Significant Reduction In Overall Survival Research Articles

Impact of cachexia on disease recurrence and survival outcomes in endometrial cancer patients

ObjectiveCancer cachexia is progressive weight loss due to muscle/adipose tissue wasting and inadequate intake that occurs in response to malignancy. It is an independent predictor of disease recurrence and reduced survival in several cancers. However, cachexia’s relationship with gynecologic malignancy outcomes has only been examined in small studies with limited follow-up and inconsistent definitions of cachexia. This study investigated the impact of cachexia on disease recurrence and overall survival in high-risk endometrial carcinoma patients. MethodsThis retrospective cohort study examined data from patients with high-risk non-metastatic primary endometrial carcinoma treated at a single institution from 2015 to 2020. Treatment for all subjects included total hysterectomy, surgical staging, pelvic external beam radiotherapy with or without adjuvant chemotherapy. Radiation planning CT datasets were used to measure skeletal musculature at the L3 vertebral level. Skeletal muscle index (SMI) was defined as total L3 skeletal muscle cross sectional area (cm2)/height2 (m2), and cachexia was defined based on SMI. Results55 patients were eligible for analysis. Several SMI thresholds were used to define cachexia, and analysis was performed for each definition. Kaplan-Meier and Cox-proportional hazards regression analysis yielded no significant reduction in overall survival (OS) or progression-free survival (PFS) in patients with cachexia, regardless of threshold chosen. However, 4 of 13 definitions of cachexia showed significantly improved OS in patients without cachexia, relative to those with cachexia. There were no significant differences in disease recurrence. ConclusionsCachexia as defined in this study was not associated with poor outcomes in endometrial carcinoma patients based on OS, PFS, or disease recurrence.

Central nervous system metastases in breast cancer patients with germline BRCA pathogenic variants compared to non-carriers: a matched-pair analysis

BackgroundBreast cancer is a common cause for central nervous system (CNS) metastasis, resulting in a significant reduction in overall survival. Germline pathogenic variants (PVs) in BRCA1/2 are the most common genetic risk factor for breast cancer, associated with poor prognostic factors. This study sought to explore the patterns and outcome of CNS metastases in breast cancer patients with germline PVs in BRCA1/2 genes.MethodsA retrospective cohort of 75 breast cancer patients with known BRCA1/2 mutation status, who were diagnosed with CNS metastases in 2006–2021. Histopathology, characteristics of CNS disease, treatments, and survival were compared between BRCA1/2 carriers (n = 25) and non-carriers (n = 50), using propensity score matching (1:2 ratio) to control for the possible influence of tumor receptor status (ER, PR, HER2) and patient age. Pearson chi-square or Fisher exact test and Kaplan-Meier survival curves with log-rank test were used for statistical analyses.ResultsPatients with PVs in BRCA1/2 had more high-grade tumors (88% vs. 68%, P = 0.060), were younger at CNS disease diagnosis (median 46.69 vs. 55.02 years, P = 0.003) and had better ECOG performance status (ECOG PS 0 in 20% vs. 2%, P = 0.033), but without significant differences in systemic or CNS-directed treatment approaches. BRCA1/2 mutation was associated with a higher rate of temporal lobe involvement (52% vs. 26%, P = 0.026) and leptomeningeal spread (40% vs. 20%, P = 0.020). Survival after diagnosis of CNS disease was shorter (median 8.03 vs. 28.36 months, P < 0.0001), with no significant differences in time to development of CNS metastases or overall-survival.ConclusionPatients with CNS metastatic breast cancer and PVs in BRCA1/2 showed a higher rate of leptomeningeal and temporal lobe involvement, and a shorter survival with CNS disease. To the best of our knowledge, this is the first study suggesting an exclusive impact of germline BRCA1/2 mutations in CNS metastatic breast cancer.

A Study to Evaluate the Effectiveness and Safety of Prephase Steroid Treatment before Remission Induction Chemotherapy in Patients with Pediatric Acute Lymphoblastic Leukemia Using Common Data Model-Based Real World Data

Introduction: Remission induction chemotherapy (RIC) is a primary treatment strategy for pediatric acute lymphoblastic leukemia (ALL), aiming to rapidly reduce leukemic cells in the bone marrow. However, this swift reduction can lead to significant complications such as tumor lysis syndrome (TLS). Pretreatment with steroids such as prednisolone or dexamethasone a week before initiating multi-agent RIC can potentially prevent TLS, but the effectiveness and utility of this approach remains unclear. We investigated whether steroid pretreatment before RIC can decrease TLS incidence and improve overall survival. Methods: We utilized clinical databases from two university-affiliated tertiary-care hospitals in Seoul, South Korea, constructed according to the OMOP Common Data Model (CDM) specifications. Eligible patients were children with ALL aged &amp;lt;18 who received RIC consisting of vincristine, prednisolone, L-asparaginase with or without daunorubicin between 2012 and 2021. Patients who received steroid pretreatment ≥7 days before RIC constituted the treated group, whereas those who didn't receive any steroid pretreatment or received it &amp;lt;7 days before were the untreated group. We used propensity score (PS) matching to make baseline characteristics comparable between the groups, based on logistic regression model that incorporated the following covariates: age at ALL diagnosis, sex, presence of Down syndrome, risk group, and baseline laboratory measurements including white blood cell count, hemoglobin, platelet count, absolute neutrophil count, uric acid, phosphorus, potassium, calcium, blood urea nitrogen, creatinine, and lactate dehydrogenase. The primary and secondary outcomes were the incidence of TLS within 14 days of starting RIC and overall survival (OS), respectively. Sensitivity analyses were performed to evaluate if unmeasured confounders resulted in any difference in the main results. Likewise, a rule-out approach and a negative control method was applied to adjust for confounders like immunophenotype and genetic alterations and for other residual confounding, respectively. Results: The study included 574 pediatric patients with ALL, with 275 in the treated group and 299 in the untreated group. After PS matching, each group included 142 patients with all baseline characteristics being comparable. Among the untreated patients, TLS was observed 32 out of 299 (10.7%), whereas in the treated group, 6 out of 275 (2.2%) developed TLS. The significant association between the treatment and reduced TLS risk persisted after adjusting for potential confounders (adjusted OR = 0.08, 95% CI: 0.01-0.31, p = 0.01). OS was numerically greater in the treated group that in the untreated group although it failed to reach statistical significance (HR 0.78, 95% CI 0.35-1.71, p=0.53). Sensitivity analyses including a rule-out approach and a negative control method indicated no substantial impact from unmeasured confounders such as immunophenotype, genetic alterations, or other residual factors. Conclusions: Steroid pretreatment ≥7 days before RIC significantly reduced the risk of TLS in pediatric patients with ALL although no significant reduction in OS was seen in the treated group than in the untreated group, partly because median OS was not reached. Because prospective randomized studies are ethically challenging to assess the efficacy and safety of steroid pretreatment before RIC, our results can provide its critical real-world evidence.

Outcomes of HSV-1 encephalitis infection in glioblastoma: An integrated systematic analysis

IntroductionHerpes Simplex Virus-1 (HSV-1) is a neurotropic DNA virus with neural latency and stereotypic viral encephalitis. It has been reported to conceal underlying glioblastoma (GBM) due to similar radiographic imaging and clinical presentation. Limited data exist on the co-occurrence of GBM and HSV-1. To better describe the pathophysiology of HSV-1 superinfections in GBM, we performed a comprehensive review of GBM cases with superimposed HSV-1. MethodsA comprehensive literature search of six electronic databases with apriori search criteria was performed to identify eligible cases of GBM with HSV-1. Relevant clinic-radiographic data were collected, Kaplan-Meier estimates, Fisher's exact test, and logistic regression analyses were used. ResultsWe identified 20 cases of HSE in GBM with an overall survival (OS) of 8.0 months. The median age of presentation was 63 years (range: 24–78 years) and the median interval between GBM or HSE diagnosis was 2 months (range: 0.05–25 months). HSE diagnosis before GBM diagnosis was a predictor for improved survival (HR: 0.06; 95% CI: [0.01–0.54]; p < 0.01). There is a significant reduction in OS in patients with concomitant HSE and GBM compared to the cancer genome atlas (TCGA) cohort (median OS: 8 months vs. 14.2 months; p < 0.05). Finally, HSV does not directly infect GBM cells but indirectly activates a local immune response in the tumor microenvironment. ConclusionsSuperimposed HSE in GBM may contribute to a significant reduction in OS compared to uninfected controls, potentially activating proto-oncogenes during active infection and latency. Preoperative HSE may induce an antiviral immune response, which may serve as a positive prognostic factor. Prompt antiviral treatment upon co-occurrence is necessary.

Radiographic duodenal invasion is associated with poor prognosis and early recurrence in patients with pancreatic ductal adenocarcinoma

BackgroundThe prognostic impact of radiographic duodenal invasion (rDI) of pancreatic ductal adenocarcinoma (PDAC) has yet to be fully elucidated. This retrospective study aimed to investigate the prognostic and clinicopathological significance of rDI in patients with PDAC after pancreatoduodenectomy (PD). Materials and methodsWe retrospectively analyzed 223 consecutive patients with resectable (R) and borderline resectable (BR)-PDAC that underwent up-front PD between 2002 and 2018. rDI was assessed by preoperative multi-detector row computed tomography. ResultsNinety-three (42%) patients with PDAC had rDI, and all of them had pathological DI (pDI). The rDI(+) group had larger tumor size, BR-PDAC was more common, there was higher serum CA19-9 level, and microscopic lymphovascular invasion was more common than in the rDI(−) group. rDI was associated with significant reduction in overall survival (OS) (P < 0.001) and recurrence-free survival (RFS) (P < 0.001). In multivariate analysis, rDI was an independent prognostic factor in OS [hazard ratio (HR) = 0.52; 95% confidence interval (CI) 0.38–0.73, P < 0.001] and RFS [HR = 0.56; 95% CI 0.40–0.78, P = 0.001]. rDI was also an independent risk factor for early recurrence within 12 months [odds ratio (OR) = 0.36; 95% CI 0.18–0.73, P = 0.005]. rDI had positive correlation with liver recurrence (P = 0.024). ConclusionBiological aggressiveness of PDAC with rDI implies short OS and early recurrence with frequent liver metastasis. Aggressive perioperative chemotherapy is recommended to improve prognosis, especially for R-PDAC patients with rDI.

Optimal number of neoadjuvant chemotherapy cycles prior to interval debulking surgery in advanced epithelial ovarian cancer: a systematic review and meta-analysis of progression-free survival and overall survival.

Neoadjuvant chemotherapy (NACT) represents a treatment option in patients with advanced epithelial ovarian cancer (AEOC) who are not good candidates for primary debulking surgery. Usually, 3 cycles of chemotherapy before surgery have been considered the best option for patient survival, although quite often some patients receive more than 3 cycles. The aim of this systematic review and meta-analysis was to identify the optimal number of NACT cycles reporting better survival in AEOC patients. PubMed, Cochrane Library, and Scopus were searched for original articles that analyzed the relationship between the number of chemotherapy cycles and clinical outcomes in AEOC patients before interval debulking surgery (IDS). The main outcomes were progression-free survival (PFS) and overall survival (OS). A total of 22 studies comprising 7,005 patients diagnosed with AEOC were included in our analysis. In terms of survival, the reviewed studies dividing the patients in ≤3 NACT cycles vs. >3, showed a trend for a decrease in PFS and a significant reduction in OS with an increasing number of cycles, while a difference in both PFS and OS was revealed if early IDS included patients with 4 NACT cycles. These results should be interpreted with caution due to the complex characteristics of AEOC patients. In conclusion, our review and meta-analysis revealed that there is not enough evidence to determine the optimal number of NACT treatments before surgery. Further research in the form of well-designed randomized controlled trials is necessary to address this issue. PROSPERO Identifier: CRD42022334959.

Smarca4 (Brg1) Controls Germinal Center B-Cell Development and Is a Haploinsufficient Tumor Suppressor in Lymphoma

SMARCA4 encodes one of two mutually exclusive ATPases present in BAF (aka SWI/SNF) chromatin remodeling complexes. SMARCA4 is dynamically expressed during normal B-cell development, with high expression in germinal center B (GCB)-cells, and is targeted by heterozygous inactivating mutations in GCB-derived lymphomas including 34% of pediatric Burkitt lymphoma (BL), 17% of adult BL, 4% of GCB-DLBCL. However, the functional role of SMARCA4 in GCB cell development and malignant transformation has not been thoroughly investigated. We generated a novel floxed Smarca4 transgenic mouse model and crossed to the Aid-Cre line for GC-specific conditional knock-out (cKO). Following immunization with sheep red blood cells (SRBCs) to induce a GC reaction, Smarca4+/- mice had a significant increase in GCB-cell abundance compared to Smarca4+/+ littermates (p<0.001) due to both an increased average GC size and number. Notably, Smarca4-/- mice displayed a significantly reduced frequency of GC B-cells (p<0.001) and sorting of residual cells revealed retention of 1 or more copies of the floxed allele, suggesting that biallelic cKO of Smarca4 is lethal to GCB cells. We therefore focused subsequent studies on comparisons between Smarca4+/- and Smarca4+/+ mice. Further analysis revealed significant polarization towards a centroblastic phenotype in Smarca4+/- mice (p<0.001), in line with the centroblastic morphology of human BL. Analysis of competitive advantage with the same GC using bone marrow chimera models showed a significant advantage of Smarca4+/- GCB cells compared to Smarca4+/+, associated with a significant increase in proliferation measured by Edu incorporation and reduction of apoptosis measured by Annexin-B. We extended upon this using single cell RNA-seq (scRNA-seq) of GCB cells from Smarca4+/- and Smarca4+/+ mice, which confirmed an increased centroblastic polarization of Smarca4+/- GCB cells and identified a significant increase in light zone to dark zone recycling cells that may underly this polarization. We validated this using the Myc-GFP allele, which confirmed increased Myc+ recycling cells in GCs from Smarca4+/- mice compared to Smarca4-/- mice. BAF complexes drive ATP-dependent mobilization and eviction of nucleosomes to convert chromatin from inactive to active states. Brg1 deficiency may therefore alter distinct BAF complexes and transcription factor programs. We therefore explored the role of Smarca4 in regulating chromatin accessibility and gene expression using ATAC-seq and RNA-seq in Smarca4+/- and Smarca4+/+ murine GCB-cells. Supervised analysis revealed predominant loss of chromatin accessibility associated with repression of nearby genes. Smarca4+/- cells showed significant loss of accessibility of genes upregulated in centrocytes, and a preferential loss of NF-ĸB target genes (GSEA FDR<0.01). MYC translocations are pathognomonic for BL, in which SMARCA4 mutations are most frequent. We therefore crossed our Smarca4 cKO mice with a cre-inducible Myc knock-in (Myc-KI) allele to mimic combined Smarca4 loss-of-function and Myc activation. The addition of Myc-KI did not lead to a significant increase in GCB cell frequency following a single SRBC immunization. However, serial re-challenge of mice with SRBCs led to lymphadenopathy, splenomegaly and infiltration of highly proliferative B-cells into the major organs (lung, liver, and kidney) in Smarca4+/- + Myc-KI mice following 3 immunizations that was not observed with Smarca4+/- or Myc-KI alleles alone. Furthermore, long term follow-up of serially-challenged mice showed a significant reduction in overall survival in Smarca4+/- + Myc-KI mice compared to Smarca4+/- or Myc-KI mice (p=0.010). Collectively, these data demonstrate a competitive advantage of GCB cells with monoallelic Smarca4 cKO, and a centroblastic GC polarization driven in part by increased recycling. Mechanistically, this is associated with loss of chromatin accessibility and gene expression of genes that are expressed in centrocytes, including NFkB target genes. Monoallelic Smarca4 cKO cooperates with Myc over-expression to drive expansion and extranodal dissemination of GCB cells following serial re-challenge, leading to reduced survival. These data provide the first functional and mechanistic insight into the role of SMARCA4 in GCB cell development and lymphomagenesis.

Regulation of Oxidative Energy Metabolism By G0S2 in FLT3+ AML

Introduction: Acute myeloid leukemia (AML) patients with mutations in the FMS-like tyrosine kinase 3 (FLT3) gene represent 20-30% of all AML cases. These patients can be treated with tyrosine kinase inhibitors (TKIs) targeting FLT3; however, up to 60% of patients develop resistance or experience adverse side effects, which makes identifying mechanisms of drug resistance a priority. Our previous work demonstrated a tumor suppressor role for G0/G1 switch gene 2 (G0S2) in chronic myeloid leukemia (CML), which is profoundly downregulated in TKI resistance (Gonzalez MA, et al. under review). However, the role of G0S2 in FLT3+ AML is unknown. G0S2 regulates multiple cellular functions, including lipolysis, de novo lipogenesis, and oxidative phosphorylation; therefore, we hypothesized that reduced G0S2 expression in FLT3+ AML results in altered oxidative energy metabolism, promoting therapy resistance. Methods: To address this hypothesis, we first used shRNA lentiviral vectors to transduce the FLT3+ AML cell lines, MOLM-13 and MOLM-14, with a non-targeting control vector (shNT), a G0S2 knockdown vector (shG0S2), and an ectopic G0S2 expression vector (pLVX G0S2). In primary FLT3+ AML MNCs, we used an empty vector (EV) and pLVX G0S2. We assessed colony formation ability by plating cells in 0.9% Methocult plus cytokines for primary cells, and measured apoptosis using AnnexinV and 7-aminoactinomycin D (7AAD). Cell lines were treated with Doxycycline (100 ng/ml) ± FLT3 inhibitors, either Quizartinib (20nM) or Midostaurin (50nM). We performed immunoblotting using SDS-page, PVDF membranes, and a human antibody cocktail for the 5-electron transport chain (ETC) complexes. For the in vivo experiments, NOD-scid IL2Rgammanull (NSG) mice received intravenous injections of 3 million cells/mouse of the MOLM-14 cell lines with the shNT, shG0S2, and pLVX G0S2 vectors, and all mice were immediately placed in doxycycline hyclate chow to induce vector expression. To assess the role of G0S2 in FTL3+ AML cells, we used the correlation feature available at UALCAN to calculate the genes co-expressed with G0S2 in The Cancer Genome Atlas (TCGA) AML data. Finally, we measured oxygen consumption rates (OCR) using the Cell Mito Stress Test kit for the Agilent Seahorse XFp Bioanalyzer. Results: Using publically available data, we found that G0S2 mRNA expression does not correlate with overall survival (OS) in AML, but is significantly downregulated in AML versus normal mononuclear cells (MNCs, p<0.001), and further reduced in AML patients with mutated FLT3 (p=0.006). In colony formation assays, the FLT3 TKI Midostaurin reduced colony number in the presence of G0S2 ectopic expression when compared to its control. In contrast, FLT3 TKIs had less of an effect on apoptosis in the presence of G0S2 ectopic expression. In primary FLT3+ AML MNCs, ectopic G0S2 expression resulted in a significant reduction of colony formation, which correlated with increased induction of apoptosis when compared to the empty vector control. Importantly, pathway enrichment analysis using data from The Cancer Genome Atlas (TCGA) revealed that the genes co-expressed with G0S2 in AML implicated a role in energy metabolism. After confirming G0S2 ectopic expression in the MOLM-13 cell line, immunoblotting showed reduced expression of complexes III and V of the ETC, which correlated with reductions in oxygen consumption rates using the Agilent Seahorse Bioanalyzer. In vivo, G0S2 knockdown in FLT3+ AML cell lines resulted in a significant reduction in overall survival of NSG mice compared with controls (Figure 1). Conclusion: Altogether, our data demonstrate that loss of G0S2 expression in FLT3+ AML dysregulates oxygen metabolism by altering expression of ETC components. Ultimately, we showed that G0S2 is a tumor suppressor that is downregulated in FLT3+ AML, which might promote therapy resistance by altering oxidative energy metabolism. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Proteomic Characterisation of the Plasma Proteome in Extramedullary Multiple Myeloma Identifies Potential Prognostic Biomarkers

Introduction: Extramedullary multiple myeloma (EMM) is an aggressive manifestation of multiple myeloma (MM) reported to occur in approximately 7% of patients at diagnosis and up to 30% of patients at relapse. EMM is characterised by the spread of malignant plasma cells from the bone marrow microenvironment to distal tissues or organs. It is associated with an adverse prognosis, correlating with a significant reduction in overall survival. Currently there are no validated, established biomarkers to predict EMM. Furthermore, EMM is often treated similarly to high-risk MM with no targeted therapeutic strategies. In-depth proteomic studies on EMM are lacking and the underlying molecular mechanisms that facilitate extramedullary transition are yet to be fully defined. Novel biomarkers and therapeutic targets are urgently required. To enhance our understanding of EMM and to identify novel prognostic biomarkers, we performed a mass spectrometry-based proteomic study on plasma from MM patients with and without extramedullary spread. Methods: Label-free liquid chromatography mass spectrometric analysis of age and gender-matched medullary MM (n=8) and EMM (n=9) blood plasma samples was carried out using a Thermo Q-Exactive mass spectrometer (Thermo Fisher Scientific). Proteome Discoverer 2.2 using Sequest HT (Thermo Fisher Scientific) and a percolator were employed for the identification of peptides and proteins. Several parameters were defined for protein identification: MS/MS mass tolerance was set to 0.02 Da; peptide mass tolerance was set to 10ppm; methionine oxidation was set as a variable modification; carbamido-methylation was set as a fixed modification; and up to two missed cleavages were tolerated. Peptide probability was set to high confidence. Data was imported into Perseus (1.6.14.0) for further analysis. Proteins with less than 70% valid values were removed from the analysis. Proteins of interest were identified based on an FDR-adjusted p-value ≤0.1, fold change >1.5 between experimental groups. Six proteins were selected for further validation using DuoSet enzyme linked immunosorbent assay (ELISA) kits (R&D Systems). We performed receiver operating characteristic (ROC) and area under the curve (AUC) analyses to determine the diagnostic potential of the validated proteins. Results: The median age was 65. Survival analysis revealed a statistically significant change in overall survival (OS) between the two patient cohorts (Log-rank = 3.977, P = 0.046). The median OS of patients with EMM and those without extramedullary spread was 19 months and 83 months, respectively. Our quantitative MS-based proteomic analysis identified 21 proteins of differential abundance between EMM and MM patient plasma (False discovery rate (FDR)-adjusted p-value < 0.1, fold change > 1.5) (Fig. 1A). Antibody-based validation using ELISAs was performed on six proteins (vascular cell adhesion molecule 1 (VCAM1), hepatocyte growth factor activator (HGFA), pigment epithelial-derived factor (PEDF), alpha-2-macroglobulin (A2M), cholinesterase (BCHE), aminopeptidase N (CD13)). VCAM1, HGFA and PEDF were confirmed as being significantly altered between the two cohorts (FDR-adjusted p-value < 0.05). VCAM1, HGFA and PEDF were subject to ROC analyses, demonstrating high discriminatory power for EMM diagnosis (AUC = 0.96, AUC = 0.85, and AUC = 0.97, respectively). The diagnostic efficacy was further enhanced by combining these biomarkers using a logistic regression model (AUC = 1). Conclusion: Our mass spectrometry and antibody-based study identified proteins of differential abundance in the blood plasma of MM patients with and without extramedullary spread. VCAM1, PEDF and HGFA represent promising predictive biomarkers and warrant further investigation in a larger cohort of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Haematological and renal toxicity of radiation therapy in neuroblastoma paediatric patients.

The objective of this study was to evaluate the renal and hematologic toxicity in paediatric patients with adrenal high-risk neuroblastoma who have received radiation therapy (RT) as part of radical treatment. Pediatric patients diagnosed with high-risk adrenal neuroblastoma who received RT as part of the definitive treatment between January 2004 and May 2020 in a single institution were selected. Complete blood counts (CBC) and creatinine clearance (CrCl) pre-RT and post-RT were compared through the Wilcoxon signed-rank test and correlated with survival analysis by Cox regression. Forty-two children with a median age of 3years at diagnosis and 2.8years of follow-up were selected. A significant and acute decrease in lymphocytes was found (p = 0.002) 1month from RT. Patients with a drop higher than 50% of the previous value experimented a significant reduction in overall survival (55 vs 10%; p = 0.031). At the end of the follow-up, a significant increase in all blood counts was observed. With respect to renal function, an acute and significant decrease in CrCl was observed tin patients younger than 4years who received RT (p = 0.013). However, it was not clinically relevant. Our data suggest that acute lymphopenia occurs after RT and could be associated with a poorer prognosis. Other blood counts are reduced after RT and all of them are in physiological range at the end of follow-up. Our cohort presented excellent renal outcomes without any case of chronic renal dysfunction.

Identification of prognostic biomarkers in the CMTM family genes of human ovarian cancer through bioinformatics analysis and experimental verification.

Background: Ovarian cancer (OV) is one of the most common gynecological malignancies worldwide, and its immunotherapy has considerable prospects. Multiple members of the CMTM family were aberrantly expressed in human cancers and controlled key malignant biological processes and immune regulation in cancer development. However, little is known about the function of this gene family in ovarian cancer, especially in terms of immunity. Methods: GEPIA, Oncomine, HPA, Kaplan–Meier plotter, cBioPortal, GeneMANIA, and TIMER were used to analyze the differential gene expression, prognostic value, genetic alterations, and alterations in the immune microenvironment of the CMTM family in patients with ovarian cancer. Importantly, RT-qPCR was used to verify the gene expression of the CMTM family. Results: CMTM1/3/4/6/7/8 showed abnormally high expression at the mRNA and protein levels in OV tissues based on the GEPIA and HPA databases. RT-qPCR showed that CMTM1/6/8 was highly expressed in ovarian cancer cell lines. IHC verified that CMTM8 is highly expressed in ovarian cancer tissues and is closely related to Ki-67. Survival analysis showed that high expression of CMTM1/2/3/5/8 can lead to a significant reduction in overall survival and progression-free survival. There were many types of genetic alterations in the CMTM family. Also, CMTM1/2/3/6 had a certain correlation with the changes in the immune microenvironment such as immune cell infiltration and immune checkpoint expression, which may be the potential mechanism of the CMTM family in ovarian cancer. IHC verified that CMTM6 is highly expressed in ovarian cancer tissues and is closely related to PD-L1. Conclusion: This study confirmed that the CMTM family has abnormal expression in ovarian cancer and CMTM8 can be used as a biomarker for prognostic evaluation. Also, the CMTM family may be used as a potential target for immunotherapy based on the suppression of immune checkpoints.

A Diagnostic Gene Expression Signature for Bladder Cancer Can Stratify Cases into Prescribed Molecular Subtypes and Predict Outcome.

Bladder cancer is a biologically heterogeneous disease with variable clinical presentations, outcomes and responses to therapy. Thus, the clinical utility of single biomarkers for the detection and prediction of biological behavior of bladder cancer is limited. We have previously identified and validated a bladder cancer diagnostic signature composed of 10 biomarkers, which has been incorporated into a multiplex immunoassay bladder cancer test, Oncuria™. In this study, we evaluate whether these 10 biomarkers can assist in the prediction of bladder cancer clinical outcomes. Tumor gene expression and patient survival data from bladder cancer cases from The Cancer Genome Atlas (TCGA) were analyzed. Alignment between the mRNA expression of 10 biomarkers and the TCGA 2017 subtype classification was assessed. Kaplan–Meier analysis of multiple gene expression datasets indicated that high expression of the combined 10 biomarkers correlated with a significant reduction in overall survival. The analysis of three independent, publicly available gene expression datasets confirmed that multiplex prognostic models outperformed single biomarkers. In total, 8 of the 10 biomarkers from the Oncuria™ test were significantly associated with either luminal or basal molecular subtypes, and thus, the test has the potential to assist in the prediction of clinical outcome.

Clinical predictors for thrombus progression in cirrhotic patients with untreated splanchnic vein thrombosis

IntroductionSplanchnic vein thrombosis (SVT) occurs in a heterogenous group of patients secondary to a variety of risk factors including liver disease. Minimal data regarding natural history and outcomes of SVT exists to inform management decisions. As such, there is equipoise regarding the utility of anticoagulation in cirrhotic patients with SVT. We sought to identify clinical factors predictive of new or progressive thrombosis in a cohort of patients with untreated SVT. MethodsWe conducted a retrospective cohort study of cirrhotic patients over 18 years of age diagnosed with SVT at the Oregon Health & Science University from 2015 to 2020, excluding those initially treated with anticoagulation. The primary study endpoint was a composite of the following: imaging-confirmed progression of SVT, development of cavernous transformation, intestinal ischemia, portal cholangiopathy or new venous or arterial thrombosis. Results261 patients were included in the analysis (median age 61 years, 68% male, 32% female). Forty percent of all patients experienced the primary composite endpoint. Multivariable logistic regression found that only the presence of pancreatitis or abdominal infection at diagnosis was associated with an increased likelihood of experiencing thrombus progression in patients with untreated SVT (OR 3.61, P = 0.02). There was a statistically significant overall survival difference between patients that did and did not experience the primary composite endpoint after controlling for confounding variables. (p = 0.0068). ConclusionsOverall, only the presence of pancreatitis or intrabdominal infection were found to be significantly associated with thrombotic progression, with varices identified as marginally non-significant risk factor. Notably, thrombotic progression was associated with a significant reduction in overall survival.

A Novel Hypoxic-Angiogenesis-Immune-Related Gene Model for Prognostic and Therapeutic Effect Prediction in Hepatocellular Carcinoma Patients.

Background Hepatocellular carcinoma (HCC) is one of the most heterogeneous malignant tumors that have been discovered so far, which makes the prognostic prediction difficult. The hypoxia, angiogenesis, and immunity-related genes (HAIRGs) are closely related to the development of liver cancer. However, the prognostic and treatment effect of hypoxia, angiogenesis, and immunity-related genes in HCC continues to be further clarified. Methods The gene expression quantification data and clinical information in patients with liver cancer were downloaded from the TCGA database, and HAIRG signature was built by using the least absolute shrinkage and selection operator (LASSO) technique. Patient from the ICGC database validated the model. Then, tumor immune dysfunction and exclusion (TIDE) algorithm was applied to estimate the clinical response to immunotherapy and the sensitivity of drugs was evaluated by the half-maximal inhibitory concentration (IC50). Result The HAIRGs were identified between the HCC patients and normal patients in the TCGA database. In univariate Cox regression analysis, seventeen differentially expressed genes (DEGs) were associated with overall survival (OS). An eight HAIRG signature model was constructed and was used to divide the patients into two groups according to the median value of the risk score base on the TCGA dataset. Patients in the high-risk group had a significant reduction in OS compared to those in the low-risk group (P < 0.001 in the TCGA, P < 0.001 in the ICGC). For TCGA and ICGC databases of univariate Cox regression analyses, the risk score was used as an independent predictor of OS (HR > 1, P < 0.001). Functional analysis showed that the relevant immune pathways and immune responses were enriched, cellular component analysis showed that the immunoglobulin complex and other related substances were enriched, and immune status existed a difference in the high- and low-risk groups. Then, the tumor immune dysfunction and exclusion (TIDE) algorithm presented differences in immune response in the high- and low-risk groups (P < 0.05), and based on drug sensitivity prediction, patients in the high-risk group were more sensitive to cisplatin compared to those in the low-risk group in both the TCGA and ICGC cohorts (P < 0.05). Conclusions HAIRG signature can be utilized for prognostic prediction in HCC, while it can be considered a prediction model for clinical evaluation of immunotherapy response and chemotherapy sensitivity in HCC.

P59.17 EGFR Mutation Status, Liver Metastasis, and Overall Survival in Advanced Lung Adenocarcinoma Patients

Liver metastases are associated with poor prognosis in non-small cell lung cancer patients. In this study, we explored the relationship between EGFR mutation status, incidence of liver metastases within one year of stage IV diagnosis, and overall survival in an unselected lung adenocarcinoma real-world population. Stage IV lung adenocarcinoma patients routinely tested for EGFR and ALK molecular alterations between 2014-2016 were included in this retrospective cohort analysis. Patients with ALK-rearrangements were excluded in this analysis. Clinico-demographic and pathologic data was abstracted from electronic patient records. Continuous variables were evaluated using the Mann-Whitney’s U test and categorical variables with the chi-squared test. Multivariable analyses were performed to obtain adjusted hazard ratios (aHR) for overall survival. Of 642 stage IV patients, 207 (30.4%) had EGFR-mutated tumors and 435 (64%) had wild-type (EGFR/ALK-negative) tumors. 31/207 (15%) patients with EGFR-mutated tumors and 72/435 (17%) patients with wildtype tumors developed one or more liver metastases within one year of stage IV diagnosis. Liver metastases were associated with statistically significant reduction in overall survival in the wildtype group (p<0.001; Figure 1); there was a trend of reduced overall survival in patients with EGFR-mutated tumors and liver metastases (p=0.11; Figure 2). The aHR for overall survival in the wildtype group was 1.77 (95%CI:1.31-2.41) while in the EGFR-positive group, the aHR was 1.63 (95%CI:0.96-2.77). Among the 103 patients with liver metastases, overall survival was non-significantly better in patients with EGFR mutations (aHR 0.63; 95%CI:0.28-1.40; p=0.257). In stage IV patients with tumors carrying EGFR mutations, as with patients with EGFR/ALK wildtype tumors, developing liver metastases at diagnosis or within one-year of diagnosis of stage IV disease was associated with poorer survival.

Prognostic factors in triple-negative breast cancer: a retrospective cohort.

Triple-negative breast cancer (TNBC) is characterized by lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression and accounts for 15-20% of all breast cancers. This study aims to analyze prognostic factors related to a reduction in overall survival (OS), disease-free survival (DFS), and risk of mortality and recurrence in TNBC. This is a retrospective observational cohort study. Medical records of 532 patients with breast cancer diagnosed from 2007 to 2020 were analyzed. Of these patients, 93 (17%) were women with TNBC. Ten medical records were excluded, and the final sample was composed of 83 women with TNBC. OS and DFS were estimated by the Kaplan-Meier model. Univariate analysis (log-rank test) and multivariate analysis (Cox regression) were used to examine prognostic factors related to a statistically significant reduction (p<0.05) in OS and DFS and increased risk of mortality and tumor recurrence. Smoking, advanced clinical stage, larger tumor size, angiolymphatic invasion, positive sentinel lymph node, axillary node involvement, higher cancer burden, surgical treatment with mastectomy, and recurrence were related to a significant decrease in OS and/or DFS and increased risk of mortality and/or recurrence in TNBC. The 10-year OS and DFS was around 61 and 65%, respectively. Advanced clinical stage, positive sentinel lymph node, axillary node involvement, surgical treatment with mastectomy, and higher residual cancer burden were related to a significant reduction in OS and DFS and increased risk of mortality and recurrence in TNBC.

Thrombosis is associated with worse survival in children with acute lymphoblastic leukemia: A report from CYP‐C

There are conflicting data about whether the development of cancer-associated thrombo-embolism (TE) negatively impacts survival in children. The objective was to determine whether TE during treatment was associated with overall survival (OS) and event-free survival (EFS) in children with acute lymphoblastic leukemia (ALL). We performed a population-based retrospective cohort study using the Cancer in Young People-Canada registry. Children <15 years of age were diagnosed with de novo ALL (2000-2016). The primary exposure variable was radiologically-confirmed thrombo-embolism requiring medical intervention. Multivariable Cox regression models were used to determine the impact of thrombo-embolism on survival, where TE was time-dependent. We included 2006 children (median age: 4 years, 88.5% precursor B-cell ALL). Thrombo-embolism occurred in 113 patients (5.6%), at a median time of 107 days (interquartile range: 35-184 days) after ALL diagnosis. Among standard/low-risk patients, 41/1165 (3.5%) developed TE while among high/very high-risk patients, 72/841 (8.6%) developed TE. Patients with TE had a significantly worse OS (adjusted HR [aHR] of death: 2.61, 95% CI: 1.62-4.22, p< 0.001) and EFS (aHR of an event [death, relapse, second malignancy]: 2.03, 95% CI: 1.35-3.05, p= 0.001), compared with patients without TE. No statistically significant difference was seen in standard/low risk ALL for OS and EFS, but TE was associated with a significantly lower OS and EFS in children with high/very high-risk ALL (aHR of death: 2.90, 95% CI: 1.79-4.72, p< 0.001; aHR of an event: 2.02, 95% CI: 1.30-3.12, p= 0.002). Thus, TE led to a statistically significant reduction in OS and EFS in children with high risk/very high-risk leukemia.

Predictors of Survival in Subtotally Resected WHO Grade I Skull Base Meningiomas

Simple SummaryRadical excision of meningiomas of the skull base has always been a major surgical challenge because of the complex location and the risk of neurovascular damage related to it. In these cases, the benefits of gross-total resection must be balanced with the quality of life after surgery. In the present study, we investigated a cohort of 212 consecutive patients who underwent partial resection of a benign skull base meningioma in order to find predictors of overall survival (OS). Moreover, we analyzed the clinical outcomes and cases of retreatment for progressive disease. In our case series, advanced age at surgery and a preoperative Karnofsky performance status of <70 were negative predictors of OS. Patients who underwent further procedures did not have reduced OS. Overall, surgical and neurological outcomes of STR skull base meningiomas were worse compared to case series, including also completely resected tumors.Background: Although gross total resection (GTR) is the goal in meningioma surgery, this can sometimes be difficult to achieve in skull base meningiomas. We analyzed clinical outcomes and predictors of survival for subtotally resected benign meningiomas. Methods: A total of 212 consecutive patients who underwent subtotal resection (STR) for benign skull base meningioma between 1990–2010 were investigated. Results: Median age was 57.7 [IQR 18.8] years, median preoperative Karnofsky performance status (KPS) was 80.0 [IQR 20.0], 75 patients (35.4%) had posterior fossa meningioma. After a median follow-up of 6.2 [IQR 7.9] years, retreatment (either radiotherapy or repeated surgery) rate was 16% at 1-year, 27% at 3-years, 34% at 5-years, and 38% at 10-years. Ten patients (4.7%) died perioperatively, 9 (3.5%) had postoperative hematomas, and 2 (0.8%) had postoperative infections. Neurological outcome at final visit was improved/stable in 122 patients (70%). Multivariable analysis identified advanced age and preoperative KPS < 70 as negative predictors for overall survival (OS). Patients who underwent retreatment had no significant reduction of OS. Conclusions: Advanced age and preoperative KPS were independent predictors of OS. Retreatments did not prolong nor shorten the OS. Clinical outcomes in STR skull base meningiomas were generally worse compared to cohorts with high rates of GTR.

Relationship between Low Pretreatment Geriatric Nutritional Risk Index and Poor Tolerability of Azacitidine in Patients with Myelodysplastic Syndromes

Background: Predicting tolerability and treatment-related risks associated with azacitidine (AZA) in patients with myelodysplastic syndromes (MDS) before the initiation of therapy is required for appropriate treatment. Thus, in this study, the nutritional status of patients with MDS prior to AZA treatment was evaluated using the geriatric nutritional risk index (GNRI). Tolerability and overall survival (OS) after AZA initiation were also investigated. Methods: This was a single-center retrospective observational study. A total of 59 patients with MDS treated with AZA were assessed using GNRI, and a comparison of undernourished (GNRI <92, n = 27) and non-undernourished (GNRI ≥92, n = 32) patients was performed. Results: The undernourished group had a significant reduction in the number of patients that successfully completed 4 cycles of AZA treatment compared with the non-undernourished group (undernourished group, 11/27 patients, 40.7% vs. non-undernourished group, 24/32 patients, 75.0%; p = 0.009). Factors associated with the difference included karyotype and GNRI. There was also a significant increase in the rate of infectious complications in the undernourished group compared with the non-undernourished group (undernourished group, 33/60 cycles, 55.0% vs. non-undernourished group, 31/92 cycles, 33.7%; p = 0.012). Lastly, a significant reduction in OS was observed in the undernourished group compared with the non-undernourished group (undernourished group, 11.5 months; 95% CI, 5.2–16.7 vs. non-undernourished group, 21.9 months; 95% CI, 13.8–24.0; p = 0.026). Factors associated with OS included both the revised International Prognostic Scoring System (IPSS-R) and GNRI. Conclusions: These results indicate that predicting treatment completion and adverse events in patients with MDS prior to AZA treatment is important. This study suggests GNRI may be a valuable nutritional assessment tool for determining tolerability and OS of AZA treatment.

Impact of Thromboembolism on Overall and Event-Free Survival in Children with Acute Lymphoblastic

Introduction: Thromboembolism (TE) is a well-known complication of cancer and its treatments. The impact of TE on survival outcomes remains unclear, especially in children. We assessed whether TE development was associated with overall survival (OS) and event-free survival (EFS) in children with acute lymphoblastic leukemia (ALL). Methods: We performed a population-based retrospective cohort study using the national registry Cancer in Young People Canada (CYP-C). Children 0-&amp;lt;15 years of age diagnosed with ALL (2000-2018) and treated at one of 12 Canadian pediatric centers outside of Ontario were included. OS was defined as the time between the date of cancer diagnosis and death and, EFS, as the time between the date of cancer diagnosis and the date of relapse, subsequent malignancy or death (whichever came first). Patients were categorized as to whether they experienced a radiologically-confirmed TE during treatment graded 3, 4 or 5 as per the Common Terminology Criteria for Adverse Events v.4 (i.e. requiring medical treatment, life-threatening or fatal). Only TEs that occurred before relapse or subsequent malignancy were considered. The Kaplan-Meier survival method estimated the 5-year OS and EFS of children with TE compared to those without TE. Univariate and multivariable Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of death or an event between groups, adjusted for age, sex, and leukemia risk group. A sub-analysis stratified the analysis by leukemia risk group. Results: The study included 2,208 children (median age: 4 years [interquartile range: 2-7 years], 54.9% male). Precursor B-cell ALL was the most common diagnosis (1,789, 89.1%). Patients were stratified as standard/low risk ALL in 58.0% of cases, and high/very high risk ALL in 42.0%. Of these, 121 (6.0%) developed a TE, at a median time of 100 days (interquartile range: 30-183 days) after cancer diagnosis. Eight patients (0.4%) had a life-threatening or fatal TE. Patients with TE were more likely to be aged 10 years or older, to present with T-cell ALL, and to have high risk leukemia. The 5-year OS (95% CI) of patients with and without TE was 80.2% (72.9-87.5%) and 93.7% (92.5-94.9%) respectively (log-rank test: p&amp;lt;0.001, Figure 1). The adjusted HR (95% CI) of death in children with TE was 2.09 (1.33-3.27, p=0.001). Similarly, as shown in Figure 2, the 5-year EFS (95% CI) of patients with and without TE was 68.7% (59.7-77.7%) and 88.6% (87.1-90.1%), respectively (log-rank test: p&amp;lt;0.001). The adjusted HR (95% CI) of an event was 2.01 (1.39-2.90, p&amp;lt;0.001). When stratified by leukemia risk group, no statistically significant difference was seen in standard/low risk ALL for both OS and EFS but TE was associated with a significantly lower OS and EFS in children with high/very high risk ALL (Table 1). In this group, the increased risk of death was attributable to both deaths following relapsed disease (HR [95% CI]: 2.37 [1.39-4.04]) and death not following relapse (HR [95% CI]: 2.93 [1.35-6.35]). Sensitivity analyses in which 1) patients with very high risk ALL were removed and 2) only grade 3 or 4 TE were considered showed similar results. Conclusions: Clinically relevant TE led to a statistically significant reduction in OS and EFS in children with high risk/very high risk leukemia. Further research is needed to assess whether TE prevention may improve anti-cancer outcomes. Disclosures Brandao: Boehringer Ingelheim: Other: Member of a paediatric expert working group.