performed for 3 patients. One patient who underwent total gastric tube resection died due to acute respiratory distress syndrome. In survival analysis, the 3-year overall survival rate was 52% and the 3-year disease-specific survival rate was 74%. Five patients (20%) died of aspiration pneumonia, 2 patients (8%) of another disease, and 1 patient (4%) of another type of cancer. According to multivariate analysis, independent prognostic factors for overall survival were cN status (HR, 18.021; P=0.004) and complication of aspiration pneumonia (HR, 8.373; P=0.004). The occurrence of aspiration pneumonia and cN status were prognostic factors after the treatment for GTC. Assessment of dysphagia and surveillance after treatment for GTC are important to improve the prognosis.

Gleason Pattern 5 May Be a Prognostic Factor in Radium-223 Treatment.

Radium-223 treatment reduces the risk of death in patients with metastatic castration-resistant prostate cancer (CRPC). This study analyzed the prognostic factors in patients treated with radium-223 dichloride. Patients who received radium-223 dichloride were retrospectively analyzed. Prostate-specific antigen (PSA) response and alkaline phosphatase (ALP) decline rates were analyzed. Overall survival (OS) was evaluated using Kaplan-Meier curves, and prognostic factors for OS were assessed using Cox proportional hazards analysis. Fifty-six patients were included in the study. The five-year OS rate in patients after diagnosis of CRPC was 62.2% [95% confidence interval (CI)=27.55-112.45], while the five-year OS rate in patients at the initiation of radium-223 treatment was 21.3% (95%CI=17.20-36.79). Six patients (11.1%) had a >50% PSA decline rate, and 10 (17.9%) had a >50% ALP decline rate. Cox proportional hazards analysis showed that PSA levels at the initiation of radium-223 treatment [hazard ratio (HR)=1.00; 95%CI=1.00-1.00; p=0.0054] and Gleason Pattern (GP) 5 (HR=5.42; 95%CI=1.08-27.27; p=0.0400) were associated with OS. Patients with GP 5 had a significantly poorer prognosis compared with patients with a GP ≤4. Early administration of radium-223 as a first- or second-line treatment was not associated with OS compared with late administration of radium-223 as a third-line or later treatment. GP 5 and high PSA levels at radium-223 initiation were associated with worse OS. Radium-223 as first- or second-line treatment was not associated with OS. Therefore, a treatment strategy for CRPC based on GP 5 is needed.

The Construction of a Nomogram Using the Pan-Immune-Inflammation Value Combined with a PILE Score for Immunotherapy Prediction Prognosis in Advanced NSCLC.

The purpose of this study was to investigate the predictive value of Pan-Immune-Inflammation Value (PIV) combined with the PILE score for immunotherapy in patients with advanced non-small cell lung cancer (NSCLC) and to construct a nomogram prediction model to provide reference for clinical work. Patients with advanced NSCLC who received ICIs treatment in Qingdao Municipal Hospital from January 2019 to December 2021 were selected as the study subjects. The chi-square test, Kaplan-Meier survival analysis, and Cox proportional risk regression analysis were used to evaluate the prognosis. The results were visualized by a nomogram, and the performance of the model was judged by indicators such as the area under the subject operating characteristic curve (AUC) and C-index. The patients were divided into high- and low-risk groups by PILE score, and the prognosis of patients in different risk groups was evaluated. Multivariate Cox regression analysis showed that immune-related adverse events (irAEs) were prognostic factors for overall survival (OS) improvement, and ECOG PS score ≥2, bone metastases before treatment, and high PIV expression were independent risk factors for OS. The C index of OS predicted by the nomogram model is 0.750 (95% CI: 0.677-0.823), and the Calibration and ROC curves show that the model has good prediction performance. Compared with the low-risk group, patients in the high-risk group of PILE were associated with a higher inflammatory state and poorer physical condition, which often resulted in a poorer prognosis. PIV can be used as a prognostic indicator for patients with advanced NSCLC treated with ICIs, and a nomogram prediction model can be constructed to evaluate the survival prediction of patients, thus contributing to better clinical decision-making and prognosis assessment.

BMP Signaling Is a Prognostic Marker in Patients With Colorectal Cancer and Associates With Frailty.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β superfamily of ligands and have been shown to promote or suppress colorectal cancer (CRC) growth. Developing treatments that target BMPs is challenging due to their multiple roles, including involvement in the inflammatory response and nutritional status. The present study evaluated the prognostic value of BMP-4, which is believed to be highly expressed in CRC, and its correlation with inflammatory and nutrition statuses in patients with CRC. We analyzed BMP-4 expression in tumor tissues from 144 patients who underwent CRC surgery using immunohistochemistry and evaluated the relationship between BMP-4 levels and clinical outcomes. Kaplan-Meier analysis revealed that patients with high expression levels of BMP-4 exhibited a shorter overall survival rate than those with low levels of expression. Multivariate analysis revealed that BMP-4 expression was an independent prognostic factor for overall survival and death from other diseases in CRC patients. Furthermore, high BMP-4 expression was significantly correlated with high C-reactive protein/Albumin ratio, sarcopenia, and osteopenia. BMP-4 is a significant prognostic factor in CRC, particularly in predicting death from other diseases, while also showing associations with inflammatory and nutritional statuses.

Safety and feasibility of liver resection including major hepatectomy for geriatric patients with hepatocellular carcinoma: a retrospective observational study

BackgroundIt is unclear whether hepatectomy, which ranges in invasiveness from partial to major hepatectomy, is safe and feasible for older adult patients. Therefore, we compared its postoperative complications and long-term outcomes between younger and older adult patients.MethodsPatients who underwent hepatectomies for hepatocellular carcinoma (N = 883) were evaluated. Patients were divided into two groups: aged < 75 years (N = 593) and ≥ 75 years (N = 290). Short-term outcomes and prognoses were compared between the groups in the entire cohort. The same analyses were performed for the major hepatectomy cohort.ResultsIn the entire cohort, no significant differences were found in complications between patients aged < 75 and ≥ 75 years, and the multivariate analysis did not reveal age as a prognostic factor for postoperative complications. However, overall survival was significantly worse in older patients, although no significant differences were noted in time to recurrence or cancer-specific survival. In the multivariate analyses of time to recurrence, overall survival, and cancer-specific survival, although older age was an independent poor prognostic factor for overall survival, it was not a prognostic factor for time to recurrence and cancer-specific survival. In the major hepatectomy subgroup, short- and long-term outcomes, including time to recurrence, overall survival, and cancer-specific survival, did not differ significantly between the age groups. In the multivariate analysis, age was not a significant prognostic factor for complications, time to recurrence, overall survival, or cancer-specific survival.ConclusionHepatectomy, including minor and major hepatectomy, may be safe and oncologically feasible options for selected older adult patients with hepatocellular carcinoma.

Effectiveness of immune checkpoint inhibitor therapy on bone metastases in non-small-cell lung cancer.

Bone metastases (BoMs) are prevalent in patients with metastatic non-small-cell lung cancer (NSCLC) however, there are limited data detailing how BoMs respond to immune checkpoint inhibitors (ICIs). The purpose of this study was to compare the imaging response to ICIs of BoMs against visceral metastases and to evaluate the effect of BoMs on survival. A retrospective, multicentre cohort study was conducted in patients with NSCLC treated with nivolumab or pembrolizumab in Alberta, Canada from 2015 to 2020. The primary endpoint was the real-world organ specific progression free survival (osPFS) of bone versus visceral metastases. Visceral metastases were categorized as adrenal, brain, liver, lung, lymph node, or other intra-abdominal lesions. The secondary outcome was overall survival (OS) amongst patients with and without BoMs. A total of 573 patients were included of which all patients had visceral metastases and 243 patients (42.4%) had BoMs. High PD-L1 expression was identified in 268 patients (46.8%). No significant difference in osPFS was observed between bone, liver, and intra-abdominal metastases (p=0.20 and p=0.76, respectively), with all showing shorter osPFS than other disease sites. There was no difference in the osPFS of extra-thoracic sites of disease in patients with high PD-L1 expression. There was significant discordance between visceral disease response and bone disease response to ICI (p=0.047). The presence of BoMs was an independent poor prognostic factor for OS (HR 1.26, 95%CI: 1.05-1.53, p=0.01). Metastatic bone, liver, and intra-abdominal lesions demonstrated inferior clinical responses to ICI relative to other sites of disease. Additionally, the presence of bone and liver metastases were independent poor prognostic factors for overall survival. This real-world data suggests that BoMs respond poorly to ICI and may require treatment adjuncts for disease control.

Prevalence and survival implications of malnutrition and sarcopenia in metastatic breast cancer: A longitudinal analysis

BackgroundMalnutrition and sarcopenia are challenges for patients with metastatic breast cancer and have been proposed as independent prognostic factors. Very few studies have addressed the temporal evolution of these parameters and, notably, the separate and combined analysis of sarcopenia and malnutrition. This study aimed to i) determine the prevalence of malnutrition and sarcopenia, individually and combined, and their evolution over time, ii) identify risk factors for each condition, and iii) explore their impact on overall survival (OS). MethodsThis retrospective study was conducted on 111 patients treated for at least a third-line metastatic breast cancer at the Institut Curie between January 1st and March 31st, 2018.Solitary malnutrition was defined from weight loss and body mass index values while solitary sarcopenia was defined solely based on low muscle mass. We analyzed solitary malnutrition, solitary sarcopenia, and then malnutrition with or without sarcopenia, at three key stages (T1: diagnosis of metastasis, T2: initiation of third-line treatment, and T3: 3-month re-evaluation). Univariate and multivariate logistic regression analyses were conducted to investigate the risk factors. We performed Cox proportional hazards analyses for each variable. ResultsAt T1, the prevalence of solitary malnutrition, solitary sarcopenia and malnutrition with or without sarcopenia was 18.6%, 36.1% and 48.9% respectively, increasing to 27.7%, 45.5% and 56.6% at T2. At T2, in multivariate logistic regression analyses, patients aged over 60 years were at an elevated risk of experiencing solitary malnutrition as well as malnutrition with or without sarcopenia, but not solitary sarcopenia. In multivariate analyses, solitary malnutrition was significantly associated with poorer OS (HR 2.2 [95% CI 1.1-4.1], p=0.02), while solitary sarcopenia and malnutrition with or without sarcopenia showed no association. ConclusionSolitary malnutrition and sarcopenia were highly prevalent in patients with metastatic breast cancer, affecting around a quarter and half of patients respectively at third-line treatment initiation. Notably, solitary malnutrition emerged as a prognostic factor for overall survival, whereas no significant association was observed for solitary sarcopenia or malnutrition with or without sarcopenia. This highlights the critical need for early identification of patients at risk of malnutrition and the importance of timely intervention.

The role of upfront neck dissection in definitive radiotherapy for locally advanced hypopharyngeal squamous cell carcinoma: A single-center retrospective analysis.

Hypopharyngeal cancer, constituting 3%-5% of head and neck cancers, predominantly presents as squamous cell carcinoma, with a 5-year overall survival rate of approximately 40%. Treatment modalities for locally advanced cases include chemoradiotherapy; however, the role of upfront neck dissection (UND) remains controversial. This study aimed to investigate the effect of UND on definitive radiotherapy in locally advanced hypopharyngeal carcinoma. This retrospective analysis included consecutive patients with locally advanced hypopharyngeal squamous cell carcinoma who were treated in our department between January 2007 and June 2023. All patients underwent definitive radiotherapy (dRT) at a total dose of 70 Gy in 35 fractions. The patients were categorized into two groups: dRT (radiotherapy with or without chemotherapy) and UND-dRT (surgical neck dissection followed by radiotherapy). Univariate Cox models and multivariate analyses were conducted to investigate the independent prognostic factors for overall survival and locoregional control rate. This study included 115 patients, predominantly male (109/115), with a median age of 66 years. Clinical stage and chemotherapy distribution differed significantly between the dRT and UND-dRT groups. The 3-year overall survival and locoregional control rates for all patients were 63.8% and was 63.3%, respectively. The UND-dRT group exhibited a trend toward improved locoregional control, although this difference was not statistically significant. The multivariate analysis revealed that UND was an independent factor significantly associated with improved overall survival and locoregional control. This study provided evidence supporting the effectiveness of UND in conjunction with definitive radiotherapy for locally advanced hypopharyngeal carcinoma. Future research should focus on validating and refining these findings through well-designed prospective multicenter trials.

Circ_0012152 Accelerates Acute Myeloid Leukemia Progression through the miR-652-3p/SOX4 Axis.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by abnormal myeloid blast expansion. Recent studies have demonstrated that circular RNAs play a role in AML pathogenesis. In this study, we aimed to investigate the clinical significance of circ_0012152 in AML and elucidate its underlying molecular mechanism in the pathogenesis of this condition. Circ_0012152 expression was detected by quantitative real-time polymerase chain reaction in samples obtained from 247 patients with AML and 40 healthy controls. A systematic analysis of clinical characteristics and prognostic factors was also conducted. Cell growth was assessed using the Cell Counting Kit-8 (CCK-8) assay, and apoptosis and cell cycle progression were evaluated by flow cytometry. Moreover, RNA pull-down was performed to identify target microRNAs, and transcriptome RNA sequencing and bioinformatics analyses were utilized to identify downstream mRNA targets. Circ_0012152 was significantly upregulated in samples from patients with AML and served as an independent adverse prognostic factor for overall survival (OS) (hazard ratio: 2.357; 95% confidence interval 1.258-4.415). The circ_0012152 knockdown reduced cell growth, increased apoptosis, and inhibited cell cycle progression in AML cell lines. RNA pull-down and sequencing identified miR-652-3p as a target microRNA of circ_0012152. Cell growth inhibition by circ_0012152 knockdown was significantly relieved by miR-652-3p inhibitors. We suggested that miR-652-3p targeted SOX4, as the decrease in SOX4 expression resulting from circ_0012152 knockdown was upregulated by miR-652-3p inhibitors in AML cells. Circ_0012152 is an independent poor prognostic factor for OS in AML, and it promotes AML cell growth by upregulating SOX4 through miR-652-3p.

Gustave Roussy Immune score as a prognostic biomarker in patients with platinum-refractory metastatic urothelial carcinoma treated with pembrolizumab: YUSHIMA study.

This study aimed to investigate the prognostic value of the Gustave Roussy Immune score (GRIm-score) in platinum-refractory metastatic urothelial carcinoma (UC) treated with pembrolizumab. This multicenter retrospective study (YUSHIMA study) evaluated 331 patients with metastatic UC treated with pembrolizumab after platinum-based chemotherapy between January 2018 and June 2023 at 13 institutions. We collected pretreatment variables, including the GRIm-score based on serum albumin, lactate dehydrogenase, and neutrophil-to-lymphocyte ratio. The patients were divided into low and high GRIm-score groups. Prognostic factors for overall survival (OS) and progression-free survival (PFS) were determined using the multivariate Cox proportional hazard model. During the median follow-up period of 7.3months, 278 (84%) patients showed disease progression, and 223 (67%) died from any cause. Multivariate analysis revealed that the high GRIm-score group was an independent and significant adverse prognostic factor of both OS and PFS (hazard ratio, 1.65 and 1.82, respectively; both p < 0.001) along with Eastern Cooperative Oncology Group Performance Status of ≥ 2 (both p < 0.001), presence of visceral metastasis (both p < 0.001), and hemoglobin of < 9.2g/dL (p = 0.030 and p = 0.038). C-reactive protein of > 42mg/L was a significant prognostic factor for OS (p = 0.001). The GRIm-score is an independent prognostic marker for survival outcomes in patients with platinum-refractory metastatic UC treated with pembrolizumab.

A 16 year-retrospective study of refractory meningiomas: Prognostic factors and systemic treatments.

2085 Background: Meningiomas are the most common brain tumors, with no established standard systemic treatment for refractory cases after surgical and radiotherapeutic interventions. This study aims to identify prognostic factors for overall survival in refractory meningioma and document patient evolution with systemic treatments. Methods: In a retrospective study, we identified patients with meningioma initially followed at CHUM university hospital between 2006 and 2022. Patients with progression after first-line treatment and over 6 months of follow-up were included. The population was divided into two: group 1 received surgery and/or radiotherapy for progression, and group 2 received additional systemic treatments. Survival analysis with Kaplan-Meier curves and group comparisons (Log-Rank, Fisher's Exact Tests) were conducted. Results: A total of750 patients with meningioma were identified. 99 (13%) progressed after first-line treatment. Among them, 70 (9%) were categorized in group 1 and 29 (4%), in group 2. The median follow-up time from diagnosis was 7.5 years. The overall 10-year survival rate was higher in group 1 compared to group 2 (88% vs 62%). Prognostic factors affecting survival were identified as the following: disease progression after second-line treatment, age ≥ 65 years, and grade 2 or 3. When comparing PFS-1 after first-line treatment, they were similar between group 1 and group 2 (mPFS-1: 2.63 vs 3.49 years; p = 0.421). However, PFS-2 after second-line treatment was significantly shorter in group 2 (mPFS-2 : 12.6 vs 2.3 years ; p &lt; 0.001). Age of ≥ 65 years (10-year survival: 57% vs 89%; p &lt; 0.001) and higher grades (10 year survival: 90% grade 1 vs 58% - grade 2 vs 75% - grade 3; p = 0.027) were associated with lower survival rates. The number of lesions (unique or multiple) and localization (supra or infratentorial) of tumors had no significant impact on survival (p=0.257; p = 0.482). Regarding systemic treatments, 7 patients (25%) received Bevacizumab. It was the treatment associated with the longest PFS (mPFS = 22.5 months) when compared to Hydroxyurea (n=18 [62%], mPFS = 4 months), Somatostatin (n = 5 [17%], mPFS = 8 months), a combination of Hydroxyurea and Somatostatin (n=7 [24%], mPFS = 8 months) and Sunitinib (n=3 [10%], mPFS = 14 months). For patients discontinuing systemic treatment, median survival was 5 months. Systemic treatments were well-tolerated. Among moderate to severe side effects (grade ≥ 2), we documented bradycardia (Somatostatin, n=1), elevated liver enzymes (Sunitinib, n=1), anemia and neutropenia (Hydroxyurea, n=3) and proteinuria (Bevacizumab, n=1). Conclusions: Prognostic factors for survival in meningioma include age ≥ 65 years, grades 2 and 3, and the occurrence of a second progression. Our study highlights Bevacizumab in systemic treatment strategies which was well tolerated in our patients.

Retroperitoneal sarcoma: a 10-year follow-up analysis using hospital-based cancer registry data in Japan.

We sought clinical characteristics, survival outcomes, and prognostic factors for overall survival of retroperitoneal sarcoma in Japan. A Japanese hospital-based cancer registry database with a pivotal 10-year follow-up was used to identify and enroll patients, registered from 106 institutions, diagnosed with retroperitoneal sarcoma in 2008-2009. Treating hospitals were divided by hospital care volume; high-volume hospitals and low-volume hospitals were defined as ≥4 and<4 cases/year, respectively. A total of 91 men and 97 women were included, with a median age of 64years. The most common histological type was liposarcoma in 101 patients, followed by leiomyosarcoma in 38 patients. The 5-year and 10-year overall survival rates were 44.1 and 28.3%. The majority of patients (n=152, 80.9%) were treated at low-volume hospitals. High-volume hospital patients had higher 10-year overall survival rates than low-volume hospital patients (51.2% vs 23.2%, P=0.026). Multivariate analysis revealed age over 60years, treatment in low-volume hospitals and chemotherapy were independent predictors of unfavorable survival while treatment with surgery was an independent predictor of favorable survival. The possibility of surgical removal was suggested to be the most important prognostic factor for retroperitoneal sarcoma. Better survival was shown in patients treated at high-volume hospitals in our series.

Clinicopathological features, prognostic factors, and prognostic survival prediction in patients with extrahepatic bile duct cancer liver metastasis.

Extrahepatic bile duct cancer (EBDC) is a compound malignant tumor mainly consisting of extrahepatic cholangiocarcinoma and gallbladder carcinoma. Most EBDC patients are diagnosed at an advanced stage characterized by distant metastases, and the liver is one of the common sites of metastasis. Hence, the purpose of this study is to investigate the clinicopathological features, identify prognostic risk factors, and assess the long-term prognosis of extrahepatic bile duct cancer liver metastasis (EBDCLM). We identified 1922 eligible EBDCLM patients from the SEER database.Cox regression models were used to predict independent prognostic factors for overall survival (OS) and cancer-specific survival (CSS),and Kaplan-Meier survival curves were drawn. A nomogram was constructed based on the results of multivariate Cox analysis, and the predictive effect of the nomogram was evaluated. Age, surgery, chemotherapy, brain metastasis, and lung metastasis were common independent prognostic factors for OS and CSS, and radiotherapy and bone metastasis were independent prognostic factors for CSS. The Kaplan-Meier survival curves showed a significant increase in survival for patients aged less than or equal to 70 years, undergoing surgery and chemotherapy, and without lung metastases. The results showed that the nomogram constructed by us had good predictability and ha d strong clinical application value. Our study identified age, surgery, chemotherapy, brain metastasis, and lung metastasis as independent prognostic factors for EBDCLM patients. The nomogram can accurately predict the survival probability, which is helpful for clinicians to assess the prognosis of patients with advanced EBDC and provide personalized clinical decisions.

Clinical implications and molecular features of extracellular matrix networks in soft tissue sarcomas.

The landscape of extracellular matrix (ECM) alterations in soft tissue sarcomas (STS) remains poorly characterised. We aimed to investigate the tumour ECM and adhesion signalling networks present in STS and their clinical implications. Proteomic and clinical data from 321 patients across 11 histological subtypes were analysed to define ECM and integrin adhesion networks. Subgroup analysis was performed in leiomyosarcomas (LMS), dedifferentiated liposarcomas (DDLPS) and undifferentiated pleiomorphic sarcomas (UPS). This analysis defined subtype-specific ECM profiles including enrichment of basement membrane proteins in LMS and ECM proteases in UPS. Across the cohort, we identified three distinct co-regulated ECM networks which are associated with tumour malignancy grade and histological subtype. Comparative analysis of LMS cell line and patient proteomic data identified the LCP1 cytoskeletal protein as a prognostic factor in LMS. Characterisation of ECM network events in DDLPS revealed three subtypes with distinct oncogenic signalling pathways and survival outcomes. Evaluation of the DDLPS subtype with the poorest prognosis nominates ECM remodelling proteins as candidate anti-stromal therapeutic targets. Finally, we define a proteoglycan signature which is an independent prognostic factor for overall survival in DDLPS and UPS. STS comprise heterogeneous ECM signalling networks and matrix-specific features have utility for risk stratification and therapy selection which could in future guide precision medicine in these rare cancers.

Temporal dynamics of RAS mutations in circulating tumor DNA in metastatic colorectal cancer: clinical significance of mutation loss during treatment

PurposeIn metastatic colorectal cancer (mCRC), RAS mutation loss may occur during the standard-of-care regimen. In this study, we aimed to investigate the temporal dynamics of the RAS gene and its clinical significance.MethodsThis was a retrospective, single-center study that included 82 patients with tissue RAS-mutant (RAS-MT) mCRC who underwent circulating tumor DNA (ctDNA) RAS monitoring between January, 2013–April, 2023. Patients were analyzed for the rate of change over time to acquired RAS mutation loss (aRAS-ML) and clinicopathological factors. The prognostic relevance of mutation loss was assessed.ResultsaRAS-ML was detected in 33 (40.2%) patients, 32 of whom had a mutation loss in the first ctDNA RAS assay. Patients with a RAS mutation detected in the first assay had a median time of 8 months until the second ctDNA RAS assay, with 4.5% cases newly converted to aRAS-ML; no new conversions were detected at the third assay. The aRAS-ML group exhibited more single-organ metastases in the target organ during ctDNA measurement (aRAS-ML: 84.8% vs. RAS-MT: 59.2%, p = 0.02). Of the 33 patients with aRAS-ML, seven (21.2%) received anti-epidermal growth factor receptor (EGFR) therapy, with a median progression-free survival of 8 months. Multivariate analysis revealed that persistent ctDNA RAS mutation was an independent prognostic factor for overall survival (hazard ratio: 2.7, 95% confidence interval: 1.1–6.3, p = 0.02).ConclusionThe rate of ctDNA mutation loss in patients with RAS-MT mCRC decreases over time. Therefore, using a ctDNA RAS assay early in treatment will assist in challenging the use of EGFR regimens.

#2727 Acute kidney in patients with ANCA associated vasculitis

Abstract Background and Aims Renal involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is considered an emergency situation. Early diagnosis and treatment significantly improve prognosis. The aim of this study was to investigate the characteristics of acute kidney injury (AKI) in ANCA-associated vasculitis and assess its developmental aspects. Method Our study, conducted in the Internal Medicine Department A of Charles Nicole Hospital over a four-year period (January 2018-August 2022), was retrospective and descriptive. The diagnosis of ANCA vasculitis was made based on the ACR 1990 and/or EULAR 2012 criteria. The severity of AKI was categorized according to the KDIGO AKI classification. Results Seventeen patients were included, with a mean age of 51 ± 17.42 years and a sex ratio of 0.42. The primary clinical presentation of AKI was rapidly progressive glomerulonephritis (n=11), followed by acute nephritic syndrome (n=4). Pneumo-renal syndrome was observed in 4 patients. Proteinuria and hematuria were present in all 17 patients, with 4 being oligoanuric on dipstick. The mean creatinine level was 584 μmol/L, ranging from 125 to 1151 μmol/L. Thirteen patients had KDIGO stage 3 AKI on admission. The predominant histological lesion was extracapillary crescentic glomerulonephritis, based on the Berden classification (n=6). Hemodialysis was initiated immediately in 12 cases, and plasma exchange was performed in 10 cases. The average follow-up time was 24 months, ranging from 3 months to 4 years. Evolution was marked by partial remission in 7 cases, with a mean creatinine of 173 μmol/L. Progression to end-stage renal disease (ESRD) occurred in 10 cases. Relapses, presenting as pneumo-renal syndrome, were observed in 4 patients. Seven patients succumbed, with vasculitis being the cause of death in 3 cases. In univariate analysis, age &amp;gt;70 years was associated with progression to ESRD (p=0.03). No factor studied emerged as a prognostic factor for overall survival. Conclusion The presence and severity of AKI in ANCA-associated vasculitis are linked to a poorer prognosis, affecting both patient and renal survival.

Hsa_circ_0070440 mediates the prognosis and progress of human prostate cancer.

This study was designed to explore whether hsa_circ_0070440 was dysregulated in prostate cancer (PCa), and assess the effects of hsa_circ_0070440 alteration on PCa prognosis and cell function. The expression levels of hsa_circ_0070440 were assessed in PCa tissues and cell lines. After the classification of patients with PCa based on mean hsa_circ_0070440 level in 138 cases, Chi-square test and survival analyses (Kaplan-Meier method and multivariable Cox proportional hazards analysis) were performed to assess the predictive value of hsa_circ_0070440 in treatment failure (TTF), time to PSA progression (TTPP) and overall survival time. To examine the function of hsa_circ_0070440 in PCa cells, 22Rv1 and C4-2B cells were used for CCK-8 proliferation and Transwell migration assays. Hsa_circ_0070440- and TXNDC5-specific bindings with miR-382/383-5p were validated by bioinformatic analysis and luciferase gene reporter assay. An increased expression of hsa_circ_0070440 was found in PCA tissues and cell lines, associated with clinical T stage (p=0.021) and lymph node metastasis. Hsa_circ_0070440 predicted poor overall survival, TTPP, and TTF, acting as independent prognostic factors for overall survival, TTPP, and TTF in patients with PCa. Knockdown of hsa_circ_0070440 inhibited cell proliferation and migration in vitro. Furthermore, hsa_circ_0070440 could sponge miR-382/383-5p. TXNDC5 was a common target gene for miR-382/383-5p in PCa cells. This study demonstrated that hsa_circ_0070440 can predict the prognosis of PCa patients. Hsa_circ_0070440 can facilitate the proliferation and migration of PCa cells, possibly by sponging miR-382/383-5p.

Abstract B027: The MAT2A inhibitor IDE397: a novel combination backbone for urothelial cancer subjects with MTAP deficiency

Abstract Methylthioadenosine phosphorylase (MTAP) loss, due to focal homozygous deletions in chromosome 9 (9p21.3), occurs in over 25% of urothelial carcinoma and is an adverse prognostic factor for overall survival. Furthermore, MTAP-deleted tumors are associated with a “cold” tumor immune microenvironment and are resistant to immune checkpoint inhibitor therapy. Loss of MTAP confers a dependency on methionine adenosyltransferase 2A (MAT2A), which catalyzes the production of the primary methyl donor for all cellular methyltransferase reactions, S-adenosyl methionine (SAM). IDE397, a potent small molecule inhibitor of MAT2A, was developed to selectively exploit this synthetic lethal vulnerability in MTAP −/− tumors. The accumulation of the metabolite MTA in MTAP −/− tumors combined with a reduction of SAM by MAT2A inhibition results in selective inhibition of PRMT5, a methyltransferase that governs spliceosome fidelity. This triggers pre-mRNA splicing defects that may induce RNA polymerase stalling and can cause R-loop accumulation. Furthermore, due to essential roles in 1-carbon metabolism, MAT2A inhibition together with MTAP loss leads to depletion of metabolites required for both de novo and salvage nucleotide biosynthesis, thus preventing effective management of DNA replication and DNA damage repair. Notably, R-loops must be resolved by topoisomerase activity (TOP1) to prevent replication conflict and mitotic catastrophe. These combinatorial mechanistic relationships underpin a hypothesis that dual inhibition of MAT2A and TOP1 will fully capitalize on the synthetic lethal vulnerabilities associated with MTAP loss in urothelial cancers (replication stress, genomic instability). Consistent with this, IDE397 in combination with TOP1 inhibitors demonstrated synergistic combination benefit in MTAP −/− bladder cancer cell lines in vitro and in cell-line derived xenograft (CDX) models in vivo. IDE397 exposure was associated with heavily disordered methionine metabolism and accumulation of DNA damage response intermediates. In the ongoing Phase 1 dose escalation/expansion study of IDE397 in MTAP −/− solid tumors (NCT04794699), measurable tumor shrinkage has been observed in urothelial cancers (including a CR per RECIST 1.1) along with molecular responses on serial ctDNA measurements. Supported by our preclinical data, and the clinical observation that MTAP −/− urothelial cancers may be more sensitive to sacituzumab govitecan (SG); a TROP-2-targeting TOP1 ADC (UNITE study; JCO.2023.41.16_suppl.4572), a combination of SG+IDE397 could represent a novel early-line therapy for these patients with high unmet need. We plan to evaluate the combination of SG+IDE397 in MTAP-/- urothelial cancers in the next stage of the ongoing IDE397 trial (NCT04794699). Citation Format: Claire L. Neilan, Marcus M. Fischer, Damien Garbett, Arjun A. Rao, Mili Mandal, Michael A. White, Jasgit C. Sachdev. The MAT2A inhibitor IDE397: a novel combination backbone for urothelial cancer subjects with MTAP deficiency [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B027.

Comprehensive genomic and transcriptomic characterization of high-grade gastro-entero-pancreatic neoplasms.

High-grade gastro-entero-pancreatic neoplasms (HG GEP-NENs) can be stratified according to their morphology and Ki-67 values into three prognostic classes: neuroendocrine tumors grade 3 (NETs G3), neuroendocrine carcinomas with Ki-67 < 55% (NECs <55) and NECs with Ki-67 ≥ 55% (NECs ≥55). We analyzed a cohort of 49 HG GEP-NENs by targeted Next-Generation Sequencing (TrueSight Oncology 500), RNA-seq, and immunohistochemistry for p53, Rb1, SSTR-2A, and PD-L1. Frequent genomic alterations affected TP53 (26%), APC (20%), KRAS and MEN1 (both 11%) genes. NET G3 were enriched in MEN1 (p = 0.02) mutations, while both NECs groups were enriched in TP53 (p = 0.001), APC (p = 0.002) and KRAS (p = 0.02) mutations and tumors with TMB ≥ 10 muts/Mb (p = 0.01). No differentially expressed (DE) gene was found between NECs <55% and NECs ≥55%, while 1129 DE genes were identified between NET G3 and NECs. A slight enrichment of CD4+ and CD8+ T cells in NECs and of cancer-associated fibroblasts and macrophages (M2-like) in NET G3. Multivariate analysis identified histologic type and Rb1 loss as independent prognostic factors for overall survival. This study showed that GEP-NET G3 and GEP-NECs exhibit clear genomic and transcriptomic differences, differently from GEP-NECs <55% and GEP-NECs ≥55%, and provided molecular findings with prognostic and potentially predictive value.

Clinical Significance of Primary Tumor Resection in Perihilar Cholangiocarcinoma with Positive Peritoneal Lavage Cytology.

The prognostic impact of positive peritoneal lavage cytology (CY+) in patients with perihilar cholangiocarcinoma (PHC) remains unclear. The present study investigated the clinical significance of primary tumor resection of CY+ PHC. We retrospectively evaluated 282 patients who underwent surgery for PHC between September 2002 and March 2022. The patients' clinicopathological characteristics and survival outcomes were compared between the CY negative (CY-) resected (n = 262), CY+ resected (n = 12), and CY+ unresected (n = 8) groups. Univariate and multivariate analyses were performed to identify prognostic factors for overall survival. The expected residual liver volume was significantly higher in the CY+ resected group (61%) than in the CY- resected (47%) and CY+ unresected (37%) groups (p = 0.004 and 0.007, respectively). The CY+ resected group had a higher administration rate of postoperative therapy than the CY- resected group (58% vs. 16%, p = 0.002). Overall survival of the CY+ resected group was similar to that of the CY- resected group (median survival time [MST] 44.5 vs. 44.6, p = 0.404) and was significantly better than that of the CY+ unresected group (MST 44.5 vs. 17.1, p = 0.006). CY positivity was not a prognostic factor according to a multivariate analysis in patients with primary tumor resection. The CY+ resected group showed better survival than the CY+ unresected group and a similar survival to that of the CY- resected group. Resection of the primary tumor with CY+ PHC may improve the prognosis in selected patients.