Survival In Subgroup Research Articles

Survival outcomes for right- versus left-sided colon cancer and rectal cancer in patients receiving regorafenib and/or trifluridine/tipiracil for refractory metastatic colorectal cancer: Findings from the multicenter retrospective ReTrITa study.

67 Background: Several studies show that patients (pts) with colon cancer, particularly pts with right colon cancer (RCC), have lower survival rates than those with rectal cancer. This argues that colorectal cancer should be divided into three clinical entities: RCC, left colon cancer (LCC) and rectal cancer (RC). In refractory metastatic colorectal cancer (mCRC), regorafenib (R) and trifluridine/piracil (T) were found to improve survival. This real-life subgroup survival analysis focused on treatment with R and T, sequential or not, according to the above three primary tumor sites. Methods: Clinical data of pts diagnosed with mCRC and treated with R and/or T between 2012 and 2023 were retrospectively collected at 17 Italian cancer centers. The purpose of this analysis was to compare the overall survival (OS) and progression-free survival (PFS) of pts who received R and/or T as third line and beyond, according to their primary tumor site. Results: The entire ReTrITA study enrolled 1156 patients. 261 (22.5%) of them received the T/R sequence (T/R), 155 (13.4%) the reverse sequence (R/T), 427 (37%) T, and 313 (27.1%) R. For the purpose of this subgroup analysis we identified 381 RCC pts (32.9%), 531 LCC pts (45.9%) and 244 RC pts (21.2%). When comparing the groups treated with the sequential treatment, we observed a statistically significant OS improvement for pts receiving R prior to T: 17,4 vs. 12,2 months (mos) in RCC pts (HR = 0,67; 95% CI = 0,46-0,99; P = 0,0461); 16,1 vs. 15,1 mos in LCC pts (HR = 0,71; 95% CI = 0,51-1,00; P = 0,0559) and 16,6 vs. 11,4 mos in RC pts (HR = 0,57; 95% CI = 0,36-0,89; P = 0,0153). R/T sequence was also found to provide a considerable PFS benefit: 11,8 vs. 7,8 mos in RCC pts (HR = 0,53; 95% CI = 0,37-0,76; P = 0,0006); 11,7 vs. 8,9 mos in LCC pts (HR = 0,64; 95% CI = 0,47-0,88; P = 0,0071) and 10,7 vs. 8,2 mos in RC pts (HR = 0,63; 95% CI = 0,42-0,96; P = 0,0342). The non-sequential administration of R and T had no statistically significant impact on survival outcomes in the three groups. Conclusions: Our real-world subanalysis suggests that the R/T sequence significantly increases survival for pts with primary colon and rectal cancer, even after third-line treatment. Examining the pts groups treated with R and T as monotherapy based on the primary tumour site, however, did not allow us to make any significant conclusions. Treatment decisions should, however, constantly include the patient's characteristics, such as sex, ECOG PS, and the extent of metastatic disease. However, in order to verify our findings, prospective studies are required.

Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma Neurospheres.

Changes in epigenetic processes such as histone acetylation are proposed as key events influencing cancer cell function and the initiation and progression of pediatric brain tumors. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could be repurposed as an epigenetic anticancer therapy. Here, we show that VPA reduced medulloblastoma (MB) cell viability and led to cell cycle arrest. These effects were accompanied by enhanced H3K9 histone acetylation (H3K9ac) and decreased expression of the MYC oncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers and reduced MYC while increasing TP53 expression in these neurospheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and the increased expression of differentiation marker genes TUBB3 and ENO2. The expression of stemness genes SOX2, NES, and PRTG was differentially affected by VPA in MB cells with different TP53 status. VPA increased H3K9 occupancy of the promoter region of TP53. Among the genes regulated by VPA, the stemness regulators MYC and NES showed an association with patient survival in specific MB subgroups. Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in the modulation of stemness, neuronal differentiation, and the expression of genes associated with patient prognosis in specific molecular subgroups. Importantly, the actions of VPA in MB cells and neurospheres include a reduction in the expression of MYC and an increase in TP53.

Prognostic utility of gamma-glutamyl transpeptidase to platelet ratio in patients with solitary hepatitis B virus-related hepatocellular carcinoma after hepatectomy

BACKGROUND The prognostic impact of preoperative gamma-glutamyl transpeptidase to platelet ratio (GPR) levels in patients with solitary hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) following radical resection has not been established. AIM To examine the clinical utility of GPR for prognosis prediction in solitary HBV-related HCC patients. METHODS A total of 1167 solitary HBV-related HCC patients were retrospectively analyzed. GPR levels were compared with 908 non-HCC individuals. Overall survival (OS) and recurrence-free survival (RFS) were evaluated, and cox proportional hazard model analyses were performed to identify independent risk factors. Differences in characteristics were adjusted by propensity score matching (PSM). Subgroup and stratified survival analyses for HCC risks were performed, and a linear trend of the hazard ratio (HR) according to GPR levels was constructed. RESULTS GPR levels of patients with solitary HBV-related HCC were higher than those with hepatic hemangiomas, chronic hepatitis B and healthy control (adjusted P < 0.05). Variable bias was diminished after the PSM balance test. The low GPR group had improved OS (P < 0.001) and RFS (P < 0.001) in the PSM analysis and when combined with other variables. Multivariate cox analyses suggested that low GPR levels were associated with a better OS (HR = 0.5, 95%CI: 0.36-0.7, P < 0.001) and RFS (HR = 0.57, 95%CI: 0.44-0.73, P < 0.001). This same trend was confirmed in subgroup analyses. Prognostic nomograms were constructed and the calibration curves showed that GPR had good survival prediction. Moreover, stratified survival analyses found that GPR > 0.6 was associated with a worse OS and higher recurrence rate (P for trend < 0.001). CONCLUSION Preoperative GPR can serve as a noninvasive indicator to predict the prognosis of patients with solitary HBV-related HCC.

KDM1A epigenetically enhances RAD51 expression to suppress the STING-associated anti-tumor immunity in esophageal squamous cell carcinoma

Histone lysine demethylase LSD1, also known as KDM1A, has been found to regulate multiple cancer hallmarks since it was first identified in 2004. Recently, it has emerged as a promising target for stimulating anti-tumor immunity, specifically boosting T cell activity. However, it remains unclear whether and how it remodels the tumor microenvironment to drive oncogenic processes in esophageal squamous cell carcinoma (ESCC). In this study, protein levels in ESCC tissues were evaluated by immunostaining of tissue microarrays. Cell growth was assessed by colony formation assays in vitro and subcutaneous xenograft models in vivo. High-throughput transcriptomics and spatial immune proteomics were performed using bulk RNA sequencing and digital spatial profiling techniques, respectively. Epigenetic regulation of RAD51 by methylated histone proteins was analyzed using chromatin immunoprecipitated quantitative PCR assays. Finally, our clinical data indicate that KDM1A precisely predicts the overall survival of patients with early-stage ESCC. Inhibition of KDM1A blocked the growth of ESCC cells in vitro and in vivo. Mechanistically, our transcriptomics and spatial immune proteomics data, together with rescue assays, demonstrated that KDM1A specifically removes methyl residues from the histone protein H3K9me2, a transcription repressive marker, thus reducing its enrichment at the promoter of RAD51 to epigenetically reactivate its transcription. Additionally, it significantly inhibits the expression of NF-κB signaling-dependent proinflammatory genes IL-6 and IL-1B through RAD51, thus blocking the STING-associated anti-tumor immunity in stromal tumor-infiltrating lymphocytes (sTIL). Overall, our findings not only indicate that KDM1A is a promising target for ESCC patients at early stages but also provide novel mechanistic insights into its spatial regulation of STING-associated anti-tumor immunity in sTILs to drive the oncogenic processes in ESCC. The translation of these findings will ultimately guide more appropriate combinations of spatial immunotherapies with KDM1A inhibitors to improve the overall survival of specific subgroups in ESCC.

Induction chemotherapy for locally advanced nasopharyngeal carcinoma: Efficacy and safety of the TPC regimen compared to GP and TPF

Background and objectivesGemcitabine plus cisplatin (GP) and docetaxel plus cisplatin plus fluorouracil (TPF) are induction chemotherapy (IC) regimens for locally advanced nasopharyngeal carcinoma (LA-NPC). The oral convenience of capecitabine presents its potential as a fluorouracil substitute in the TPF regimen, which has yet to be thoroughly investigated. This study aims to compare the efficacy and safety of the docetaxel, cisplatin, and capecitabine (TPC) with GP and TPF in LA-NPC. MethodsA retrospective analysis was conducted on newly diagnosed stage III-IVa nasopharyngeal carcinoma patients who received GP, TPC, or TPF induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) between February 2019 and December 2021. A comparison of the prognostic outcomes and associated adverse reactions among patients receiving different IC regimens. Multivariate Cox regression was applied to analyze independent prognostic factors, and subgroup survival analyses were conducted based on these factors. ResultsA total of 291 LA-NPC patients were included, with 70 receiving TPC, 119 receiving GP, and 102 receiving TPF. Kaplan-Meier survival analysis indicated no significant differences in OS, PFS, LRFS, and DMFS among the 3 groups. Multivariate Cox regression identified T classification and clinical stage as independent prognostic factors. Subgroup analyses revealed no significant differences in OS and PFS between the 3 groups across T1-2 and T3-4 classifications or III and IVa stages.The TPC group exhibited lower incidence rates of treatment-related acute toxicity reactions, including grade 3–4 toxicities. ConclusionThe TPC induction chemotherapy regimen demonstrates comparable efficacy to GP and TPF, while maintaining a favorable safety profile.

Oncology safety of proximal gastrectomy for advanced Siewert II adenocarcinoma of the esophagogastric junction compared with total gastrectomy: a propensity score-matched analysis

ObjectiveThe safety of proximal gastrectomy (PG) for the treatment of advanced Siewert II adenocarcinoma of the esophagogastric junction (AEG) remains debatable. In this study, we aim to evaluate the oncological safety of PG and the metastasis rate of key distal lymph node dissection, which is typically excluded in PG.MethodThis study retrospective collected advanced Siewert II AEG patients who underwent gastrectomy at the First Medical Center of the General Hospital of the People’s Liberation Army (PLA) from January 2014 to December 2019. A total of 421 patients were enrolled, including 237 PG and 184 total gastrectomy (TG). Propensity score matching (PSM) in a 1:1 ratio was performed to reduce the influence of confounding variables.ResultsAfter PSM, 153 cases were matched in each group. The TG group had longer operation time, more lymph node detection and longer postoperative hospitalization time than the PG group (Both P < 0.05). The postoperative complications of the two groups were not statistically significant (P > 0.05). For long-term complications, the incidence of reflux esophagitis and anastomotic stenosis were significantly higher in the PG group than in the TG group (Both P < 0.05), but dumpling syndrome and anemia were significantly lower in the PG group compared to the TG group (Both P < 0.05). The 3-year overall survival (OS) and disease-free survival (DFS) between the two groups were no statistically significant difference (OS: 77.4% and 80.9%, P = 0.223; DFS: 69.7% and 76.1%, P = 0.063). Distal lymph node metastasis rates for No.4d, 5, and 6 were all less than 5%, and the therapeutic value index were also relatively low, with values of 1.09%, 3.26%, and 1.45%, respectively. In addition, the distal No.4d, 5, or No.6 lymph node metastasis rates were significantly higher in patients with tumor size ≥ 4 cm and T4 stage (14.29% and 23.40%) than in patients with tumor size < 4 cm and T2-3 (2.78% and 5.11%) (Both P < 0.05). The results of subgroup survival analysis showed that for patients with tumor size ≥ 4 cm or T4 stage, the TG group had better DFS compared with the PG group (HR 0.618, 0.387–0.987, P = 0.044), while no significant survival benefits were observed in other subgroups.ConclusionIn summary, for Siewert II AEG with tumor size < 4 cm and T2-3 stage, PG may be a reasonable choice with comparable oncological efficacy to TG. But for higher survival benefits, TG remains gold standard particularly for patients with tumor size ≥ 4 cm or T4 stage.

MS O12 - HPB The efficacy of CA19-9 in predicting resectability and survival in pancreatic cancer patients with jaundice: A retrospective cohort study

Abstract Background Carbohydrate antigen 19-9 (CA19-9) is the most utilised biochemical marker in pancreatic ductal adenocarcinoma (PDAC); shown to be related to resectability and prognosis. However, concurrent cholestasis, commonly seen in PDAC, can also elevate CA19-9, which may lead to unreliability and hence limit its efficacy in jaundiced patients, making management planning and prognostication more challenging. This study aims to investigate the impact of jaundice on the efficacy of CA19-9 in predicting resectability and survival in PDAC patients. Method 715 patients undergoing attempted resection for PDAC between 2010-2023 were identified from a prospectively maintained surgical database for retrospective analysis. The ability of CA19-9 to predict resectability and survival in different bilirubin sub-groups was assessed using receiver operating characteristic and Kaplan-Meier curves. Existing adjustment methodologies were applied and the curves replotted to assess their effects on the predictive efficacy of CA19-9. Multivariate analysis was then utilised to screen other potentially predictive factors which could be incorporated in the future. Results Of the 554 (77.4%) patients who underwent resection, CA19-9 predicted resectability in the first three bilirubin subgroups: ≤21 µmol/l (AUROC:0.660, 95% CI:0.551-0.769, p=0.004), 21&amp;lt;x≤130 µmol/l (AUROC:0.689, 95% CI:0.595-0.784, p&amp;lt;0.001) and 130&amp;lt;x≤315 µmol/l (AUROC:0.710, 95% CI:0.614-0.807, p&amp;lt;0.001). However, CA19-9 did not predict resectability in patients with bilirubin levels &amp;gt;315 µmol/l (AUROC:0.579, 95% CI:0.452-0.707, p=0.222). CA19-9 was a significant predictor of overall survival in the non-jaundiced (p=0.048) cohort but did not predict survival in patients with bilirubin levels &amp;gt;21 µmol/l. Existing adjustment methodologies did not improve predictive efficacy of CA19-9 for resectability or prognosis. Conclusion These findings support the prospect of decreased ability of CA19-9 to predict resectability and survival in PDAC patients with jaundice. Further investigation is required to find a method of adjusting CA19-9 values based on jaundice to aid diagnostic and treatment decision making.

Mild intracerebral bleeding does not adversely affect survival and neurological outcome of surgical therapy for left-sided infective endocarditis

Abstract Background Intracerebral bleeding (IB) is a serious condition that requires increased attention and has implications for treatment options. For patients with infective endocarditis (IE), current guidelines recommend postponing surgery if IB is present. IB can be classified into four relevant groups (following European Cooperative Acute Stroke Study and Heidelberger Bleeding classification): hemorrhagic transformation (HT) 1 and 2, and parenchymal hemorrhage (PH) 1 and 2. PH2 is the only IB with neurological deterioration. These classifications were originally introduced for stroke patients following thrombolysis but without IE. The hypothesis tested in our study is that IB may influence IE treatment and thus outcome. Method Patients were retrospectively identifyied who were operated for left-sided IE, neuroradiologists re-evaluated and classified preoperative cerebral imaging for any IB. Outcome was quantified using the modified Rankin score (mRS), and mRS were extracted from the patients’ hospital chart at admission and by follow-up telephone call (FU), also including mortality. To ensure that the influence of IB was comparable, patients with IB (IB+) were propensity matched (EuroScore 2, Charlson Comorbidity Index, C-reactive protein; nearest neighbor match) to patients without IB (IB-) who also received surgical IE therapy. All IB+ patients underwent a careful risk-benefit analysis before therapy. Results Of 286 consecutive patients (January 2015 - November 2022) operated for left-sided IE, 36 had IB (65±13 years, 26% female): 11 with HT1, 9 with HT2, 8 with PH1, and 8 with PH2. These patients were matched with 36 operated IB- patients. Survival analysis showed no overall effect of IB+ vs. IB- (p = 0.112, 95% CI of hazard ratio was 0.246-1.243 vs. 0.709-3.572). Although there was no effect of IB on survival in the mild IB subgroup (HT1/2, Figure A), there was a difference in patients with severe IB (PH1/2) with less survival in IB+ (Figure B). Neurological outcome (ΔmRS) showed an effect of IB grade in the two-way ANOVA analysis (p = 0.029). Intergroup comparison showed a significantly better outcome for IB- (vs. IB+) in the PH2 subgroup (p = 0.034), but not in other subgroups. For all groups, the mean ΔmRS for IB+ was 1.1±1.6 vs. 0.70±1.4 for IB- (p = 0.256). The mean FU time was 2.6±2.1 years. Conclusion In patients operated for left-sided IE, mild IB did not affect survival or neurological outcome. In the more severe forms of IB, i.e. PH1 and PH2, survival was less favorable compared to matched controls. Furthermore, we observed a difference in neurological outcome in patients with severe IB. Thus, surgical therapy of left-sided IE should be avoided in patients with severe IB, whereas we can add evidence to the safety of surgical therapy in mild IB. Therefore, we recommend regular assessment of the degree of IB in such patients.Figure

CMR phenotypes and clinical outcomes in NYHA class I versus II-IV hypertrophic cardiomyopathy: identifying high-risk asymptomatic patients

Abstract Background Cardiac myosin inhibition therapy can deliver symptomatic benefit for NYHA class≥II patients with obstructive hypertrophic cardiomyopathy (HCM) and is being actively explored for non-obstructive phenotypes. However, expanding interest in clinical outcome reduction supports growing need to identify high risk cohorts across both symptomatic and asymptomatic cohorts. We aimed to examine phenotypic characteristics of NYHA-I versus NYHA≥II patients with HCM and their association with future outcomes. Methods 727 patients with HCM from the CIROC Registry who completed simultaneous CMR and patient health assessments, inclusive of NYHA evaluation and quality of life surveys, were studied. Baseline clinical and CMR characteristics were compared between NYHA-I and NYHA≥II cohorts, followed by risk modelling for the prediction of major adverse cardiovascular events (MACE), defined as: all-cause mortality, heart failure hospitalization, ventricular arrhythmia, new onset atrial fibrillation, or stroke. Cox models were constructed to identify independent predictors of MACE. Results Of the 727 patients, 546 (75%) reported NYHA-I and 181 (25%) NYHA≥II symptoms. Baseline characteristics are shown in Table 1. Compared to NYHA≥II, NYHA-I patients were younger, more likely male, and had a lower prevalence of diabetes and hypertension. No meaningful differences in CMR chamber volumes, function, left ventricular (LV) mass, or fibrosis burden were observed. Over a median follow up of 3.7 years, 109 patients (15%) experienced MACE: 12% in NYHA-I and 23% in NYHA≥II sub-groups (p&amp;lt;0.001). Baseline LV mass z-scores (determined from sex-matched, BSA-indexed SCMR healthy reference values) were independently associated with MACE by multivariable Cox modelling. An optimal LV mass z-score threshold of 3.9 for prediction of MACE was identified and combined with NYHA status to stratify patients into 4 categories. Kaplan-Meier curves showed patients with LV Mass z-scores &amp;gt;3.9 experienced worse event-free survival in both NYHA sub-groups (Figure 1a). Cox modelling in the overall cohort (Figure 1b) showed NYHA-I patients with LV Mass z-scores &amp;gt;3.9 experienced a 2.2-fold increased risk (p=0.007) of MACE, this exceeding the risk of NYHA ≥II patients below this threshold. Separate NYHA I and ≥II sub-group multivariable models showed LV Mass z-score &amp;gt;3.9 to remain a strong and independent predictor of MACE, providing respective hazards of 2.6 and 4.7 (p=0.001 and &amp;lt;0.001). Conclusions NYHA-I patients with HCM experience significantly lower rates of MACE versus NYHA≥II. However, LV mass z-scoring permits powerful sub-stratification of these sub-groups, identifying NYHA-I patients with higher LV mass who will experience worse outcomes versus NYHA≥II patients with lower LV mass. This simple yet powerful stratification offers unique potential to identify asymptomatic patients with HCM who may benefit from targeted therapeutics to reduce future MACE.

Gender differences in long-term survival after coronary artery bypass surgery is womens cardiovascular health at risk?

Abstract Introduction Cardiovascular healthcare for women tends to be influenced by various factors. This patient group is generally associated with a worse prognosis following coronary artery bypass surgery (CABG). Aims To assess the impact of gender on long-term survival after CABG and the potential effect of age on this association; to compare the survival of these patients with the expected survival of the general national population, and to compare immediate postoperative outcomes between genders. Methods Longitudinal, retrospective, single center study, involving consecutive patients who underwent isolated primary CABG between 2004 and 2014. Exclusion criteria included emergency/salvage surgeries or the use of extracorporeal circulation without aortic clamping. Included patients were categorized into age subgroups: ≤60, 60-70, and ≥70 years. All-cause mortality was assessed in February 2023, and a time-to-event analysis was performed using Kaplan-Meier curves, Log-Rank tests, and multivariable Cox regressions. To compare expected mortality (matched for sex and age with the general population) with observed mortality in the patient cohort, survival tables for the years 2004-2022 were consulted. Kaplan-Meier curves for the reference population, stratified by gender, were constructed and compared to the surgical cohort using one-sample Log-Rank tests with specific software. Standardized mortality ratios (SMR) were estimated. The mean follow-up time was 11 years, with a maximum of 19 years. Results From 3978 patients included patient’s, 21% were women (W). W were older (mean age 67±9 vs. 63±10 years, p&amp;lt;0.001) and had a higher prevalence of cardiovascular risk factors and severe chronic kidney disease compared to men (M). M more frequently had peripheral arterial disease and smoking habits. Although three-vessel disease was similar between sexes (p=0.111), W were less frequently implanted with ≥3 grafts (p&amp;lt;0.001). At 5,10 and 15 years of follow-up, cumulative survival for MvsW was 89%vs88%, 73%vs68%, and 57%vs46%, respectively (Log-rank test p&amp;lt;0.001). After stratification by age, Log-Rank tests showed no differences between sexes. Multivariable adjustment did not identify gender as an independent predictor of long-term survival in any age subgroup. However, a time-stratified analysis at 10 years of follow-up in the ≥70 years subgroup showed that W had a higher risk than M after 10 years of follow-up (HR:0.7[0.5-0.9],p=0.03). Comparing with the survival of the Portuguese population, CABG allowed M to equalize the risk of mortality to what was expected (SMR =1.1;95%CI:0.9-1.1), but W showed a higher risk of mortality after CABG than W in the reference population (SMR =1.6,95%CI:1.3-1.8). Conclusion Women undergoing isolated primary CABG at an age &amp;gt;70 years, with longest periods follow-up, exhibited poorer long-term survival than men of the same age.Women demonstrated inferior survival outcomes compared to the general population.

Changing patterns in clinical, echocardiographic and haemodynamic characteristics, and management strategies that may be translated to improved survival in pulmonary hypertension

Abstract Background and aims In this retrospective analysis of a single-center series on pulmonary hypertension (PH), we aimed to evaluate clinical, echocardiographic, and hemodynamic characteristics, management strategies, morbidity, and mortality in PH subgroups across three consecutive periods. Methods The study included 1071 patients enrolled in the Evaluation of Pulmonary Hypertension Risk factors Associated with Survival study (EUPHRATES). In reference to enrollment time, patients were assessed in three periods ; before 2016, the era of primarily monotherapy or sequential combinations; between 2016 and 2019, post-approval and reimbursement of macitentan in our country, marking a shift towards more proactive sequential combinations; and after 2019, signifying the initiation of earlier sequential combinations with selexipag in pulmonary arterial hypertension (PAH). The ESC/ERS 2022 risk scoring, COMPERA 2.0 and REVEAL lite 2 models were used for risk predictions. Composite endpoint (CEP) definitions were adopted from the SERAPHIN and GRIPHON trials. Annual incidence curves for mortality and CEP were evaluated, but 2020 analysis was adjusted to account for the possible adverse effects of the COVID-19. Results During the 1st, 2nd and 3rd periods, 481, 352, and 238 patients with PH were diagnosed, respectively. Incident cases comprised 91% of them. Idiopathic PAH (IPAH), PAH-associated with congenital heart diseases (CHD-PAH), PAH-associated with connective tissue diseases (CTD-PAH), group II, III, IV and V PH were documented in 24 %, 28 %, 4.6 %, 4.3 %, 11%, 27 % and 0.7 % of patients, respectively. Age and female dominance remained unchanged. Incidences of Group 1 PH and CHD-PAH decreased while IPAH, drug-associated PAH, and Group II and IV PH increased across three periods (p-values varying from &amp;lt;0.001 to 0.03). Although baseline functional class became worse (p=0.013), six-minute walk distance, N-terminal pro brain natriuretic peptide and risk scores showed no change (p=NS). Baseline echo and hemodynamic measures became better, and triple combinations increased after 2019 (p&amp;lt;0.001 for all). For overall PH, rates of all-cause mortality and CEPs at 1st, 2nd and 3rd periods were 52 % and 59 %, 30 % and 35 %, and 11 % and 13 %, respectively (p&amp;lt; 0.001, for all). Mortality rates for 1st, 2nd and 3rd periods were 36 %, 38 % and 26 % in IPAH, 60 %, 28 % and 13 % in CHD-PAH, 55 %, 22% and 22% in CTD-PAH, 38 %, 38% and 24 % in group IV PH, respectively (p&amp;lt; 0.001, for all). Mortality curves showed sudden increases in 2020, but excluding 2020, a steady improvement in the annual mortality was evident. Conclusions Our findings suggest a trend towards better clinical, echocardiographic, and hemodynamic presentations and improved survival in the PAH subgroups, and Group IV PH across the three periods that might be attributed to more proactive management strategies favouring earlier initiation of combinations.

Survival in patients with chronic congestive heart failure and correlation of presence of risk factors and all-cause mortality

Abstract Background Right heart function is known to be an independent risk factor for early mortality in patients with acute and chronic heart failure (HF). The prognostic value of cardiopulmonary exercise testing (CPET) is established for risk stratification in patients with Heart Failure. Further, markers of inflammation may predict clinical outcomes. Purpose We performed a single-center retrospective analysis of a large single center cohort and assessed all-cause mortality. A simple score including presence of RVD, systemic inflammation and reduced O2 uptake was applied to all patients and a subgroup survival analysis was performed. Methods A total of 612 patients with HF across the whole spectrum of left ventricular ejection fraction (LVEF) were analyzed. We stratified patients according to RV function, peak relative oxygen consumption in ml/min/kg (VO2max) and CRP levels. Patients were classified as RV Dysfunction when a right ventricular dilation (RVEDD &amp;gt; 40 mm or RVOT &amp;gt; 30 MM) or decreased tricuspid annular systolic excursion (TAPSE &amp;lt; 17 mm) was seen in the echocardiography. All patients were followed up by phone or by hospital records if available. The primary end-point of all-cause mortality was assessed. Results For the primary analysis, 612 patients (mean age 59.8 ± 13.8 years, 71.41% male) were included. According to LVEF 248 (40.5%) patients had preserved LVEF (HFpEF), 82 (13.0%) had mid-range LVEF (HFmrEF) and 282 (46.0%) had reduced LVEF (HFrEF). HF etiology was in 27% ischemic. Mean BNP values were 514.1 ± 827.1 pg/l. Mean VO2max 15,9 ± 5,9 ml/min per kg. Patients were followed up for a median of 4.0 years (IQR: 3.4 - 4.9 years). Over this period, the primary end-point occurred in 17.6% of patients. 135 (22%) of patients had evidence of RV dysfunction, 26% had increased CRP-levels and 256 (41.8%) had a VO2max &amp;lt; 14 ml/min per kg. Patients with elevated CRP, VO2max &amp;lt; 14 ml/min/kg and RV-dysfunction showed worse survival according to the Kaplan-Meier-Estimate with a significant difference (Log Rank: Chi²: 1480, p = 0.013) compared to patients with only RV dysfunction low VO2 max or only increased CRP values. Conclusion A combined evaluation of systemic inflammation, cardiopulmonal exercise testing and right ventricular dysfunction is useful in predicting long-term outcomes of patients with HF. Patients with both risk factors show worse survival than patients with signs of inflammation or RV dysfunction only.Kaplan-Meier-Estimates

Is Carmustine Wafer Implantation in Progressive High-Grade Gliomas a Relevant Therapeutic Option? Complication Rate, Predictors of Complications and Onco-Functional Outcomes in a Series of 53 Cases.

Background/Objectives: The aim was to determine the complication rate and the predictors of complications and survival in high-grade glioma surgically managed at progression with implantation of Carmustine wafers. Methods: A retrospective series of 53 consecutive patients operated on between 2017 and 2022 was built. Results: The median age was 55 ± 10.9 years. The rates of global and infectious complications were 35.8% and 18.9%, respectively. In multivariate analysis, patients with a preoperative neurological deficit were more prone to develop a postoperative complication (HR = 5.35 95% CI 1.49-19.26, p = 0.01). No predictor of infectious complication was identified. In the grade 4 glioma subgroup (n = 44), progression-free and overall survival (calculated starting from the reresection) reached 3.95 months, 95% CI 2.92-5.21 and 11.51 months, 95% CI 9.11-17.18, respectively. Preoperative KPS > 80% (HR = 0.97 95% CI 0.93-0.99, p = 0.04), Gross Total Resection (HR = 0.38 95% CI 0.18-0.80, p = 0.01), and 3-month postoperative KPS > 80% (HR = 0.35 95% CI 0.17-0.72, p = 0.004) were predictors of prolonged overall survival. Conclusions: Surgical resection is a relevant option in high-grade gliomas at progression, especially in patients with a preoperative KPS > 80%, without preoperative neurological deficit, and amenable to complete resection. In patients elected for surgery, Carmustine wafer implantation is associated with a high rate of complications. It is consequently critical to closely monitor the patients for whom this option is chosen.

Lymph node ratio–based model for predicting survival and assessing the benefit of adjuvant chemotherapy in postoperative duodenal adenocarcinoma

BackgroundThis study aimed to evaluate the prognostic significance of lymph node ratio in postoperative duodenal adenocarcinoma and develop a nomogram-based model for prognosis assessment and treatment optimization. MethodsClinical information of patients with duodenal adenocarcinoma were retrieved from the Surveillance, Epidemiology, and End Results database, and prognostic factors were identified by univariate and multivariable analyses. Prognostic factors influencing patient outcomes were identified using univariate and multivariable Cox analyses. Subsequently, a novel nomogram and risk stratification system were developed based on these identified factors. ResultsA total of 943 eligible patients were included, with 656 in the training cohort and 287 in the validation cohort. Lymph node ratio ≥0.12 were associated with poorer overall survival (hazard ratio 1.562, 95% confidence interval 1.195–2.041, and P = .001 for lymph node ratio = 0.12–0.30; hazard ratio 2.431, 95% confidence interval 1.847–3.199, and P < .001 for lymph node ratio >0.30). Prognostic factors including age at diagnosis, race, T stage, lymph node ratio, and tumor size were integrated into the nomogram. Patients in the low-risk group demonstrated significantly better overall survival compared with those in the high-risk group. Additionally, adjuvant chemotherapy significantly improved overall survival in the high-risk subgroup, whereas low-risk patients might be exempt from adjuvant chemotherapy. ConclusionsThis study represented the pioneering endeavor in introducing a lymph node ratio–based nomogram model for prognosis stratification and adjuvant chemotherapy decision-making protocol for patients with duodenal adenocarcinoma, thereby guiding personalized treatment strategies and minimizing overtreatment.

Up-regulation of MSMO1 was associated with poor survival in cervical cancer.

Methylsterol monooxygenase 1 (MSMO1) catalyzes C4-methylsterols demethylation in cholesterol biosynthesis pathway. MSMO1 is increased and up-regulation of MSMO1 is correlated with progression of some tumor. But the correlation of MSMO1 to cervical cancer is unknown. The current study aimed to explore the expression pattern of MSMO1 in cervical cancer and its correlation to clinical characteristics. In this study, 306 cervical cancer cases and 13 non-tumor cases were included. We compared MSMO1 expression level in non-tumor cervical tissues and cervical cancer samples using the Wilcoxon rank sum test. Univariate regression was used to investigate the correlation between MSMO1 expression as well as other clinical characteristics and prognosis. Clinical characteristics associated with prognosis in univariate analysis were used as adjustments for multivariate analysis to further validate the relationship between MSMO1 expression and cervical cancer prognosis. Patients' survival in different subgroups was compared by Kaplan-Meier (KM) method. The potential protein interaction was analyzed. T cell infiltration level in MSMO1 high and low group patients was compared. MSMO1 expression level was up-regulated in cervical cancer (P<0.001). Patients who had stage III-IV diseases (P=0.04) and did not achieve complete response after primary treatment had higher MSMO1 expression (P<0.001). High MSMO1 expression patients showed a lower overall survival (OS) (P=0.004), disease-specific survival (DSS) (P=0.004) and progression-free survival (PFS) (P=0.002). High MSMO1 expression was a risk factor to OS (P=0.01), DSS (P=0.009) and PFS (P=0.009). Multiple variate analysis showed that high MSMO1 expression was an independent risk factor to OS [hazard ratio (HR) =1.902, 95% confidence interval (CI): 1.156-3.129, P=0.01], DSS (HR =2.172, 95% CI: 1.210-3.897, P=0.009) and PFS (HR =1.975, 95% CI: 1.189-3.282, P=0.009) in cervical squamous cell carcinoma (CESC). The prognostic value of high MSMO1 expression was further examined in other databases, including KM-plotter, Gene Expression Profiling Interactive Analysis (GEPIA) and Gene Expression Omnibus (GEO) database. The current research showed that MSMO1 was increased and was associated with poor prognosis in CESC.

Immunotherapy in operable non-small cell lung cancer: a systematic review and network meta-analysis of efficacy between neoadjuvant immunochemotherapy and perioperative immunotherapy.

A series of randomized controlled trials (RCTs) have demonstrated the promising prospect of immunotherapy in operable non-small cell lung cancer (NSCLC) and further changed the clinical practice. However, current studies still yet to answer which immunotherapy mode is the optimal strategy, and there is currently a lack of direct comparison between neoadjuvant immunochemotherapy and perioperative immunotherapy ("sandwich mode", including neoadjuvant immunochemotherapy and adjuvant immunotherapy). Thus, we conducted a network meta-analysis (NMA) to evaluate the efficacy between neoadjuvant immunochemotherapy and perioperative immunotherapy. We performed a Bayesian NMA (PROSPERO registration number: CRD42024495955) by retrieving relevant eligible studies from PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, and major international conferences until December 31, 2023. Phase II or III RCTs that evaluated the efficacy of different strategies of immunotherapy in operable NSCLC, including neoadjuvant immunochemotherapy and perioperative immunotherapy ("sandwich mode"), were retrieved for analysis. The patients were grouped into neoadjuvant chemotherapy alone (arm A), neoadjuvant immunotherapy plus chemotherapy (arm B); neoadjuvant immunotherapy plus chemotherapy followed by surgery and adjuvant immunotherapy (arm C), respectively. The endpoint was event-free survival (EFS) in different subgroups. Seven studies of 2,934 patients were selected for this NMA finally. Compared with neoadjuvant chemotherapy, both neoadjuvant immunochemotherapy [hazard ratio (HR) 0.61, 95% confidence interval (CI): 0.36-0.98] and perioperative immunotherapy (HR 0.56, 95% CI: 0.42-0.71) significantly improved the EFS in intention-to-treat population, but there was no statistical difference between these two treatments (HR 1.1, 95% CI: 0.62-1.9). There was no statistical difference between perioperative immunotherapy and neoadjuvant immunochemotherapy in all subgroup analysis of EFS. However, in patients with non-squamous disease, programmed cell death-ligand 1 (PD-L1) expression more than 50%, or stage III disease, both neoadjuvant immunotherapy [(HR 0.50, 95% CI: 0.26-0.97), (HR 0.24, 95% CI: 0.061-0.96), (HR 0.50, 95% CI: 0.39-0.63)] and perioperative immunotherapy [(HR 0.64, 95% CI: 0.46-0.87), (HR 0.40, 95% CI: 0.21-0.71), (HR 0.54, 95% CI: 0.34-0.85)] improved EFS significantly compared with neoadjuvant chemotherapy. Both neoadjuvant immunochemotherapy and perioperative immunotherapy significantly increased EFS compared with neoadjuvant chemotherapy. There is no evidence that perioperative immunotherapy is better than neoadjuvant immunochemotherapy in EFS. Patients with non-squamous disease, PD-L1 expression more than 50%, or stage III disease can try the neoadjuvant immunochemotherapy mode.

Role of PET/CT in improving the cost effectiveness of nimotuzumab in nasopharyngeal carcinoma.

This study aims to use the maximum standardised uptake value (SUVmax) of 18F-fluorodeoxyglucose positron emission tomography to improve the cost effectiveness of nimotuzumab (NTZ) in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Two hundred and forty-eigh patients with LA-NPC, who met the inclusion criteria, were recruited from January 2012 to June 2019. The survival differences and independent factors were assessed using the Kaplan-Meier method and by Cox proportional hazards regression analysis. A cost effectiveness analysis was performed. The optimal cut-off value for SUVmax was 12.92. Multivariable analysis indicated a prognostic significance of overall survival (OS) for the NTZ treatment (p = 0.023) and SUVmax (p = 0.014). The exploratory subgroup survival analysis revealed that LA-NPC patients with SUVmax > 12.92 treated with concurrent chemoradiotherapy (CCRT) and NTZ had a significantly improved 3-year OS compared to patients treated with CCRT alone (96.2 vs 73.2%, p = 0.047). Furthermore, the treatment cost for NTZ was $6,317.61. This incurred an additional cost of $274.68 for every 1% increase in OS. For patients with LA-NPC with SUVmax > 12.92, the addition of NTZ to CCRT can improve OS and is cost effective.

Identification of DLAT as a potential therapeutic target via a novel cuproptosis-related gene signature for the prediction of liver cancer prognosis.

The prognosis for liver cancer (LC) is dismal. Researchers recently discovered cuproptosis, a novel form of controlled cell death whose expression in LC and prognosis are unclear. This study reveals a gene signature to predict LC prognosis. RNA and clinical data for 371 LC patients were obtained from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) were identified by comparing cancerous and normal samples. Genes linked to overall survival (OS) were found using univariate Cox regression and least absolute shrinkage and selection operator (LASSO). The gene signature was validated across all patients. Gene expression and clinical traits were analyzed, and Kaplan-Meier (KM) curves were generated for high- and low-risk groups. DEGs were used for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), immune infiltration, and drug prediction analyses. DLAT's functions were assessed using real-time polymerase chain reaction (RT-PCR), transwell invasion, Cell Counting Kit-8 (CCK-8), colony formation, and drug resistance assays. A total of 12 cuproptosis regulators were discovered in LC and normal liver tissues. A 3-gene signature based on LASSO Cox regression was utilized to categorize TCGA LC patients into low- and high-risk categories. Low-risk patients exhibited better survival than high-risk patients (P<0.05). Tumor grade, stage, and T stage differed between high- and low-risk groups. Long-term prognosis was well predicted by male subgroup survival studies. We predicted LC patient survival using sex, tumor grade, tumor stage, and risk score. Functional enrichment showed that extracellular matrix (ECM) architecture, channel function, and tumor-associated pathways were enriched in LC, suggesting that cancer related functions were collected. Immune microenvironment inhibition was found in the high-risk group suggesting that immunosuppression was closely related. We also discovered five small molecules that could be potentially useful for LC treatment. DLAT was discovered to promote the migration and proliferation of LC cells and is connected to drug resistance as a prognostic marker. Cuproptosis-related genes contribute to tumor development and can aid the prediction of LC patient prognosis. DLAT is a potential LC prognostic and therapeutic target.

Effect of laterality on the postoperative survival of non-small cell lung cancer patients undergoing pneumonectomy.

Pneumonectomy is one of the important surgical methods for non-small cell lung cancer (NSCLC). This study evaluated the effects of laterality on the short- and long-term survival of NSCLC patients undergoing pneumonectomy. We reviewed the Surveillance, Epidemiology, and End Results database to retrieve the data of patients who underwent pneumonectomy for stage I-III NSCLC from 2004 to 2015. Propensity score matching (PSM) was used to reduce the selection bias. Logistic regression was used to analyze the correlation between laterality and mortality at 3, 6, and 9 months. The Kaplan-Meier curve was used to further assess the effect of laterality on overall survival (OS). A total of 4,763 patients met the enrollment criteria [right-sided, 1,988 (41.7%); left-sided, 2,775 (58.3%)]. After PSM, 1,911 patients for each side were included in the further analysis. The first 6 months following pneumonectomy was the main period of death, with 32.0% (428/1,336) and 19.9% (250/1,258) of right- and left-sided deaths occurring during this period. The logistic regression analysis showed that right-sided pneumonectomy was an independent risk factor for 3- (P<0.001) and 6-month (P<0.001) mortality. However, laterality had no significant effect on postoperative death at 7-9 months (P=0.82). In the total cohort, right-sided patients had worse OS (P<0.001), but the subgroup survival analysis of patients with a follow-up period >6 months revealed that laterality had no statistically significant effect on OS (P=0.75). Right-sided pneumonectomy was associated with a higher perioperative mortality risk that lasted about 6 months. After that period, laterality was not observed to have a significant prognostic effect on the OS of patients undergoing pneumonectomy.

Modulation of Stemness and Differentiation Regulators by Valproic Acid in Medulloblastoma.

Changes in epigenetic processes such as histone acetylation are proposed as key events influencing cancer cell function and the initiation and progression of pediatric brain tumors. Valproic acid (VPA) is an antiepileptic drug that acts partially by inhibiting histone deacetylases (HDACs) and could be repurposed as an epigenetic anticancer therapy. Here, we show that VPA reduced medulloblastoma (MB) cell viability and led to cell cycle arrest. These effects were accompanied by enhanced H3K9 histone acetylation (H3K9ac) and decreased expression of the MYC oncogene. VPA impaired the expansion of MB neurospheres enriched in stemness markers, and reduced MYC while increasing TP53 expression in these spheres. In addition, VPA induced morphological changes consistent with neuronal differentiation and increased expression of differentiation marker genes TUBB3 and ENO2. Expression of stemness genes SOX2, NES, and PRTG was differentially affected by VPA in MB cells with different TP53 status. VPA increased H3K9 occupancy of the promoter region of TP53. Among genes regulated by VPA, stemness regulators MYC and NES showed association with patient survival in specific MB subgroups. Our results indicate that VPA may exert antitumor effects in MB by influencing histone acetylation, which may result in modulation of stemness, neuronal differentiation, and expression of genes associated with patient prognosis in specific molecular subgroups. Importantly, the actions of VPA in MB cells and neurospheres include a reduction in expression of MYC and increase in TP53.