Additional Survival Benefit Research Articles

Stenotrophomonas maltophilia bacteremia in adult patients with hematological diseases: clinical characteristics and risk factors for 28-day mortality.

Patients with hematological diseases are at high risk for Stenotrophomonas maltophilia (SM) bacteremia. This study retrospectively analyzed the clinical characteristics and risk factors for 28-day mortality among 140 adult hematological patients diagnosed with SM bacteremia from January 2012 to July 2023. he overall 28-day mortality was 31.43% (44/140), with a median age of 44 years. The median hospital stay before SM bacteremia onset was 25 days, and 69.29% of patients had unresolved neutropenia. All patients had received broad-spectrum antibiotics in the past month, and 69.29% developed breakthrough bacteremia during carbapenem therapy. Independent risk factors for mortality included a Sequential Organ Failure Assessment (SOFA) score ≥5, tigecycline exposure, age ≥60, and pulmonary infection. Patients with ≥2 risk factors were stratified into the high-risk group, with a significantly higher 28-day mortality compared with the low-risk group (56.52% vs 7.04%, P < 0.001). Treatment with trimethoprim-sulfamethoxazole (TMP/SMX) (P = 0.008) or TMP/SMX combined with cefoperazone/sulbactam (CSL) (P = 0.005) was associated with survival benefits among high-risk patients. Overall, SM bacteremia usually occurs in hematological patients with prolonged hospitalization, unresolved neutropenia, and extensive use of broad-spectrum antibiotics, especially carbapenems. Patients with high SOFA scores, advanced age, pulmonary infection, or recent tigecycline exposure are at higher risk of mortality. The preferred treatment is TMP/SMX rather than fluoroquinolones, with combination therapy of TMP/SMX and CSL considered a feasible treatment option.IMPORTANCEThis study, representing the largest cohort of adult hematological patients with SM bacteremia to date, strengthens the validity of existing findings and provides new insights into its clinical management. We identify risk factors for 28-day mortality, revealing that patients with two or more risk factors experience particularly high mortality rates. This highlights the importance of early identification and targeted management of high-risk individuals. Our findings also demonstrate that TMP/SMX is superior to fluoroquinolones and suggest that combining TMP/SMX with CSL may offer additional survival benefits.

Gliocidin is a nicotinamide-mimetic prodrug that targets glioblastoma.

Glioblastoma is incurable and in urgent need of improved therapeutics1. Here we identify a small compound, gliocidin, that kills glioblastoma cells while sparing non-tumour replicative cells. Gliocidin activity targets a de novo purine synthesis vulnerability in glioblastoma through indirect inhibition of inosine monophosphate dehydrogenase 2 (IMPDH2). IMPDH2 blockade reduces intracellular guanine nucleotide levels, causing nucleotide imbalance, replication stress and tumour cell death2. Gliocidin is a prodrug that is anabolized into its tumoricidal metabolite, gliocidin-adenine dinucleotide (GAD), by the enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) of the NAD+ salvage pathway. The cryo-electron microscopy structure of GAD together with IMPDH2 demonstrates its entry, deformation and blockade of the NAD+ pocket3. In vivo, gliocidin penetrates the blood-brain barrier and extends the survival of mice with orthotopic glioblastoma. The DNA alkylating agent temozolomide induces Nmnat1 expression, causing synergistic tumour cell killing and additional survival benefit in orthotopic patient-derived xenograft models. This study brings gliocidin to light as a prodrug with the potential to improve the survival of patients with glioblastoma.

Role of Adjuvant Chemotherapy After Surgical Resection of Paraaortic Lymph Node Metastasis from Colorectal Cancer-A Multicenter Retrospective Study.

Surgical removal of metastasized paraaortic lymph nodes (PALNs) can prolong the survival of certain patients with colorectal cancer (CRC). However, the role of postoperative chemotherapy in such patients remains unknown. This multicenter retrospective study examined 97 patients with PALN metastasis from CRC who underwent surgical resection at 36 centers in Japan between 2010 and 2015. On the basis of adjuvant chemotherapy (AC) after the lymphadenectomy, patients were classified into non-AC and AC groups (27 and 70 patients, respectively). After the exclusion of patients receiving irinotecan, the latter group was further categorized into 5-fluorouracil (5-FU) and oxaliplatin (L-OHP) subgroups (14 and 52 patients, respectively) according to the use of L-OHP. Background characteristics and postoperative survival were compared among the groups. Marked differences were not seen in background characteristics, except for neoadjuvant treatment, between the non-AC and AC groups. The AC group exhibited better recurrence-free survival (RFS; p = 0.009) and overall survival (OS; p = 0.040 by the Wilcoxon test) than the non-AC group. However, RFS and OS of the 5-FU group did not differ from those of the L-OHP group (p = 0.73 and p = 0.92 by the Wilcoxon test, respectively). AC may be associated with improved prognosis of patients after the removal of PALN metastasis from CRC, but L-OHP did not offer additional survival benefits. Prospective studies comparing non-AC with 5-FU- and L-OHP-based AC are needed to confirm these findings.

EXTH-09. GENE MODIFICATION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS FOR IMPROVEMENT OF IMMUNOTHERAPIES FOR MALIGNANT GLIOMAS

Abstract Patients living with high-grade gliomas have a poor survival prognosis. Furthermore, standard of care treatment for these malignant gliomas has not significantly improved in the past decades. Our laboratory previously demonstrated that the combination of two different immunotherapies with HSPCs provided a significant survival benefit in preclinical brain tumor models, however, this therapeutic combination is still not 100% curative. We hypothesized that gene modification of HSPCs could add additional therapeutic benefit to immunotherapies for the treatment of resistant gliomas. Hematopoietic stem and progenitor cells (HSPCs) have been widely used in different clinical settings due to their ability to self-renew and differentiate into all immune cell lineages. In recent years, HSPCs have been the target of a variety of gene editing research efforts to decipher the most effective method for gene modification to use for therapeutic purposes. After comparison with previously established methods, we optimized a protocol for the successful editing of murine HSPCs and human CD34+ cells. Using Cas9 mRNA and sgRNAs in HSPCs, we achieved up to 80% reduction in gene expression. This method is superior to others due to its efficient, quick, inexpensive, and reliable nature. We also showed that, by knocking-down IL-6R in HSPCs, we can drive their differentiation into dendritic cells, while decreasing MDSCs and macrophages. Furthermore, gene-modified HSPCs are also capable of bone marrow reconstitution of lethally irradiated mice. Currently, we are testing whether the combination of gene-modified HSPCs with immunotherapy provides additional survival benefit to unmodified HSPCs with immunotherapy in a resistant murine glioma model.

Efficacy and safety of osimertinib plus bevacizumab versus osimertinib alone for advanced non-small-cell lung cancer with EGFR mutations: A meta-analysis of randomized controlled trials.

To systematically evaluate the efficacy and safety of osimertinib plus bevacizumab in treating advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Up to May 26, 2024, the databases of PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, Chinese Biomedical Literature, China Science and Technology Journal, and Wanfang were searched, and the randomized controlled clinical trials (RCTs) of osimertinib plus bevacizumab in the treatment of advanced EGFR-mutant NSCLC were included. Two researchers independently screened the literature, assessed the quality of the included literature, and extracted the literature data. Revman5.4 software was used for meta-analysis. A total of 824 patients were included in 10 RCTs. The results of meta-analysis showed that compared with the control group (osimertinib alone), the experimental group (osimertinib plus bevacizumab) had a higher objective response rate (ORR) (relative risk [RR] = 1.23, 95% confidence interval [CI] = 1.03-1.47, P = .02), and the experimental group could significantly reduce the expression levels of carcinoembryonic antigen (mean difference [SMD] = 0.82, 95% CI = 0.30-1.35, P = .002), vascular endothelial growth factor (SMD = 0.43, 95% CI = 0.13-0.73, P = .005), neuron-specific enolase (SMD = 0.88, 95% CI = 0.60-1.17, P < .00001), cytokeratin 19 fragments (SMD = 1.33, 95% CI = 0.34-2.33, P = .009), and carbohydrate antigen 125 (SMD = 0.46, 95% CI = 0.15-0.77, P = .004) in serum. However, the experimental group did not significantly improve the disease control rate (DCR) (RR = 1.17, 95% CI = 1.00-1.36, P = .05), 1- and 2-year progression-free survival (PFS) rates (RR = 1.15, 95% CI = 1.00-1.33, P = .05; RR = 1.02, 95% CI = 0.74-1.40, P = .92), 1- and 2-year overall survival (OS) rates (RR = 1.11, 95% CI = 0.92-1.36, P = .28; RR = 0.99, 95% CI = 0.84-1.18, P = .95). Interestingly, the results of subgroup analysis showed that the experimental group significantly improved ORR, DCR, 1-year PFS, and OS rates in the Chinese population and patients under 65 years old (P < .05). In addition, when the dose of bevacizumab was 7.5 mg/kg q3w in the experimental group, ORR, DCR, 1-year PFS, and OS rates were significantly better than those in the control group (P < .05). In terms of adverse events of drugs, the incidence of proteinuria, hypertension, oral mucositis, bleeding, nausea, and vomiting in the experimental group was higher than that in the control group (P < .05). For patients with advanced EGFR-mutant NSCLC, osimertinib plus bevacizumab has some clinical benefit compared with osimertinib alone. Still, it does not provide additional long-term survival benefits and has higher toxicity. More well-designed, multicenter RCTs are needed to identify the subgroups of patients most likely to benefit from this combination regimen and to validate the optimal dose of this combination regimen.

Outcomes of implantable cardioverter-defibrillators in patients with a left ventricular assist device: a systematic review and meta-analysis

Abstract Introduction Implantable Cardioverter-Defibrillators (ICDs) improve survival in advanced heart failure with reduced ejection fraction (HFrEF) and prevent sudden cardiac death. However, the prognostic benefits of ICDs among patients with a Left Ventricular Assist Device (LVAD) remain uncertain and controversial. Therefore, we conducted a systematic review and meta-analysis to assess the effectiveness and safety of ICD implantation among LVAD recipients. Methods We performed a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched PubMed and EMBASE for the peer-reviewed articles published in English assessing the impact of ICD implantation among LVAD recipients, till 10/01/2024. ICD implantation was defined as implantation before LVAD, simultaneous implantation with LVAD, or within 30 days of LVAD insertion. Two independent review authors assessed the quality and risk of bias of the included studies. A random-effect model was used to combine data in forest plots. The primary outcome was all-cause mortality associated with ICD implantation compared to no ICD implantation, and the secondary outcomes included ventricular arrhythmia (VT), and hemorrhagic stroke. Heterogeneity was assessed using Q test and I2, with I2 &amp;gt; 50% indicating marked heterogeneity. Results A total of 13 observational studies comprising 54571 recipients of LVAD were included in the analysis of the primary outcome. All-cause mortality was similar among patients with ICD versus no ICD (Odds Ratio [OR]= 0.77; 95% CI, 0.57-1.04, I2= 89%, P=0.09), as shown in Figure 1. Likewise, ICD implantation was associated with similar rates of VT and hemorrhagic stroke (VT: OR= 1.81, 95% Cl, 0.82-4.01, I2= 90%, P=0.14; hemorrhagic stroke: OR= 1.01, 95% Cl, 0.81-1.25, I2= 0%, P= 0.95). Conclusion Among patients with HFrEF and LVAD as advanced heart failure therapy, ICD implantation didn’t provide additional prognostic survival benefit, suggesting possible use of LVAD without ICD implantation.Figure 1.Forest plot of mortality

Survival benefit added by adjuvant chemotherapy in adenoid cystic carcinoma of salivary gland

The aim of this study was to investigate the potential survival advantages associated with chemoradiotherapy (CRT) compared to radiotherapy (RT) as standalone modalities in the treatment of adenoid cystic carcinoma (ACC) of the salivary glands. Patients diagnosed with resected salivary gland ACC were retrospectively enrolled and categorized into two groups based on the type of adjuvant therapy received. The overall survival outcomes between the CRT and RT cohorts were evaluated using a multivariable Cox model. Post propensity score-matching, a total of 114 patients (57 in each treatment group) were included in the analysis. In the general patient population, CRT did not confer an additional survival benefit compared to RT alone. High-grade tumors, positive surgical margins, and the presence of five or more positive lymph nodes were identified as independent prognostic factors associated with poorer overall survival. Specifically, for patients with positive surgical margins, CRT was significantly associated with improved overall survival relative to RT, displaying a hazard ratio of 0.93 (95% CI: 0.81–0.99). Furthermore, in patients with more than four metastatic lymph nodes, CRT significantly reduced the risk of mortality by 6% (95% CI: 1-24%) when compared to RT alone. Conversely, in patients with high-grade tumors, the addition of adjuvant chemotherapy to RT did not yield significant alterations in survival outcomes compared to RT alone (p = 0.437, HR: 0.95, 95% CI: 0.75–2.07). CRT may offer an overall survival benefit for patients with salivary gland ACC, particularly those characterized by positive margin or the presence of five or more metastatic lymph nodes.

Comparing the impact of targeting limited driving pressure to low tidal volume ventilation on mortality in mechanically ventilated adults with COVID-19 ARDS: an exploratory target trial emulation

BackgroundAn association between driving pressure (∆P) and the outcomes of invasive mechanical ventilation (IMV) may exist. However, the effect of a sustained limitation of ∆P on mortality in patients with...

Significant Reduction of Radiation-Induced Death in Mice Treated with PrC-210 and G-CSF after Irradiation.

The search for single or combined radiation countermeasures that mitigate the development of Acute Radiation Syndrome (ARS) after radiation exposure remains a prominent goal of the U.S. government. This study was undertaken to determine whether PrC-210 and G-CSF, when administered 24-48 h postirradiation, would confer an additive or synergistic survival benefit and mitigate ARS in mice that had received an otherwise 96% lethal radiation dose. Our results show that optimum systemic doses of PrC-210 and G-CSF, when administered 24 h or later after a 96% lethal dose of whole-body irradiation, conferred: 1. strong individual survival benefits (PrC-210 44%, P = 0.003), (G-CSF 48%, P = 0.0002), 2. a profound combined 85% survival benefit (P < 0.0001) when administered together, and on day 14 postirradiation, 3. peripheral white blood cell/lymphocyte counts equal to unirradiated controls, 4. dense bone marrow cell density (>65% of unirradiated controls), 5. jejunal villi density that equaled 90% of unirradiated controls, and 6. spleen weights that equaled 93% of unirradiated controls. Our results show that PrC-210 and G-CSF given together 24 h after irradiation confer strong additive efficacy by protecting the immune system, and enabling recovery of the bone marrow, and they work synergistically to enable recovery of peripheral white blood cells in circulating blood.

Effect of liver abnormalities on mortality in Fontan patients: a systematic review and meta-analysis

BackgroundFontan-associated liver disease (FALD) is one of the most common complications following Fontan procedure, but the impact of FALD on survival outcomes remains controversial. The aim of this systematic review and meta-analysis was to examine and quantify the influence of liver disease on the survival of Fontan patients.MethodsThe Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines were followed, and relevant human studies published from inception up to 12 August 2022 were searched. Stata (version 17.0) was applied to perform the meta-analysis, using random effects (Mantel-Haenszel) models. The I2 statistic was used to assess the heterogeneity. Subgroup analysis and meta-regression were employed to explore the potential sources of heterogeneity and sensitivity analysis was performed to determine the potential influence of each study on the overall pooled results.ResultsA total of 312 records were initially identified and 8 studies involving 2,466 patients were selected for inclusion. Results revealed a significant association between the severity of liver disease following Fontan procedure and mortality, which was confirmed by sensitivity analysis and subgroup analysis assessing post-HT mortality. Meta-regression showed that diagnostic methods for liver disease may be a source of heterogeneity. After removal of the FALD patients identified by international classification of disease codes, heterogeneity was markedly reduced, and the positive association between all-cause mortality and the severity of liver disease became significant.ConclusionsThis meta-analysis showed the severity of liver disease following the Fontan procedure has a significant association with mortality. Lifelong follow-up is necessary and imaging examinations are recommended for routine surveillance of liver disease. Among patients with failing Fontan and advanced liver disease, combined heart-liver transplantation may provide additional survival benefits.

Chemoradiotherapy versus radiotherapy in high risk salivary gland cancer

ObjectiveThe aim of this study was to investigate the potential survival benefits associated with chemoradiotherapy (CRT) as opposed to radiotherapy (RT) in patients with resected high-risk salivary gland cancer (SGC), with a specific focus on determining whether these benefits are influenced by the number of high-risk variables.MethodsPatients who underwent surgical treatment for high-risk SGC were retrospectively enrolled and categorized into either CRT or RT groups. The impact of adjuvant therapy on locoregional control (LRC) and overall survival (OS) was assessed using a multivariable Cox model.ResultsA total of 152 patients were included following propensity score-matching. In comparison to RT, CRT did not demonstrate a significant survival advantage in terms of LRC (p = 0.485, HR: 1.14, 95%CI: 0.36–4.22) and OS (p = 0.367, HR: 0.99, 95%CI: 0.17–3.87) in entire population. But among patients with T3/4 stage, high-grade tumors, and 5 or more positive lymph nodes, the addition of chemotherapy to RT significantly (p = 0.042) correlated with a 15% reduction in the risk of cancer recurrence (95%CI: 4-54%). Conversely, in other subgroups with varying combinations of high-risk variables, CRT did not provide additional survival benefits for LRC and OS compared to RT.ConclusionAdjuvant chemotherapy may be considered in conjunction with RT specifically in cases where there is a presence of T3/4 stage, high-grade tumors, and 5 or more metastatic lymph nodes in high-risk SGC.

Survival Difference of Endometrial Cancer Patients with Peritoneal Metastasis Receiving Cytoreductive Surgery (CRS) with and without Hyperthermic Intraperitoneal Chemotherapy (HIPEC): A Systematic Review and Meta-Analysis.

Although several studies have been completed to investigate the effect of cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in endometrial cancer with peritoneal metastasis (ECPM), a direct comparison was not performed previously. A meta-analysis was performed to investigate the suspected additional survival benefits of CRS plus HIPEC over CRS only. Twenty-one and ten studies with a total number of 1116 and 152 cases investigating CRS only and CRS plus HIPEC were identified, respectively. When all articles were analyzed, the 1-year survival rate was 17.60% higher for CRS plus HIPEC (82.28% vs. 64.68%; p = 0.0102). The same tendency was observed for the 2-year (56.07% vs. 36.95%; difference: 19.12%; p = 0.0014), but not for the 5-year (21.88% vs. 16.45%; difference: 5.43%; p = 0.3918) survival rates. The same clinical significance, but statistically less strong observations, could be made if only the studies published after 2010 were investigated (1-year survival rate: 12.08% and p = 0.0648; 2-year survival rate: 10.90% and p = 0.0988). CRS remains one of the core elements of ECPM treatment, but the addition of HIPEC to CRS can increase the positive clinical outcome, especially in the first 2 years.

Docetaxel-oxaliplatin-capecitabine/5-fluorouracil (DOX/F) followed by docetaxel versus oxaliplatin-capecitabine/5-fluorouracil (CAPOX/FOLFOX) in HER2-negative advanced gastric cancers.

We evaluated whether the addition of docetaxel (D) to a combination comprising 5-fluorouracil/leucovorin (5-FU/LV) or capecitabine (C) plus oxaliplatin (O) (DOF/DOX) improved overall survival (OS) compared with 6 months of5-fluorouracil (5-FU) or capecitabine in combination with oxaliplatin (FOLFOX/CAPOX) alone in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas (G/GEJ). This study was an investigator-initiated, open-label, multi-institutional, randomized phase III trial in adult patients with HER2-negative advanced G/GEJs. The primary endpoint of the study was a comparison of median OS by Kaplan-Meier method. Next-generation sequencing was performed on tissue. Of the 324 patients randomly assigned between July 2020 and November 2022, 305 patients were evaluable for analysis (FOLFOX/CAPOX: 156; DOF/DOX: 149). With a median follow-up time of 19.2 months(95% Confidence Interval [CI] = 16.5 months to 21.9 months) for the entire cohort, the median OS was 10.1 months (95% CI = 9.2 to 10.9) for FOLFOX/CAPOX and 8.9 months (95% CI = 7.3 to 10.5) for DOF/DOX, and this difference was not statistically significant (P = .70). An increased proportion ofgrade 3 or grade 4 neutropenia (21% vs 3%; P < .001) and grade 2/3 neuropathy (17% vs 7%; P = .005) was seen in patients receiving DOF/DOX. Genomic profiling revealed a low incidence of microsatellite instability (1%) and a high incidence of BRCA1 (8.4%) and BRCA2 (7.5%) somatic alterations. FOLFOX or CAPOX chemotherapy for 6 months remains one of the standards of care in advanced HER2-negative gastroesophageal junction and gastric adenocarcinomas, with no additional survival benefit seen with the addition of docetaxel. Genomic profiling of patients revealed a higher than previously known incidence of somatic BRCA alterations, which requires further evaluation.CTRI (Clinical Trial Registry of India: CTRI/2020/03/023944).

Chemotherapy with or without surgery for locally advanced or borderline resectable pancreatic ductal adenocarcinoma: A retrospective multicenter international study.

e16352 Background: Current clinical guidelines recommend surgery for patients with locally advanced (LA)/borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) who achieve disease control after induction therapy. However, the additional survival benefit of surgery in these patients is unknown. Methods: In this multicenter international retrospective cohort study, consecutive patients with BR/LA PDAC who achieved disease control after three to six months of induction therapy (combination chemotherapy or chemoradiotherapy) between January 2014 and July 2021 were retrospectively identified at 8 centers in Germany and Italy. Resectability status was determined by consensus in a multidisciplinary tumor board based on imaging findings, serum CA19-9, performance status and clinical response. Patient characteristics, progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox regression analysis was used to compare survival data. Results: A total of 138 patients who achieved disease control with induction therapy were analyzed. The median age at diagnosis was 66 years (range 45-82) and 43% of patients were female. 73 patients underwent surgery and 65 patients did not (median age 64 and 69 years, respectively, p = 0.02). Median OS was 20.0 months (95%CI 16.1-23.8) in the surgery group and 18.0 months (95%CI 13.6-22.4) in the nonsurgery group (hazard ratio for death, 0.90; 95%CI, 0.63 to 1.29, p = 0.57). Median PFS was 14.0 months (95%CI 8.9-19.1) in the surgery group and 15.0 months (95%CI 11.7-18.3) in the nonsurgery group (hazard ratio for disease progression, 1.04; 95%CI, 73 to 1,47, p = 0.83). The 2-year survival rates in the surgery and nonsurgery groups were 32.9% and 40.0%, respectively, with an overall odds ratio of 0.74 (95% CI: 0.37-1.47). Conclusions: In our multicenter international retrospective analysis, additional surgery did not confer a survival advantage to patients with BR/LA PDAC who achieved disease control with induction therapy.

Atezolizumab plus taxane chemotherapy for the treatment of non-BRAF, non-RAS mutated anaplastic thyroid carcinoma: Final analysis.

e18070 Background: Anaplastic thyroid carcinoma (ATC) is an aggressive malignancy with a historical dismal prognosis. Although BRAF/MEK inhibitors have revolutionized the treatment of BRAF-mutant ATC, treatment options remain limited for those without a BRAF mutation. Single agent immunotherapy showed modest efficacy, while combination of immunotherapy with the anti-VEGF lenvatinib led to marked improvement in survival. Yet, given the locally advanced nature of this disease, many patients have contra-indications to antiangiogenics. We assessed the safety and efficacy of the anti-PD-L1 atezolizumab combined with taxane chemotherapy in patients with non- BRAF, non- RAS/NF mutated ATC with contra-indications to VEGF inhibitors. Methods: We enrolledpatientswith ATC in a single-center phase II prospective trial of atezolizumab plus mutation-determined targeted therapy (NCT03181100). Patients without a BRAF, RAS or NF mutation who had a contra-indication to anti-VEGF therapy (such as high risk for bleeding or fistula) were included in an exploratory cohort and were treated with nab-paclitaxel 100 mg/m2 on days 1, 8 and 15, combined with atezolizumab 1200 mg intravenously every 21 days. Paclitaxel could be substituted for nab-paclitaxel, but the latter was preferred as it does not require prophylactic steroids. Here we present results for this exploratory cohort. Best response to therapy was assessed per RECIST v1.1; survival by the Kaplan-Meier method. Results: Nine patients were enrolled in the exploratory cohort. All were naïve to systemic therapies, and 3/9 (33%) received prior bridging cytotoxic chemotherapy. Prior to study entrance, 6/9 (67%) had radiation therapy to the neck and 4/9 (44%) had surgery to resect the primary tumor. Seven (78%) had distant metastatic disease at time of enrollment. Most frequent baseline mutations were in TP53 (89%), APC (33%), PTEN (33%) and TERT promoter (33%). Median duration of follow-up was 4.4 months. Best response to therapy was partial response in 2 patients (1 confirmed and 1 unconfirmed), stable disease in 3 patients, and progressive disease in 4 patients. Overall response rate was 11 %, while disease control rate was 56%. Median OS was 4.44 months (95% CI, 1.12 –25.33) and median progression-free survival was 2.73 months (95% CI, 1.12 – 7.13). All patients had died at the time of data cut-off. Regarding treatment safety, the combination of atezolizumab plus taxane chemotherapy was overall well tolerated, with most adverse events being grade 2 or lower. Conclusions: Combination of atezolizumab plus taxane chemotherapy, although safe, offers limited additional survival benefit compared to single agent immunotherapy (median OS = 5.9 months) or the historical median OS of 5 months. Additional novel treatment strategies for patients with non- BRAF mutated ATC are warranted, especially when antiangiogenic drugs are contra-indicated. Clinical trial information: NCT03181100 .

A time-dependent analysis of sacubitril/valsartan and gliflozins benefits in patients receiving cardiac resynchronization therapy

Abstract Background While sacubitril/valsartan (ARNi), gliflozins (or SGLT2i) and cardiac resynchronization therapy (CRT) are firmly recognized as cornerstones of therapy for heart failure with reduced ejection fraction (HFrEF), robust evidence validating the long-term efficacy of their combination remains elusive. The few data suggesting a synergistic advantage of these drugs alongside CRT have not rigorously considered their time-varying administration, leading to potential selection bias, since only patients with longer initial survival could commence these treatments. As a result, the literature to date lacks a comprehensive and persuasive demonstration of the additional survival benefits conferred by ARNi and gliflozins over CRT alone in HFrEF. Purpose To evaluate the impact of ARNi and gliflozins on reducing cardiovascular and overall mortality among HFrEF patients undergoing CRT. Methods Patients with heart failure and an ejection fraction ≤ 35%, who were referred for CRT-D implantation from 2015 to 2023, were retrospectively recruited for the study. These patients were grouped into two cohorts: those not receiving drugs (no drugs group) and those treated with ARNi and/or SGLT2i (ARNi/SGLT2i group). Importantly, ARNi and SGLT2i treatments were considered as time-dependent covariates in order to account for patients who initiated or discontinued therapy during follow-up. Results The cohort included 183 ischemic and non-ischemic HFrEF patients (148 male [80.9 %], 113 ischemic [61.7 %], median [IQR] age 73 [65-80] years). 117 (74 %) patients started ARNi (61, 52.1 %), gliflozins (7, 6 %) or both drugs (49, 41.9 %) and were assigned to ARNi/SGLT2i group. During a median follow-up of 5.67 (CI 95 %, 5 – 6.5) years, 63 (34.4 %) patients died, of whom 47 (74.6 %) died of cardiovascular HF-related death. Specifically, 44 (of whom 35 (79 %) due to HF-related death) died in the no drugs group vs 19 (12 (63 %) due to HF-related death) in ARNi/SGLT2i patients. At univariable analysis (Panel A in the Figure), ARNi and/or SGLT2i treatments reduced all-cause (HR 0.59 [0.34-1.02], p = 0.056) and cardiovascular (HR 0.47 [0.24-0.92], p = 0.029) mortality. However, after multivariable adjustment for key covariates (1-year CRT response, age, atrial fibrillation, baseline LVEF, chronic obstructive pulmonary disease, glomerular filtration rate), the survival benefits of ARNi and SGLT2i use diminished, and the only factor strongly associated with reduced mortality risk remained 1-year positive response to CRT (Panel B). Conclusions Despite their recognized therapeutic benefits, ARNi and SGLT2i have not demonstrated additional survival benefit compared to CRT alone in patients with HFrEF. A 1-year positive response to CRT remains the most significant prognostic factor. Further studies with larger sample sizes and extended follow-up periods are needed to confirm this hypothesis, also evaluating whether the timing of introduction of these medications may impact survival.

Predictors for lymph node metastasis and survival of patients with T1b esophageal adenocarcinoma treated with surgery and endoscopic therapy: an analysis of the Surveillance, Epidemiology, and End Results database

Limited data exist regarding the long-term outcomes of endoscopic therapy (ET) with or without chemoradiation therapy (CRT) for T1b esophageal adenocarcinoma (EAC). Our aim was to identify the risk factors for lymph node metastasis (LNM) in T1b EAC and assess how the chosen treatment modality affects overall survival (OS) and cancer-specific survival (CSS). We analyzed patients with histologically confirmed T1b EAC diagnosed between 2004 and 2018 using the Surveillance, Epidemiology, and End Results database. Focusing on T1bN0M0 staging, the patients were divided into 2 groups (ET [n= 174] and surgery [n= 769]), and OS and CSS rates were calculated. Of 1418 patients with T1b EAC, 228 cases (16.1%) exhibited LNM at diagnosis. Notable risk factors for LNM included poorly differentiated tumor and lesion size≥20mm. For T1bN0M0 cases, ET was commonly performed from 2009 to 2018 (odds ratio [OR], 4.3), especially for patients aged≥65 years (OR, 3.1) with tumor size<20mm (OR, 2.3). During the median 50 months of follow-up, age≥65 years (hazard ratio [HR], 1.9), ET (HR, 1.5), and CRT (HR, 1.4) were associated with poorer OS. Factors linked to decreased CSS were age≥65 years (subhazard ratio [SHR], 1.6), poorly differentiated tumors (SHR, 1.5), and CRT (SHR, 1.5). In T1b EAC, tumor size≥20mm and poor differentiation are notable risk factors for LNM. ET exhibited comparable CSS outcomes to surgery for carefully selected T1bN0M0 lesions. CRT did not provide additional survival benefit for these lesions; however, large-scale studies are required to validate this finding.

Supramaximal resection: retrospective study on IDH-wildtype Glioblastomas based on the new RANO-Resect classification.

The prognostic value of the extent of resection in the management of Glioblastoma is a long-debated topic, recently widened by the 2022 RANO-Resect Classification, which advocates for the resection of the non-enhancing disease surrounding the main core of tumors (supramaximal resection, SUPR) to achieve additional survival benefits. We conducted a retrospective analysis to corroborate the role of SUPR by the RANO-Resect Classification in a single center, homogenous cohort of patients. Records of patients operated for WHO-2021 Glioblastomas at our institution between 2007 and 2018 were retrospectively reviewed; volumetric data of resected lesions were computed and classified by RANO-Resect criteria. Survival and correlation analyses were conducted excluding patients below near-total resection. 117 patients met the inclusion criteria, encompassing 45 near-total resections (NTR), 31 complete resections (CR), and 41 SUPR. Median progression-free and overall survival were 11 and 15months for NTR, 13 and 17months or CR, 20 and 24months for SUPR, respectively (p < 0.001), with inverse correlation observed between survival and FLAIR residual volume (r -0.28). SUPR was not significantly associated with larger preoperative volumes or higher rates of postoperative deficits, although it was less associated with preoperative neurological deficits (OR 3.37, p = 0.003). The impact of SUPR on OS varied between MGMT unmethylated (HR 0.606, p = 0.044) and methylated (HR 0.273, p = 0.002) patient groups. Results of the present study support the validity of supramaximal resection by the new RANO-Resect classification, also highlighting a possible surgical difference between tumors with methylated and unmethylated MGMT promoter.

Patients with Advanced or Metastasised Non-Small-Cell Lung Cancer with Viscum album L. Therapy in Addition to PD-1/PD-L1 Blockade: A Real-World Data Study.

Immunotherapy with PD-1/PD-L1 inhibitors has significantly improved the survival rates of patients with metastatic non-small-cell lung cancer (NSCLC). Results of a real-world data study investigating add-on VA (Viscum album L.) to chemotherapy have shown an association with the improved overall survival of patients with NSCLC. We sought to investigate whether the addition of VA to PD-1/PD-L1 inhibitors in patients with advanced or metastasised NSCLC would have an additional survival benefit. In the present real-world data study, we enrolled patients from the accredited national registry, Network Oncology, with advanced or metastasised NSCLC. The reporting of data was performed in accordance with the ESMO-GROW criteria for the optimal reporting of oncological real-world evidence (RWE) studies. Overall survival was compared between patients receiving PD-1/PD-L1 inhibitor therapy (control, CTRL group) versus the combination of anti-PD-1/PD-L1 therapy and VA (combination, COMB group). An adjusted multivariate Cox proportional hazard analysis was performed to investigate variables associated with survival. From 31 July 2015 to 9 May 2023, 415 patients with a median age of 68 years and a male/female ratio of 1.2 were treated with anti-PD-1/PD-L1 therapy with or without add-on VA. Survival analyses included 222 (53.5%) patients within the CRTL group and 193 (46.5%) in the COMB group. Patients in the COMB group revealed a median survival of 13.8 months and patients in the CRTL group a median survival of 6.8 months (adjusted hazard ratio, aHR: 0.60, 95% CI: 0.43-0.85, p = 0.004) after adjustment for age, gender, tumour stage, BMI, ECOG status, oncological treatment, and PD-L1 tumour proportion score. A reduction in the adjusted hazard of death by 56% was seen with the addition of VA (aHR 0.44, 95% CI: 0.26-0.74, p = 0.002) in patients with PD-L1-positive tumours (tumour proportion score > 1%) treated with first-line anti-PD-1/PD-L1 therapy. Our findings suggest that add-on VA correlates with improved survival in patients with advanced or metastasised NSCLC who were treated with PD-1/PD-L1 inhibitors irrespective of age, gender, tumour stage, or oncological treatment. The underlying mechanisms may include the synergistic modulation of the immune response. A limitation of this study is the observational non-randomised study design, which only allows limited conclusions to be drawn and prospective randomised trials are warranted.

Lymph node dissection in small-sized pulmonary metastasectomy: Impact on the long-term survival

Pulmonary metastasectomy has been clarified in improving long-term survival in most primary malignancies with pulmonary metastasis, while the role of additional lymph node dissection remained controversial. We aimed to investigate the prognosis of lymph node involvement and identify the role of lymph node dissection during pulmonary metastasectomy in a real-world cohort. We identified patients diagnosed with pulmonary metastases with ≤3cm in size and received pulmonary metastasectomy between 2004 and 2017 in the Surveillance, Epidemiology, and End Results database. We compared the survival via Kaplan-Meier analysis and propensity score matching method, and the multivariable analysis was conducted by cox regression analysis. A total of 3452 patients were included, of which 2268(65.7%) received lymph node dissection, and the incidence of node-positive was 11.3%(256/2268). In total, the median overall survival was 62.8 months(interquartile range, 28.6-118.9 months), and the lymph node involvement was referred to an impaired survival compared to node-negative diseases(5-year overall survival rate, 58.0% versus 38.6%), with comparable survival between N1 and N2 diseases(P=0.774). Lymph node dissection was associated with improved survival(HR=0.80; 95%CI, 0.71-0.90; P<0.001), and the survival benefits remained regardless of age, sex, the number of metastases, and surgical procedures, even in those with node-negative diseases. At least eight LNDs might lead to a significant improvement in survival, and additional survival benefits might be limited with additional dissected lymph nodes. Lymph node involvement was associated with impaired survival, and lymph node dissection during pulmonary metastasectomy could improve long-term survival and more accurate staging.