Independent Poor Prognostic Factor Research Articles

Factors Involved in Preoperative Edema in High-Grade Gliomas.

Background Expansion of preoperative edema (PE) is an independent poor prognostic factor in high-grade gliomas. Evaluation of PE provides important information that can be readily obtained from magnetic resonance imaging (MRI), but there are few reports on factors associated with PE. The goal of this study was to identify factors contributing to PE in Grade 3 (G3) and Grade 4 (G4) gliomas. Methodology PE was measured in 141 pathologically proven G3 and G4 gliomas, and factors with a potential relationship with PE were examined in univariate and multivariate analyses. The following eight explanatory variables were used: age, sex, Karnofsky performance status (KPS), location of the glioma, tumor diameter, pathological grade, isocitrate dehydrogenase (IDH)-1-R132H status, and Ki-67 index. Overall survival (OS) and progression-free survival (PFS) were calculated in groups divided by PE (<1 vs. ≥1 cm) and by factors with a significant correlation with PE in multivariate analysis. Results In univariate analysis, age (p = 0.013), KPS (p = 0.012), pathology grade (p = 0.004), and IDH1-R132H status (p = 0.0003) were significantly correlated with PE. In multivariate analysis, only IDH1-R132H status showed a significant correlation (p = 0.036), with a regression coefficient of -0.42. The median follow-up period in survivors was 38.9 months (range: 1.2-131.7 months). The one-, two-, and three-year OS rates for PE <1 vs. ≥1 cm were 77% vs. 68%, 67% vs. 44%, and 63% vs. 24% (p = 0.0001), respectively, and those for IDH1-R132H mutated vs. wild-type cases were 85% vs. 67%, 85% vs. 40%, and 81% vs. 21% (p < 0.0001), respectively.The one-, two-, and three-year PFS rates for PE <1 vs. ≥1 cm were 77% vs. 49%, 64% vs. 24%, and 50% vs. 18% (p = 0.0002), respectively, and those for IDH1-R132H mutated vs. wild-type cases were 85% vs. 48%, 77% vs. 23%, and 73% vs. 14% (p < 0.0001), respectively. Conclusions IDH1-R132H status was found to be a significant contributor to PE. Cases with PE <1 cm and those with the IDH1-R132H mutation clearly had a better prognosis.

Prognostic Impact of Positive Peritoneal Lavage Cytology on Resectable Pancreatic Body and Tail Cancer: A Retrospective Study

BackgroundThe prognostic impact of positive peritoneal lavage cytology on pancreatic cancer is unclear. Therefore, this study aimed to evaluate its impact in resectable pancreatic body and tail cancer.MethodsBetween January 2006 and December 2019, 97 patients with pancreatic body and tail cancer underwent peritoneal lavage cytology and curative resection at our institution. We analyzed the impact of positive peritoneal lavage cytology on clinicopathological factors and on the prognosis of pancreatic body and tail cancer.ResultsMalignant cells were detected in 14 patients (14.4%) using peritoneal lavage cytology. In these patients, the tumor diameter was significantly larger (p < 0.001) and anterior serosal invasion (p = 0.034), splenic artery invasion (p = 0.013), lympho-vessel invasion (p = 0.025), and perineural invasion (p = 0.008) were significantly more frequent. The R1 resection rate was also significantly higher in patients with positive peritoneal lavage cytology than in negative patients (p = 0.015). Positive peritoneal lavage cytology had a significantly poor impact on overall survival (p = 0.001) and recurrence-free survival (p < 0.001). This cytology was also an independent poor prognostic factor for recurrence (p = 0.022) and was associated with peritoneal dissemination and liver metastasis.ConclusionsPositive peritoneal lavage cytology is considered to be indicative of more systemic disease in patients with resectable pancreatic body and tail cancer than in patients with negative peritoneal lavage cytology. Early detection of pancreatic cancer before it develops micrometastases is important to improve prognosis, and CY+ patients require more intensive multimodality treatment than standard treatment for resectable pancreatic cancer.

Co-mutation landscape and clinical significance of RAS pathway related gene mutations in patients with myelodysplastic syndrome.

Single gene mutations in the RAS pathway are uncommon and of unknown significance in myelodysplastic syndrome (MDS) patients, RAS pathway-related gene mutations (RASwaymut ) as a whole may be significant and require further elucidation. The clinical and molecular data of 370 MDS patients who were newly diagnosed between 1 November 2016 and 31 August 2020 in our hospital were collected and retrospectively reviewed. RASwaymut were detected in 57 (15.41%) patients. Higher median percentage of marrow blasts (2% vs. 1%, P=0.00), more co-mutated genes (4, interquartile range[IQR]: 2-5. vs. 2, IQR:1-4, P=0.00), more higher risk patients according to international prognostic scoring system-revised(IPSS-R) (80.70% vs. 59.11%, P=0.002) as well as higher acute myeloid leukemia transformation rate (35.09% vs. 14.38%, P=0.02) were observed in patients with RASwaymut when compared to those with wild type RAS pathway-related genes (RASwaywt ). The most frequent co-mutated genes were ASXL1 (28.6%), TET2 (23.2%), U2AF1, RUNX1, TP53 (14.3%); DNMT3A (12.5%), among which ASXL1 mutation rate were significantly higher than those with RASwaywt (p < 0.05). RASwaymut had no significant effect on response to disease-modifying treatment in MDS patients. However, Overall survivals (OS) of RASwaymut patients were significantly shorter than those with RASwaywt (16.05m. vs. 92.3m, P=0.00), especially in patients with marrow blasts less than 5% (P=0.002), normal karyotype (P=0.01) and lower risk (P=0.00). While multivariate prognostic analysis showed that RASwaymut co-mutated with TET2 was an independent poor prognostic factor for all MDS patients (P=0.00, hazrad ratio [HR]=4.77 with 95% confidence interval [CI]: 2.4-9.51) and RASwaymut patients (P=0.02, HR 2.76, 95% CI 1.21-6.29). In conclusion, RASwaymut was associated with higher IPSS-R risk, higher incidence of leukemic transformation thus shorter OS in MDS patients, it could be viewed as a whole to predict poor prognosis. Co-mutation with TET2 may promote disease progression and was an independent poor prognostic factor in MDS patients.

Abstract 11931: Plasma Volume Status at Cardiovascular Intensive Care Unit Discharge and Hospital Discharge is Associated With Overall Survival in Patients With Acute Decompensated Heart Failure

Background: Plasma volume status (PVS), a measure of plasma volume, has been evaluated as a prognostic marker for chronic heart failure. However, the significance of PVS in patients with acute decompensated heart failure (ADHF) admitted to the cardiovascular intensive care unit (CICU) remains unclear. Therefore, we examined the relationship between PVS and the long-term mortality. Method: Of 389 consecutive patients admitted to our CICU for ADHF from January 2018 to December 2020, a total of 206 patients (74.9 ± 12.9 years, 64.6% male) were enrolled, excluding those who received red blood cell transfusion, underwent dialysis, were discharged directly from the CICU, or died in the hospital. We measured PVS during the CICU stay and at discharge using the Kaplan-Hakim formula, and examined the association with all-cause mortality during the observation period (1037 days). Result: The group with decreasing PVS at 3 points, at admission to the CICU, at transfer to the GW, and at discharge, had a 3-year mortality rate of 0%. Cut-off values to predict long-term mortality were 10% and 9% for PVS at transfer to the GW and discharge according to ROC curve, respectively. All patients were divided into 2 groups by cut-off values, respectively, and the high PVS group had a significantly higher mortality rate (Figure 1, 2). In COX regression analysis, significant poor prognostic factors were PVS at transfer to the GW (HR=1.086 [1.04-1.13], P&lt;0.001), PVS at discharge (HR=1.073 [1.03-1.12], P&lt;0.001), and age (HR=1.052 [1.00-1.10], P=0.04). In multivariate analysis, PVS at discharge (HR=1.058 [1.00-1.12], P=0.048) was independent poor prognostic factor. Conclusions: In patients with ADHF who were admitted to the CICU, PVS at discharge may be useful in predicting prognosis. It is necessary to consider whether the treatment of heart failure that lowers PVS contributes to improved prognosis.

Clinicopathological features of cytokeratin 5-positive pulmonary adenocarcinoma.

Cytokeratin 5 (CK5) is a marker for pulmonary squamous cell carcinoma; however, CK5 is sometimes present in pulmonary adenocarcinoma (ADC), and there is insufficient information regarding the clinicopathological features of CK5-positive ADC. We aimed to explore the clinicopathological characteristics of CK5-positive ADC using immunohistochemistry. We prepared the following two cohorts: a resected cohort containing 220 resected tumours for primarily studying the detailed morphological characteristics, and a tissue microarray (TMA) cohort containing 337 samples for investigating the associations of CK5 expression with other protein expressions, genetic and prognostic findings. CK5-positive ADC was defined to have ≥ 10% tumour cells and presence of CK5-positive tumour cells in the resected and TMA cohorts, respectively. CK5-positive ADCs were identified in 91 (16.3%) patients in the combined cohort. CK5-positive ADCs had male predominance (P= 0.012), smoking history (P= 0.001), higher stage (P< 0.001), histological high-grade components (P< 0.001), vascular invasion (P< 0.001), mucinous differentiation (P< 0.001), spread through airspaces (P< 0.001), EGFR wild-type (P< 0.001), KRAS mutations (P< 0.001), ALK rearrangement (P< 0.001) and ROS1 rearrangement (P= 0.002). In the resected cohort, more than half the CK5-positive ADCs (19 cases, 65.5%) showed mucinous differentiation; the remaining cases harboured high-grade components. In the TMA cohort, CK5-positive ADCs correlated with TTF-1 negativity (P= 0.002) and MUC5B, MUC5AC and HNF4alpha positivity (P< 0.001, 0.048, < 0.001). Further, CK5-positive ADCs had significantly lower disease-free and overall survival rates than CK5-negative ADCs (P< 0.001 for each). Additionally, multivariate analysis revealed that CK5 expression was an independent poor prognostic factor. CK5-positive ADCs showed aggressive clinical behaviour, with high-grade morphology and mucinous differentiation.

Circulating tumor cells correlating with Ki-67 predicts the prognosis of bladder cancer patients

PurposeTo investigate the value of circulating tumor cells (CTCs) and Ki-67 in predicting the prognosis of bladder cancer. Here, we tested CTC counts and Ki-67 levels to assess patient prognosis.Methods84 patients with bladder cancer who underwent surgery were included in this study. Peripheral blood CTCs were detected by SE-iFISH technology before and after surgery, and Ki-67 levels were analyzed by immunohistochemistry. The association between CTCs and Ki-67 and the combination of the two was analyzed to predict the prognosis of patients.Results76 out of 84 patients (90.5%) were positive. ROC curve analysis showed that preoperative and postoperative CTC counts = 4 and 2 were the best thresholds for predicting patient recurrence or death. In multivariate analysis, high postoperative CTC count (≥ 2) (P < 0.001) and Ki-67 high expression (≥ 15%) (P < 0.001) were independent poor prognostic factors for PFS in bladder cancer patients. In addition, the study found that Ki-67 levels were positively correlated with high postoperative CTC counts, Bladder cancer patients with Ki-67 high expression and high postoperative CTC counts were associated with extremely poor progression-free survival.ConclusionKi-67 high expression is associated with high postoperative CTC counts, both of which predict poor prognosis in bladder cancer patients.

Efficacy of Adjuvant Chemotherapy Following Curative Resection of Colorectal Cancer Liver Metastases.

Routine use of adjuvant chemotherapy (AC) following hepatectomy for colorectal liver metastases (CRLM) is not universally practiced because of the lack of supporting evidence. Therefore, we investigated the efficacy of AC following curative CRLM resection. Among the 742 patients who underwent their first hepatectomy for CRLM at our institution, 335 were stratified into surgery alone (SA; n=162) and AC (n=173) groups. Poor prognostic factors for SA were identified using multivariate logistic regression analysis. Propensity score matching was used to compare the clinical outcomes between SA and AC groups according to the number of prognostic factors. Multivariate analysis showed that preoperative carcinoembryonic antigen (CEA) levels (≥10 ng/ml; p=0.01), primary lymph node metastases (≥1; p=0.0001), and the number (n≥4; p=0.01) and maximum diameter (≥5 cm; p=0.00001) of CRLM tumours were independent poor prognostic factors for overall survival (OS) in the SA group. Patients with ≥3 risk factors were categorized as being high risk. After propensity score matching, the 5-year OS rate was significantly higher in the AC group (n=13) than that in the SA group (n=15; 47.9% vs. 7.3%; p=0.03) among high-risk patients. Adjuvant chemotherapy after curative CRLM resection may improve the prognosis of patients with three or more risk factors including preoperative CEA levels ≥10 g/ml, primary lymph node metastases ≥1, number (≥4) and maximum diameter (≥5 cm) of CRLM tumours.

Association between systemic inflammation and water composition and survival in colorectal cancer.

Systemic inflammation and water composition are important factors affecting cancer prognosis. This study aimed to explore the association between the neutrophil-to-lymphocyte ratio (NLR) and intracellular water/total body water (ICW/TBW) ratio and overall survival (OS) in colorectal cancer (CRC). This multicenter, prospective cohort included 628 patients with CRC between June 2012 and December 2019. The association between the covariates and OS was assessed using a Cox proportional hazards model and restricted cubic spline models. Concordance index (C-index), which integrated discriminant improvement (IDI) index and continuous net reclassification index, (cNRI) was used to compare the predictive ability of the markers. The optimal cutoff values for the NLR and ICW/TBW ratio were 2.42 and 0.61, respectively. The NLR was negatively associated with OS, while the ICW/TBW ratio was positively correlated with OS. NLR ≥2.42 and ICW/TBW ratio <0.61 were both independent poor prognostic factors (hazard ratio [HR]: 2.04, 95% confidence interval [CI]: 1.44-2.88 and HR: 1.45, 95% CI: 1.04-2.02, respectively). Subsequently, we combined the two factors to construct an inflammation-water score (IWS). Patients with IWS (2, ≥1) had worse OS (HR: 2.86 and 95% CI: 1.77-4.63; HR: 1.74 and 95% CI 1.17-2.57, respectively) than those without one. Compared to its component factors, IWS score showed better predictive ability for C-index, IDI index, and cNRI. A high NLR and a low ICW/TBW ratio were independent risk factors for poor prognosis in patients with CRC. The combination of the two factors can provide a better prognostic prediction effect.

The effect of sarcopenia on erlotinib therapy in patients with metastatic lung adenocarcinoma.

Erlotinib, a tyrosinekinase inhibitor, has been shown to improve the survival of patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. Sarcopenia is a status with increasing importance in lung cancer, and it may predict a poor prognosis. We aimed to evaluate the impact of sarcopenia on erlotinib therapy and prognosis in patients with EGFR-mutated (exon 19 or 21 L858R) metastatic lung adenocarcinoma. Sarcopenia was defined as skeletal muscle index ≤39 cm2/m2 for women and ≤55 cm2/m2 for men. The patient characteristics, inflammation parameters, clinical and survival outcomes of the erlotinib therapy were examined according to sarcopenia status. We also analyzed the erlotinib treatment-related toxicity. Seventy-two patients were included in our retrospective study, and the mean age of the patients was 63.7 years. A total of 39 (54.2%) patients were diagnosed with sarcopenia. Patients with sarcopenia had a poor prognosis and had a shorter median progression-free survival (PFS) than patients without sarcopenia (10.5 months vs. 21.8 months, p=0.002). Sarcopenia (HR 2.08) and C-reactive protein > 6.5 mg/L (HR 2.57) were determined as independent poor prognostic factors for PFS of erlotinib therapy. Treatment-related toxicity occurred in 34.7% of patients treated with erlotinib, and sarcopenia did not significantly affect treatment-related toxicity. We also found that sarcopenia significantly affected the response to erlotinib. The expected survival outcomes may be low when erlotinib therapy is used in patients with sarcopenia and metastatic lung adenocarcinoma. This study showed that survival and clinical outcomes could be better predicted by detecting sarcopenia in patients with lung cancer using erlotinib.

High-Risk pT1-2N0 Breast Cancer may Benefit from Postmastectomy Radiotherapy: A Risk Stratification Analysis Based on Nomogram

<h3>Purpose/Objective(s)</h3> Postmastectomy radiation therapy (PMRT) had heterogeneous effects on clinical outcome of patients with pT1-2N0 breast cancer. We aimed to develop nomograms for predicting locoregional recurrence-free survival (LRRFS) and disease-free survival (DFS), and to explore the potential effect of PMRT in pT1-2N0 breast cancer. <h3>Materials/Methods</h3> Clinical data were collected from 840 patients with newly diagnosed pT1-2N0 breast cancer between January 2015 and December 2018. Nomograms predicting the LRRFS and DFS rates were developed based on the risk factors identified by Cox regression analysis in patients treated with mastectomy alone (n =671). Furthermore, the effect of PMRT was indirectly investigated by comparing patients treated with mastectomy alone with those treated with breast-conserving surgery (BCS) plus radiotherapy (n =169) in different risk subgroups stratified by the nomogram scores. The optimal cut-off points were identified by X-tile software. LRRFS and DFS were evaluated using the Kaplan-Meier method, and the differences were compared using the log-rank test. Propensity score matching analysis (PSM) was performed to balance the backgrounds of patients between the mastectomy alone and BCS plus radiotherapy sets. <h3>Results</h3> After a median follow-up duration of 62 months (range, 9–79 months) and 50 months (range, 10–79 months) in the mastectomy alone and BCS plus radiotherapy sets, respectively. The 5-year LRRFS rates (97.0% vs. 97.3%, P = 0.516) and the 5-year DFS rates (92.0% vs. 92.7%, P = 0.339) were similar between the mastectomy alone and BCS plus radiotherapy sets, respectively. Multivariate Cox regression showed that larger tumor size, high grade, and hormone receptor (HR)-negative status were independent poor prognostic factors for both LRRFS and DFS (P<0.05 for all), while premenopausal status was independently associated with worse LRRFS (P=0.019). Incorporation of these factors into the constructed nomograms showed high accuracy when predicting the 5-year LRRFS and DFS rates, with concordance indexes of 0.794 (95%CI: 0.704-0.884) and 0.726 (95%CI: 0.659-0.793), respectively, after internal validation. Based on nomogram scores, patients were classified into different risk groups. After PSM in subgroups, compared with mastectomy alone, BCS plus radiotherapy significantly improved the LRRFS (84.9% vs. 96.6%, p = 0.026) and DFS (71.8% vs. 100%, p = 0.033) in the high-risk group, but not in the low-risk or intermediate-risk group (P>0.05 for all). <h3>Conclusion</h3> The constructed nomograms can not only estimate the individualized 5-year LRRFS and DFS rates among patients with pT1-2N0 breast cancer after mastectomy but can also stratify patients into different risk subgroups, and thus, they can help identify high-risk patients who are more likely to benefit from PMRT.

Sarcopenia is Associated With Oncological Prognosis and the Incidence of Secondary Cancer in Patients With Middle/Lower Rectal Cancer

ObjectiveThis study evaluated the clinical implications of sarcopenia for patients with rectal cancer according to cancer progression. Summary Background DataThe negative impact of body composition on long-term outcome has been demonstrated for various malignancies. MethodsWe retrospectively reviewed 708 patients with rectal cancer who underwent curative resection at our institution between 2003 and 2020. Factors contributing to long-term outcomes and the incidence of secondary cancer (ISC) were analyzed. Psoas muscle mass index (PMI) was assessed using preoperative computed tomography. Sarcopenia was defined using the PMI cut-off values for Asian adults (6.36 cm2/m2 for males and 3.92 cm2/m2 for females). ResultsSarcopenia was identified in 306 patients (43.2%). Sarcopenia was associated with advanced age, low body mass index, smoking history, and advanced T-stage. Multivariate analysis showed sarcopenia was an independent poor prognostic factor for OS (HR 1.71; P = .0102) and cancer-specific survival (HR 1.64; P = .0490). Patients with sarcopenia had significantly higher mortality due to cancer-related death in stages III and IV, whereas non-rectal cancer-related death, including secondary cancer, was markedly increased in stage 0-II sarcopenic rectal patients. Five-year cumulative ISC in patients with and without sarcopenia was 11.8% and 5.9%, respectively. Multivariate analysis revealed that sarcopenia was an independent predictive factor for ISC (HR 2.05; P = .0063). ConclusionsSarcopenia helps predict survival outcomes and cause of death according to cancer stage for patients with middle/lower rectal cancer who underwent radical surgery. Furthermore, sarcopenia increased the development of secondary cancer in those patients.

The safety of early discharge following transfemoral transcatheter aortic valve replacement under general anesthesia.

There is growing evidence of the safety of same-day discharge for low-risk conscious sedated TAVR patients. However, the evidence supporting the safety of early discharge following GA-TAVR with routine transesophageal echocardiography (TEE) is limited. To assess the safety of early discharge following transcatheter aortic valve replacement (TAVR) using General Anesthesia (GA-TAVR) and identify predictors for patient selection. We used data from 2,447 TEE-guided GA-TAVR patients performed at Cedars-Sinai between 2016 and 2021. Patients were categorized into three groups based on the discharge time from admission: 24 h, 24-48 h, and >48 h. Predictors for 30-day outcomes (cumulative adverse events and death) were validated on a matched cohort of 24 h vs. >24 h using the bootstrap model. The >48 h group had significantly worse baseline cardiovascular profile, higher surgical risk, low functional status, and higher procedural complications than the 24 h and the 24-48 h groups. The rate of 30-day outcomes was significantly lower in the 24 h than the >48 h but did not differ from the 24-48 h (11.3 vs. 15.5 vs. 11.7%, p = 0.003 and p = 0.71, respectively). Independent poor prognostic factors of 30-day outcomes had a high STS risk of ≥8 (OR 1.90, 95% CI 1.30-2.77, E-value = 3.2, P < 0.001), low left ventricle ejection fraction of <30% (OR 6.0, 95% CI 3.96-9.10, E-value = 11.5, P < 0.001), and life-threatening procedural complications (OR 2.65, 95% CI 1.20-5.89, E-value = 4.7, P = 0.04). Our formulated predictors showed a good discrimination ability for patient selection (AUC: 0.78, 95% CI 0.75-0.81). Discharge within 24 h following GA-TAVR using TEE is safe for selected patients using our proposed validated predictors.

Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract.

Neuroendocrine carcinomas of the gastrointestinal tract (GI-NECs) remain a disease of grim prognosis with limited therapeutic options. Their molecular characteristics are still undefined. This study aimed to explore the underlying genetic basis and heterogeneity of GI-NECs. Comprehensive genomic analysis using whole-exome sequencing was performed on 143 formalin-fixed, paraffin-embedded samples of surgically resected GI-NEC with a thorough histological evaluation. Mutational signatures, somatic mutations, and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes. Survival analysis was conducted to identify the independent factors. In total, 143 GI-NECs were examined: the stomach, 87 cases (60.8%); the esophagus, 29 cases (20.3%); the colorectum, 20 cases (14.0%); and the small intestine, 7 cases (4.9%). Eighty-three (58.0%) and 60 (42.0%) cases were subclassified into small cell and large cell subtypes, respectively. GI-NECs showed distinct genetic alterations from their lung counterparts and non-neuroendocrine carcinomas in the same locations. Obvious heterogeneity of mutational signatures, somatic mutations, and copy number variations was revealed across anatomic locations rather than histological subtypes. Except for tumor protein p53 (TP53) and retinoblastoma 1 (RB1), the most frequently mutated genes in the stomach, esophagus, colorectum, and small intestine were low-density lipoprotein receptor-related protein 1B (LRP1B), notch receptor 1 (NOTCH1), adenomatosis polyposis coli (APC), catenin beta 1 (CTNNB1), respectively. Mutations in the WNT-β-catenin, NOTCH and erythroblastic leukemia viral oncogene B (ERBB) pathways were prevalently identified in gastric, esophageal, and colorectal NECs, respectively. Importantly, 104 (72.7%) GI-NECs harbored putative clinically relevant alterations, and non-gastric location and RB1 bi-allelic inactivation with copy number alterations were identified as two independent poor prognostic factors. Furthermore, we found that tumor cells in GI-NECs first gain clonal mutations in TP53, RB1, NOTCH1 and APC, followed by subsequent whole-genome doubling (WGD) and post-WGD clonal mutations in LRP1B, CUB and Sushi multiple domains 3 (CSMD3), FAT tumor suppressor homolog 4 (FAT4) and erb-b2 receptor tyrosine kinase 4 (ERBB4), and finally develop subclonal mutations. GI-NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations. Moreover, potentially actionable alterations and prognostic factors were revealed for GI-NECs.

Pan-cancer analysis of oncogenic TNFAIP2 identifying its prognostic value and immunological function in acute myeloid leukemia

BackgroundTumor necrosis factor alpha-induced protein 2 (TNFAIP2), a TNFα-inducible gene, appears to participate in inflammation, immune response, hematopoiesis, and carcinogenesis. However, the potential role of TNFAIP2 in the development of acute myeloid leukemia (AML) remains unknow yet. Therefore, we aimed to study the biological role of TNFAIP2 in leukemogenesis.MethodsTNFAIP2 mRNA level, prognostic value, co-expressed genes, differentially expressed genes, DNA methylation, and functional enrichment analysis in AML patients were explored via multiple public databases, including UALCAN, GTEx portal, Timer 2.0, LinkedOmics, SMART, MethSurv, Metascape, GSEA and String databases. Data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and Beat AML database were used to determine the associations between TNFAIP2 expression and various clinical or genetic parameters of AML patients. Moreover, the biological functions of TNFAIP2 in AML were investigated through in vitro experiments.ResultsBy large-scale data mining, our study indicated that TNFAIP2 was differentially expressed across different normal and tumor tissues. TNFAIP2 expression was significantly increased in AML, particularly in French–American–British (FAB) classification M4/M5 patients, compared with corresponding control tissues. Overexpression of TNFAIP2 was an independent poor prognostic factor of overall survival (OS) and was associated with unfavorable cytogenetic risk and gene mutations in AML patients. DNA hypermethylation of TNFAIP2 at gene body linked to upregulation of TNFAIP2 and inferior OS in AML. Functional enrichment analysis indicated immunomodulation function and inflammation response of TNFAIP2 in leukemogenesis. Finally, the suppression of TNFAIP resulted in inhibition of proliferation by altering cell-cycle progression and increase of cell death by promoting early and late apoptosis in THP-1 and U937AML cells.ConclusionCollectively, the oncogenic TNFAIP2 can function as a novel biomarker and prognostic factor in AML patients. The immunoregulation function of TNFAIP2 warrants further validation in AML.

Low TINAGL1 expression is a marker for poor prognosis in breast cancer.

Tubulointerstitial nephritis antigen-like 1 (TINAGL1) was reported to suppress tumor metastasis and growth in triple-negative (TN) breast cancer. We aimed to determine the associations of TINAGL1 expression with clinicopathological factors and prognosis in breast cancer patients with long-term follow-up. A total of 599 consecutive primary invasive breast cancer patients with available tissue specimens from surgery in our hospital were included in the study. TINAGL1 mRNA expression was examined in all 599 tissue specimens using a TaqMan real-time PCR system. TINAGL1 protein expression was further examined in 299 patients with available tissue specimens for immunohistochemical staining. Survival analyses were performed using the Kaplan-Meier method and Cox proportional hazards models. The median follow-up period was 12.0years. In the total patients, low TINAGL1 mRNA expression was associated with significantly shorter disease-free survival (DFS) and overall survival than high expression (P = 0.003 and P = 0.01, respectively). Furthermore, hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer patients with low TINAGL1 mRNA expression had a worse prognosis. Multivariate analysis identified low TINAGL1 mRNA expression, combined with lymph node positivity, as an independent poor prognostic factor for DFS in invasive breast cancer patients (HR 1.41; 95% CI 1.02-1.96; P = 0.036). TINAGL1 mRNA expression also varied with menopausal status, with low TINAGL1 mRNA expression being positively associated with poor prognosis in premenopausal patients, but not in postmenopausal patients. Our findings demonstrate that TINAGL1 may be a promising candidate biomarker and therapeutic target in breast cancer patients.

Genomic Instability in Cerebrospinal Fluid Cell-Free DNA Predicts Poor Prognosis in Solid Tumor Patients with Meningeal Metastasis.

Simple SummaryWe established a genomic instability score using unfiltered sequencing data from meningeal metastasis (MM) cell-free circulating tumor DNA (ctDNA) samples and found that substantial genomic instability (GI) was present in cerebrospinal fluid ctDNA rather than plasma ctDNA, implying that MM lesions have a significantly increased GI status compared to primary tumors or extracranial metastatic lesions, which may suggest tumor clonal evolution. We also found that high GI status was an independent poor prognostic factor in lung adenocarcinoma MM patients, including meningeal metastasis-free survival (MFS) and overall survival (OS). Considering that genomically unstable tumors are more sensitive to PARP inhibitors, targeting GI alone or in combination with conventional therapy may be a promising treatment strategy for solid tumor patients with MM.Genomic instability (GI), which leads to the accumulation of DNA loss, gain, and rearrangement, is a hallmark of many cancers such as lung cancer, breast cancer, and colon cancer. However, the clinical significance of GI has not been systematically studied in the meningeal metastasis (MM) of solid tumors. Here, we collected both cerebrospinal fluid (CSF) and plasma samples from 56 solid tumor MM patients and isolated cell-free ctDNA to investigate the GI status using a next-generation sequencing-based comprehensive genomic profiling of 543 cancer-related genes. According to the unfiltered heterozygous mutation data-derived GI score, we found that 37 (66.1%) cases of CSF and 3 cases (6%) of plasma had a high GI status, which was further validated by low-depth whole-genome sequencing analysis. It is demonstrated that a high GI status in CSF was associated with poor prognosis, high intracranial pressure, and low Karnofsky performance status scores. More notably, a high GI status was an independent poor prognostic factor of poor MM-free survival and overall survival in lung adenocarcinoma MM patients. Furthermore, high occurrences of the co-mutation of TP53/EGFR, TP53/RB1, TP53/ERBB2, and TP53/KMT2C were found in MM patients with a high GI status. In summary, the GI status in CSF ctDNA might be a valuable prognostic indicator in solid tumor patients with MM.

Effect of mutation allele frequency on the risk stratification of myelodysplastic syndrome patients.

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal myeloid malignancies. Though several recurrent mutations are closely correlated with clinical outcomes, data concerning the association between mutation variant allele frequencies (VAF) and prognosis are limited. In this study, we performed comprehensive VAF analyses of relevant myeloid-malignancy related mutations in 698 MDS patients and correlated the results with their prognosis. Mutation VAF in DNMT3A, TET2, ASXL1, EZH2, SETBP1, BCOR, SFSF2, ZRSR2, and TP53 mutations correlated with outcomes. In multivariable analysis, DNMT3A and ZRSR2 mutations with high VAF and mutant IDH2, CBL, U2AF1, and TP53 were independent poor prognostic factors for overall survival. A substantial portion of patients in each revised International Prognostic Scoring System (IPSS-R) risk group could be adjusted to different prognostic groups based on the integrated VAF and mutational profiles. Patients with these unfavorable mutations in each IPSS-R risk subgroup had survivals worse than other patients of the same risk but similar to those in the next higher-risk subgroup. Furthermore, patients harboring U2AF1 mutation might benefit from hypomethylating agents. This study demonstrated the critical role of VAF of mutations for risk stratification in MDS patients and may be incorporated in novel scoring systems.

CYTOGENETIC ANALYSIS OF MYELODYSPLASTIC SYNDROME PATIENTS WITH COMPLEX KARYOTYPE IN NORTHEASTERN BRAZIL

Cytogenetic abnormalities occurs in almost half of myelodysplastic syndrome (MDS) patients and are considered to be the most important prognostic factor for survival, so they have been included in the International Prognostic Scoring System (IPSS) since 2007. Complex karyotype (CK) is defined as more than or equal to 3 independent chromosomal abnormalities at the same metaphase and is an independent poor prognostic factor, usually associated with a shorter median overall survival and propensity toward malignant transformation. From January 2008 through June 2022, 1744 patients with suspected or diagnosed hematological neoplasms (including MDS/AML) who had a bone marrow evaluation and concurrent conventional karyotype were identified. Karyotyping was successfully performed on 1167 (67%) of 1744 patients. In total, 914 (54%) with an adequate karyotypic analysis carried out a diagnosis of myelodysplastic syndrome. Among the cases, 9,7% were classified as complex karyotype. Del(5q)/-5 was identified in 52% of patients with complex karyotype, followed by chromosome 11 and chromosome 7 as well as chromosome 17 abnormalities, accounting for 38%, 23% and 23%, respectively. Besides, complex karyotype patients with translocations and derivation involvements, accounted for 28% and 14%, respectively. It is likely that pathogenetic mechanisms in del(5q) may involve hemizygous mutations or haploinsufficiency and be modified by additional somatic lesions affecting genes on other chromosomes. This report shows that the presence of deletion 5q may be the first step to the development of complex karyotype and is a determinant key of the genetic and genomic complexity and clonal hierarchy in MDS with 5q abnormalities.

ALL-056 Late Intensification With Autologous HSCT After Non-Myeloablative CEAM Conditioning Can't Improve Results of Therapy in Adults With T-Cell Acute Lymphoblastic Leukemia (ALL) Treated by Non-Intensive Protocol: Data of the Multicentral Prospective Randomized RALL Study

The Russian ALL group applied a protocol based on a less intensive and also non-interruptive approach. RALL-2009 study showed that fulfilled auto-hematopoietic stem cell transplantation (HSCT) in T-cell ALL could reliably improve disease free survival (DFS). This is a non-randomized trial, and selection is limited to patients with auto-HSCT vs chemotherapy (ChT) only. To appreciate the role of fulfilled auto-HSCT in T-ALL adult patients treated by RALL-2006 protocol. In RALL-2016 protocol all T-ALL patients who achieved complete response (CR) were brought to randomization after the informed consent to one of two groups: auto-HSCT vs ChT only. 267 Ph-negative ALL adult patients were included from Dec 2016 until Apr 2022. 111 patients had T-ALL, 74% were male, and median age was 31. 5y overall survival (OS) and DFS in T-ALL patients were 68% and 66%, respectively. We observed that early T-cell precursor (ETP)-ALL is group of patients with reliably poor prognosis, with high probability of relapse (PR) (52% in 1st year after CR). 87 T-ALL patients (pts) were randomized: 43 pts to ChT, and 44 to auto-HSCT. 1 patient refused in ChT group, and 4 refused in auto-HSCT; patients were censored on data of refuse. We observed similar number of deaths in CR in both arms, and similar cases of patients who went to allo-HSCT - mixed-lineage leukemia (MLL) leukemia, Niimegem syndrome or long MRD persistence). 25 auto-HSCT were done. For transplanted patients: time from CR to transplant was 7 months. All pts were conditioned with iomustine, etoposide, cytarabine, and melphalan (CEAM) before auto-HSCT. Maintenance start was 1.5 months after HSCT. Transplant-related mortality was 5%. Landmark analysis from a median of 7 months post-HSCT, didn't detect differences in DFS and PR (67% vs 78%, and 25% vs 22% auto-HSCT vs ChT). Auto-HSCT does not improve DFS in T-ALL with MRD after induction. In both auto-HSCT and only ChT groups with MRD persistence after induction have poor DFS (MRD-: 86% vs 81% and MRD+: 67% and 40%, respectively ChT vs auto-HSCT). We didn't detect that auto-HCST could improve long-term result for T-cell ALL. ETP-phenotype is an independent poor prognostic factor. Addition of auto-HSCT as late high-dose consolidation for T-ALL with MRD persistence does not improve results of therapy.

Salvage Mastectomy Is not the Treatment of Choice for Aggressive Subtypes of Ipsilateral Breast Cancer Recurrence: A Single-Institution Retrospective Study.

Patients with triple-negative (TN) or human epidermal growth factor 2 (HER2)-enriched ipsilateral breast cancer recurrence (IBCR) seem to be excluded from a second breast-conserving surgery (BCS) under the assumption that salvage mastectomy would provide better oncological outcomes. The objective of this study was to describe the clinical features of these patients, to compare the two surgical alternatives (salvage mastectomy versus second BCS) in terms of oncological results, and to identify independent factors influencing prognosis and surgical treatment. We retrospectively reviewed all the consecutive patients with histologically confirmed TN or HER2-enriched IBCR. Disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS) were analyzed and compared between the two groups. Eighty-five patients were affected by TN or HER2-enriched IBCR. The majority of patients (72.9%) were treated with salvage mastectomy. There was no significant difference in terms of DFS between patients receiving a second BCS or mastectomy (p = 0.596). However, patients undergoing a second BCS had significantly better DDFS, OS and BCSS compared to mastectomy (p = 0.009; p = 0.002; p = 0.001, respectively). Tumor dimension <16 mm was found to significantly increase the probability of receiving a second BCS and positively affects recurrence and survival outcomes. Salvage mastectomy represents an independent poor prognostic factor for OS and BCSS. Salvage mastectomy is not always necessary and it does not seem to increase survival compared to a second BCS. In patients with small aggressive subtypes of IBCR, a second conservative approach can still be evaluated and offered, presenting acceptable loco-regional control and survival.