Survival In High-risk Patients Research Articles

Early Versus Delayed Androgen Deprivation Therapy for Biochemical Recurrence After Local Curative Treatment in Non-Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review of the Literature.

The ideal timing of androgen deprivation therapy (ADT) for patients with biochemical recurrence (BCR) of prostate cancer (PCa) remains controversial due to its side effects and uncertain impact on survival outcomes. We performed a review of the current literature by comprehensively searching the PubMed, Embase, and Cochrane databases to determine the optimal timing of ADT initiation after biochemical recurrence. We selected 26 studies including systematic reviews, randomized controlled trials (RCTs), and retrospective studies, while also reviewing practice guidelines. Not all patients with BCR cancer experience clinical or radiological progression. While early ADT may delay progression, evidence of its effect on PCa-specific mortality remains inconclusive. The PSA thresholds for initiating ADT vary, complicating decision-making. Key predictors of progression include a short PSA doubling time (PSADT), a high Gleason score (GS), and a brief interval to BCR of PCa post-radiotherapy (RT). Combining ADT with androgen receptor pathway inhibitors (ARPIs) has been shown to improve metastasis-free survival in high-risk patients. The ideal timing of ADT initiation in BCR PCa remains uncertain. Early ADT can help control the progression, but its effect on PCa-specific mortality is unclear. Stratifying patients by their risk factors, such as their PSADT, GS, and time to BCR can guide individualized treatment. In high-risk patients, delaying ADT should be avoided, while combining ADT with an androgen receptor pathway inhibitor (ARPI) may further improve outcomes.

Tracheostomy is associated with decreased in-hospital mortality during severe COVID-19 infection.

Tracheostomy is often performed in patients with a prolonged course of endotracheal intubation. This study sought to examine the clinical utility of tracheostomy during severe Coronavirus disease 2019 (COVID-19) infection. A retrospective single-system, multicenter observational cohort study was performed on patients intubated for COVID-19 infection. Patients who received intubation alone were compared with patients who received intubation and subsequent tracheostomy. Patient demographics, comorbidities, and hospital courseswere analyzed. The University of Pennsylvania Health System from 2020 to 2021. Logistic regression analysis was performed on patient demographics and comorbidities. Kaplan-Meier survival curves were generated depending on whether patients received a tracheostomy. Of 777 intubated patients, 452 were male (58.2%) and 325 were female (41.8%) with a median age of 63 (interquartile range [IQR]: 54-73) years. One-hundred and eighty-five (23.8%) patients underwent tracheostomy. The mean time from intubation to tracheostomy was (17.3 ± 9.7) days. Patients who underwent tracheostomy were less likely to expire during their hospitalization than those who did not undergo tracheostomy (odds ratio [OR] = 0.31, P < 0.001), and patient age was positively associated with mortality (OR = 1.04 per year, P < 0.001). Likelihood of receiving tracheostomy was positively associated with being on extra-corporeal membranous oxygenation (ECMO) (OR = 101.10, P < 0.001), immunocompromised status (OR = 3.61, P = 0.002), and current tobacco smoking (OR = 4.81, P = 0.041). Tracheostomy was also associated with a significantly longer hospital length of stay ([57.5 ± 32.2] days vs. [19.9 ± 18.1] days, P < 0.001). Tracheostomy was associated with reduced in-hospital mortality, despite also being associated with increased comorbidities. Tracheostomy should not be heldback from patients with comorbidities for this reason alone and may even improve survival in high-risk patients.

Identification of prognostic biomarkers in neuroblastoma using WGCNA and multi-omics analysis

BackgroundNeuroblastoma (NB) is one of the most frequent parenchymal tumors among children, with a high degree of heterogeneity and wide variation in clinical presentation. Despite significant therapeutic advances in recent years, long-term survival in high-risk patients remains low, emphasizing the urgent need to find new biomarkers and construct reliable prognostic models.MethodsIn this study, data from neuroblastoma samples in the ArrayExpress database were utilized to identify key gene modules and pivotal genes associated with NB prognosis by weighted gene co-expression network analysis (WGCNA). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis was performed using the DAVID database. Based on these hub genes, survival prognosis models were constructed and validated on an independent validation set in the Gene Expression Omnibus (GEO) database. Differences in biological functions and immune microenvironments and the sensitivity to pharmacological and immunotherapeutic treatments of patients in the high- and low-risk groups were examined by gene set enrichment analysis (GSEA) and immune infiltration analysis.ResultsWGCNA identified 14 gene modules and screened the module with the highest relevance to the International Neuroblastoma Staging System (INSS), containing 60 pivotal genes. GO and KEGG analyses demonstrated that these pivotal genes were mainly implicated in biological processes and signaling pathways including DNA replication, cell division, mitotic cell cycle, and cell cycle. Based on Lasso regression and COX regression analysis, a prognostic model containing DHFR, GMPS and E2F3 was constructed, and the RiskScore was significantly correlated with the 1-, 3- and 5-year survival of the patients. GSEA and immune infiltration analyses revealed significant differences in the levels of cell cycle-related pathways and immune cell infiltration between the high and low RiskScore groups. In particular, patients in the high-risk group are less likely to benefit from immunotherapy and may be better suited for treatment with drugs such as Oxaliplatin and Alpelisib.ConclusionThis research systematically identified biomarkers related to NB prognosis and developed a reliable prognostic model applying WGCNA and multiple bioinformatics methods. The model has important application value in predicting patients’ prognosis, evaluating drug sensitivity and immunotherapy effect, and provides new ideas and directions for precise treatment of neuroblastoma.

Novel prediction model combining PET/CT metabolic parameters, inflammation markers, and TNM stage: prospects for personalizing prognosis in nasopharyngeal carcinoma.

This study aims to develop a novel prediction model and risk stratification system that could accurately predict progression-free survival (PFS) in patients with nasopharyngeal carcinoma (NPC). Herein, we included 106 individuals diagnosed with NPC, who underwent 18F-FDG PET/CT scanning before treatment. They were divided into training (n = 76) and validation (n = 30) sets. The prediction model was constructed based on multivariate Cox regression analysis results and its predictive performance was evaluated. Risk factor stratification was performed based on the nomogram scores of each case, and Kaplan-Meier curves were used to evaluate the model's discriminative ability for high- and low-risk groups. Multivariate Cox regression analysis showed that N stage, M stage, SUVmax, MTV, HI, and SIRI were independent factors affecting the prognosis of patients with NPC. In the training set, the model considerably outperformed the TNM stage in predicting PFS (AUCs of 0.931 vs. 0.841, 0.892 vs. 0.785, and 0.892 vs. 0.804 at 1-3years, respectively). The calibration plots showed good agreement between actual observations and model predictions. The DCA curves further justified the effectiveness of the model in clinical practice. Between high- and low-risk group, 3-year PFS rates were significantly different (high- vs. low-risk group: 62.8% vs. 9.8%, p < 0.001). Adjuvant chemotherapy was also effective for prolonging survival in high-risk patients (p = 0.009). Herein, a novel prediction model was successfully developed and validated to improve the accuracy of prognostic prediction for patients with NPC, with the aim of facilitating personalized treatment.

Identification and evaluation of a six-lncRNA prognostic signature for multiple myeloma

PurposeMultiple myeloma (MM) is the second most common hematologic malignancy, and there is no cure for this disease. This study aimed to explore the prognostic value of long noncoding RNAs (lncRNAs) in MM and to reveal related immune and chemotherapy resistance mechanisms.MethodsIn this study, lncRNA profiles from the Multiple Myeloma Research Foundation (MMRF) and Gene Expression Omnibus (GEO) databases were analyzed to identify lncRNAs linked to MM patient survival. A risk assessment model stratified patients into high- and low-risk groups, and survival was evaluated. Additionally, a triple-ceRNA (lncRNA–miRNA–mRNA) network was constructed, and functional analysis was performed. The research also involved immune function analysis and chemotherapy drug sensitivity assessment using oncoPredict and the GDSC dataset.ResultsWe identified 422 lncRNAs significantly associated with overall survival in MM patients and ultimately focused on the 6 with the highest prognostic value. These lncRNAs were used to develop a risk score formula that stratified patients into high- and low-risk groups. Kaplan–Meier analysis revealed shorter survival in high-risk patients. We integrated this lncRNA signature with clinical parameters to construct a nomogram for predicting MM prognosis. Additionally, a triple-ceRNA network was constructed to reveal potential miRNA targets, coding genes related to these lncRNAs and significantly enriched pathways. Immune checkpoint gene expression and immune cell composition were also analyzed in relation to the lncRNA risk score. Finally, using the oncoPredict tool, we observed that high-risk patients exhibited decreased sensitivity to key MM chemotherapeutics, suggesting that lncRNA profiles are linked to chemotherapy resistance.

Phase II study of neoadjuvant ipilimumab and nivolumab in combination with paclitaxel following anthracycline-based chemotherapy in patients with treatment resistant stage III triple negative breast cancer (TNBC): BCT1702—Survival results.

608 Background: We examined the efficacy and safety of neoadjuvant ipilimumab and nivolumab combined with paclitaxel following suboptimal response to anthracycline-based chemotherapy in patients with early-stage TNBC. Methods: This single arm phase 2 study enrolled 34 patients at 8 sites. Patients had stage 3 TNBC, after 4 cycles of anthracycline-based therapy, with ≥15mm of tumor remaining or ≥10mm of tumor with ≥1 positive lymph node. A suboptimal response at baseline was defined as &lt;50% reduction in tumor volume after anthracycline-based therapy. Patients received neoadjuvant ipilimumab 1mg/kg IV 6 weekly for 2 doses and nivolumab 240mg every 2 weeks for 6 doses, with weekly paclitaxel at 80mg/m2 for 12 weeks, followed by surgery. Nivolumab (480mg 4-weekly) continued post operatively for a further 9 months. Primary endpoint was pathological complete response (pCR: ypT0/is, ypN0) in breast and axilla, with secondary endpoints pCR in the suboptimal responders, pCR in PD-L1 positive (≥1% by SP142) or TIL% high (≥30%), event-free (EFS) and overall survival (OS). Results: Between December 2018 and April 2020, 34 patients were enrolled, 33 were evaluable for the primary endpoint. Median age was 46.6yrs. At diagnosis, 97% patients were clinical stage III, 24/34 (70.5%) were clinically node positive, 9/31 (27%) were PD-L1 positive and 6/30 (20%) were TILs% high. At study entry (after anthracycline-based chemo), the median tumor size by ultrasound was 28mm (12-62). The pCR rate was 24.2% (95% CI, 11.09-42.26) in all evaluable, 44.4% [4/9] in PD-L1+ and 9.5% [2/21] in PD-L1- patients. In suboptimal responders, the pCR rate was 25% (95% CI,8.6-49.1) (3/16). At a median follow up of 36.6 months, 9 patients have died. The KM estimates for EFS and OS at 12 months were 96.8% and 93.7%, at 24 months were 84.4% and 84.4% and at 36 months 61.2% and 71.9%, respectively. Patients who achieved a pCR had numerically better EFS (HR 3.61 (0.47-28.2, p=0.2) and OS (HR 2.6 (0.33-21.08); p=0.34). Patients with PD-L1+ tumors vs PD-L1- had a 3-year EFS of 100% vs 52% (p=0.01) and 100% vs 67% OS (p=0.05). Results were similarly favorable for TIL high vs low. Conclusions: The addition of ipilimumab and nivolumab to neoadjuvant chemotherapy resulted in 100% survival for high-risk patients with PD-L1+ and/or TIL% high tumors. Combination CTLA4 and PD-1 targeting agents should be further investigated in Stage 3 TNBC patients. Translational research is ongoing. Clinical trial information: ACTRN12617000651381. [Table: see text]

Anti-cancer Effect of Neocuproine on Oxidative Stress and Inflammatory Levels Induced by Neuroblastoma Cancer Cells

Neocuproine is a free radical scavenger. Neuroblastoma cancer is seen mostly in children. It accounts for approximately 15% of all pediatric cancer deaths. Treatments against SH-SY5Y may be ineffective due to the development of drug resistance, resulting in poor survival in high-risk patients. The goal of this study was to find out how the anti-cancer concentration of Neocuproine affected the levels of oxidants, antioxidants, and cytokines in the SH-SY5Y cell line. Five different concentrations of Neocuproine (12.5, 25, 50, 100, and 200 µM) were applied to the cell line for 24 h. MTT cytotoxicity tests, total oxidant status and total antioxidant capacity tests, and anti-inflammatory cytokine tests were used to look at the uses of Neocuproine. In our results, 100 µM Neocuproine application reduced cancer cell viability up to 69.76%. In addition, it was determined that 100 µM Neocuproine reduced oxidant activity, increased antioxidant capacity, and regulated anti-inflammatory cytokine levels in neuroblastoma cells, consistent with the cytotoxicity test. As a result, it was concluded that Neocuproine has an anti-cancer effect on the SH-SY5Y cell line.

Rituximab-combined anthracycline-free chemotherapy in newly diagnosed paediatric and adolescent patients with non-high-risk aggressive mature B cell lymphoma: protocol for a single-arm, open-label, multicentre, phase II study (the Japan Children’s Cancer Group Multicentre Trial, JPLSG B-NHL-20)

IntroductionChildren and adolescents with mature B cell non-Hodgkin lymphoma (B-NHL) are treated with short-intensive chemotherapy. The burden of short-term and long-term toxicity is highly relative to its high cure rate...

Patient years lost due to cytomegalovirus serostatus mismatching in the scientific registry of transplant recipients.

The cytomegalovirus (CMV) mismatch rate in deceased donor kidney transplant (DDKT) recipients in the US remains above 40%. Since CMV mismatching is common in DDKT recipients, the cumulative effects may be significant in the context of overall patient and graft survival. Our primary objective was to describe the short- and long-term risks associated with high-risk CMV donor positive/recipient negative (D+/R-) mismatching among DDKT recipients with the explicit goal of deriving a mathematical mismatching penalty. We conducted a retrospective, secondary analysis of the Scientific Registry of Transplant Recipients (SRTR) database using donor-matched DDKT recipient pairs (N=105,608) transplanted between 2011-2022. All-cause mortality and graft failure hazard ratios were calculated from one year to ten years post-DDKT. All-cause graft failure included death events. Survival curves were calculated using the Kaplan-Meier estimation at 10 years post-DDKT and extrapolated to 20 years to provide the average graft days lost (aGDL) and average patient days lost (aPDL) due to CMV D+/R- serostatus mismatching. We also performed an age-based stratification analysis to compare the relative risk of CMV D+ mismatching by age. Among 31,518 CMV D+/R- recipients, at 1 year post-DDKT, the relative risk of death increased by 29% (p<0.001), and graft failure increased by 17% (p<0.001) as compared to matched CMV D+/R+ group (N=31,518). Age stratification demonstrated a significant increase in the risk associated with CMV mismatching in patients 40 years of age and greater. The aGDL per patient due to mismatching was 125 days and the aPDL per patient was 100 days. The risks of CMV D+/R- mismatching are seen both at 1 year post-DDKT period and accumulated throughout the lifespan of the patient, with the average CMV D+/R- recipient losing more than three months of post-DDKT survival time. CMV D+/R- mismatching poses a more significant risk and a greater health burden than previously reported, thus obviating the need for better preventive strategies including CMV serodirected organ allocation to prolong lifespans and graft survival in high-risk patients.

Role of pembrolizumab in relapsed Hodgkin lymphoma patients

About 10–15% of patients with early-stage and 15-30% with relapsed Hodgkin lymphoma after primary conventional treatment. Despite the approval of novel therapies, autologous stem cell transplantation (ASCT) remains the standard of care in these patients. However, up to half of transplanted individuals may relapse. Pembrolizumab is an FDA-approved monoclonal antibody directed against programmed cell death protein 1 (PD-1), it has received approval for the treatment of solid cancer and showed increased progression-free survival in high-risk patients with relapsed Hodgkin lymphoma receiving autologous stem cell transplantation. This study aims to investigate the role of relapsed Hodgkin lymphoma after using Pembrolizumab. This study was conducted for 80 patients with relapsed Hodgkin lymphoma who received Pembrolizumab and 50 patients had completed treatment with 40% complete response. In conclusion, Pembrolizumab showed a good response in patients with relapsed Hodgkin lymphoma.

Navigating the Crossroads: Cytomegalovirus (CMV), Neutropenia, and Kidney Transplant Survival in High-Risk Patients

Navigating the Crossroads: Cytomegalovirus (CMV), Neutropenia, and Kidney Transplant Survival in High-Risk Patients

Factors Associated with Receipt of Adjuvant Chemotherapy in Stage II Colon Cancer.

The benefits of chemotherapy in stage II colon cancer remain unclear, but it is recommended for high-risk stage II disease. Which patients receive chemotherapy and its impact on survival remains undetermined. The National Cancer Database was surveyed between 2004 and 2016 for stage II colon cancer patients. Patients were categorized as high- or average-risk as defined by the National Comprehensive Cancer Network. The demographic characteristics of high- and average-risk patients who did and did not receive chemotherapy were compared using univariate and multivariable analyses. The survival of high- and average-risk patients was compared based on receipt of chemotherapy with Cox hazard ratios and Kaplan-Meier curves. Overall, 84,424 patients met the inclusion criteria. A total of 34,868 patients were high-risk and 49,556 were average-risk. In high-risk patients, the risk factors for not receiving chemotherapy included increasing age, distance from the treatment facility, Charlson-Deyo score, and lack of insurance. In average-risk patients, factors associated with receipt of chemotherapy were decreasing age, distance from the treatment facility, Charlson-Deyo score, and non-academic association of the treatment facility. In both, chemotherapy was significantly associated with increased survival on the Kaplan-Meier curve. In the Cox hazard ratio, only high-risk patients benefited from chemotherapy (hazard ratio 1.183, confidence interval 1.116-1.254). Factors associated with not receiving chemotherapy in high-risk stage II colon cancers included increasing age, medical comorbidities, increasing distance from the treatment facility, and lack of insurance. Chemotherapy is associated with improved overall survival in high-risk patients.

Aggressive Pursuit of No Evidence of Disease Status in Hepatoblastoma Improves Survival: An Observational Study

BackgroundThe utility of repeated surgical interventions in hepatoblastoma to achieve no evidence of disease (NED) is not well-defined. We examined the effect of aggressive pursuit of NED status on event-free (EFS) and overall survival (OS) in hepatoblastoma with subgroup analysis of high-risk patients. MethodsHospital records were queried for patients with hepatoblastoma from 2005 to 2021. Primary outcomes were OS and EFS stratified by risk and NED status. Group comparisons were performed using univariate analysis and simple logistic regression. Survival differences were compared with log-rank tests. ResultsFifty consecutive patients with hepatoblastoma were treated. Forty-one (82%) were rendered NED. NED was inversely correlated with 5-year mortality (OR 0.006; CI 0.001–0.056; P < .01). Ten-year OS (P < .01) and EFS (P < .01) were improved by achieving NED. Ten-year OS was similar between 24 high-risk and 26 not high-risk patients when NED was attained (P = .83). Fourteen high-risk patients underwent a median of 2.5 pulmonary metastasectomies, 7 for unilateral disease, and 7 for bilateral, with a median of 4.5 nodules resected. Five high-risk patients relapsed, and three were salvaged. ConclusionsNED status is necessary for survival in hepatoblastoma. Repeated pulmonary metastasectomy and/or complex local control strategies to obtain NED can achieve long-term survival in high-risk patients. Level of evidenceLevel III – Treatment Study - Retrospective Comparative Study.

Long-term outcomes of frontline intensification in primary CNS lymphoma: A real-world single-center experience.

Frontline intensification (including consolidative whole-brain radiotherapy or high-dose chemotherapy with autologous stem-cell transplantation after induction therapy) has been proposed to treat primary central nervous system lymphoma (PCNSL). However, no prospective randomized trials have answered whether frontline intensification can offer a survival benefit to PCNSL patients. We aim to clarify the outcomes and survival influence of frontline intensification on real-world patients with different risk-stratified PCNSLs. Between January 2003 and December 2016, 110 PCNSL adults were retrospectively included, and 76 patients achieved at least PR after induction therapy, including 38 patients who received frontline intensification. The median follow-up with the 31 survivors was 7.52 years. Of the 38 induction-completed patients who had not received frontline intensification, 95% achieved post-induction therapy CR/CRu; however, all inevitably recurred. In the 38 who received frontline intensification, CR/CRu improved from 45% (pre-frontline intensification) to 84% (post-frontline intensification), and they achieved significantly better PFS (non-reach vs. 522 days, p< 0.001) and OS (non-reach vs. 899 days, p< 0.001). Additionally, patients had similar PFS and OS rates when receiving HDC-ASCT and/or WBRT as frontline intensification. Frontline intensification significantly improved PFS and OS survival in higher-risk patients (intermediate/high IELSG risk, MSKCC group 2/3, or Nottingham/Barcelona score ≥ 2 points) but did not improve OS in lower-risk patients. Among the 38 patients who received frontline intensification, two had treatment-related mortality; 14 recurred after frontline intensification. MTX-based chemotherapy was the main salvage modality, and the median OS was 295 days after recurrence. Progressive disease and infection (especially pneumonia) are two major causes of mortality in patients who receive frontline intensification. When achieving CR/CRu/PR after induction chemotherapy, frontline intensification should be adopted to improve PFS and OS in real-world PCNSL patients, especially higher-risk patients.

Integrated profiling uncovers prognostic, immunological, and pharmacogenomic features of ferroptosis in triple-negative breast cancer.

Ferroptosis is an iron-dependent type of regulated cell death triggered by the toxic buildup of lipid peroxides on cell membranes. Nonetheless, the implication of ferroptosis in triple-negative breast cancer (TNBC), which is the most aggressive subtype of breast carcinoma, remains unexplored. Three TNBC cohorts-TCGA-TNBC, GSE58812, and METABRIC-were adopted. Consensus molecular subtyping on prognostic ferroptosis-related genes was implemented across TNBC. Ferroptosis classification-relevant genes were selected through weighted co-expression network analysis (WGCNA), and a ferroptosis-relevant scoring system was proposed through the LASSO approach. Prognostic and immunological traits, transcriptional and post-transcriptional modulation, therapeutic response, and prediction of potential small-molecule agents were conducted. Three disparate ferroptosis patterns were identified across TNBC, with prognostic and immunological traits in each pattern. The ferroptosis-relevant scoring system was proposed, with poorer overall survival in high-risk patients. This risk score was strongly linked to transcriptional and post-transcriptional mechanisms. The high-risk group had a higher response to anti-PD-1 blockade or sunitinib, and the low-risk group had higher sensitivity to cisplatin. High relationships of risk score with immunological features were observed across pan-cancer. Two Cancer Therapeutics Response Portal (CTRP)-derived agents (SNX-2112 and brefeldin A) and PRISM-derived agents (MEK162, PD-0325901, PD-318088, Ro-4987655, and SAR131675) were predicted, which were intended for high-risk patients. Altogether, our findings unveil prognostic, immunological, and pharmacogenomic features of ferroptosis in TNBC, highlighting the potential clinical utility of ferroptosis in TNBC therapy.

Outcomes of Allogeneic Stem Cell Transplant for Multiple Myeloma

Background Allogeneic stem cell transplant (allo-SCT) for treatment of multiple myeloma (MM) is controversial. For some, allo-SCT may drive treatment-resistant disease into remission through a graft vs myeloma effect. For others, it incurs considerable morbidity from opportunistic infections and graft vs host effects. Allo-SCT usage for MM has increased over the past 25 years despite mixed efficacy and the absence of clear treatment guidelines. We aimed to determine the natural history of patients who underwent an allo-SCT following an autologous stem cell transplant (ASCT) and identify characteristics associated with outcome. Methods We retrospectively analyzed 89 patients diagnosed with multiple myeloma who had received an allo-SCT following an ASCT between 2000 and 2022 at Mayo Clinic Rochester. Patient data were obtained from the Mayo Clinic Transplant Center Database and our institution's electronic medical records. Overall survival (OS) and progression free survival (PFS) were calculated as time from allo-SCT to death from any cause and first observation of relapse or death, respectively. OS and PFS rates were estimated using the Kaplan-Meier method. P < 0.05 was considered statistically significant. Results The cohort is characterized as follows: median patient age of 51.3 years, 71% male, 90% white/Caucasian. Indication for allo-SCT were 91.0% (N=81) relapsed/progressive disease, 9.0% (N=8) high risk in remission. Cytogenetic risk stratification at diagnosis was available for 94% of patients (N=84) with 63% (N=56) standard risk, 32% (N=28) high risk according to International Myeloma Working Group criteria. By conditioning regimen, 55% (N=49) underwent full myeloablative allo, 45% (N=40) non-myeloablative (mini)-allo. Median follow-up, OS, and PFS was 11.5, 1.7, and 0.8 years, respectively (Table 1). OS was 46% (N=41) at 2 years, 26% (N=21) at 4 years, and 16% (N=14) at 8 years (Figure 1). Outcome was not significantly impacted by age, sex, race, indication for allo-SCT, or myeloablative regimen. Patient cytogenetic risk at diagnosis approached, but did not reach, statistical significance (p=0.22) with overall survival of high-risk patients being 32% (N=9), 18% (N=5), and 7.1% (N=2) at 2, 4, and 8 years, respectively, compared to 52% (N=29), 27% (N=15), and 20% (N=11) over the same times in standard risk. PFS was 27% (N=24) at 2 years follow-up, 16% (N=14) at 4 years, and 7.9% (N=7) at 8 years (Figure 1). This did not vary significantly by age, race, indication for allo-SCT, cytogenetic risk, or conditioning regimen. Sex approached, but did not reach, statistical significance (p=0.16) with progression-free survival of females being 19% (N=5), 15% (N=4), and 7.7% (N=1) at 2, 4, and 8 years follow-up, respectively, compared to males at 30% (N=19), 16% (N=10), and 9.5% (N=6) over the same times. Discussion Long-term survival was achieved in less than 20% of patients who underwent allo-SCT following an ASCT. Nearly 75% of patients experienced disease progression or death by 2 years. This suggests minimal benefit to the use of allo-SCT as treatment for multiple myeloma outside of select patients. Novel therapeutics such as chimeric antigen receptor T cells (CAR-T) or bispecific T-cell engager (BiTE) should be considered as an alternative. Subsequent studies will further examine patient characteristics and associated outcomes to determine the population best suited for allo-SCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Development of a prognostic prediction model based on a combined multi-omics analysis of head and neck squamous cell carcinoma cell pyroptosis-related genes.

This study aimed to understand the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) and to develop and validate a prognostic model for HNSCC based on pyroptosis-associated genes (PAGs) in nasopharyngeal carcinoma. The Cancer Genome Atlas database was used to identify differentially expressed PAGs. These genes were analyzed using the Kyoto Encyclopedia of Genes and Genomes functional annotation analyses and Gene Ontology analyses. The NLR family pyrin domain containing 1 (NLRP1) gene, charged multivesicular body protein 7 (CHMP7) gene, and cytochrome C (CYCS) gene were used to create a prognostic model for HNSCC. The results of the Kaplan-Meier (K-M) and Cox regression analyses indicated that the developed model served as an independent risk factor for HNSCC. According to the K-M analysis, the overall survival of high-risk patients was lower than that of low-risk patients. The hazard ratios corresponding to the risk scores determined using the multivariate and univariate Cox regression analyses were 1.646 (95% confidence interval (CI): 1.189–2.278) and 1.724 (95% CI: 1.294–2.298), respectively, and the area under the receiver operator characteristic curve was 0.621. The potential mechanisms associated with the functions of the identified genes were then identified, and the tumor microenvironment and levels of immune cell infiltration achieved were analyzed. The immune infiltration analysis revealed differences in the distribution of Th cells, tumor-infiltrating lymphocytes, regulatory T cells, follicular helper T cells, adipose-derived cells, interdigitating dendritic cells, CD8+ T cells, and B cells. However, validating bioinformatics analyses through biological experiments is still recommended. This study developed a prognostic model for HNSCC that included NLRP1, CHMP7, and CYCS.

Risk Prediction Model for Synchronous Oligometastatic Non-Small Cell Lung Cancer: Thoracic Radiotherapy May Not Prolong Survival in High-Risk patients.

Background and PurposeOn the basis of the promising clinical study results, thoracic radiotherapy (TRT) 1 has become an integral part of treatment of synchronous oligometastatic non–small cell lung cancer (SOM-NSCLC). However, some of them experienced rapid disease progression after TRT and showed no significant survival benefit. How to screen out such patients is a more concerned problem at present. In this study, we developed a risk-prediction model by screening hematological and clinical data of patients with SOM-NSCLC and identified patients who would not benefit from TRT.Materials and MethodsWe investigated patients with SOM-NSCLC between 2011 and 2019. A formula named Risk-Total was constructed using factors screened by LASSO-Cox regression analysis. Stabilized inverse probability treatment weight analysis was used to match the clinical characteristics between TRT and non-TRT groups. The primary endpoint was overall survival (OS).ResultsWe finally included 283 patients divided into two groups: 188 cases for the training cohort and 95 for the validation cohort. Ten prognostic factors included in the Risk-Total formula were age, N stage, T stage, adrenal metastasis, liver metastasis, sensitive mutation status, local treatment status to metastatic sites, systemic inflammatory index, CEA, and Cyfra211. Patients were divided into low- and high-risk groups based on risk scores, and TRT was found to have improved the OS of low-risk patients (46.4 vs. 31.7 months, P = 0.083; 34.1 vs. 25.9 months, P = 0.078) but not that of high-risk patients (14.9 vs. 11.7 months, P = 0.663; 19.4 vs. 18.6 months, P = 0.811) in the training and validation sets, respectively.ConclusionWe developed a prediction model to help identify patients with SOM-NSCLC who would not benefit from TRT, and TRT could not improve the survival of high-risk patients.

Abstract 1823: Imipridones show pre-clinical efficacy in MYCN-amplified and MYCN non-amplified neuroblastoma cell lines

Abstract Neuroblastoma is the most common extracranial solid tumor of childhood, accounting for 15% of all pediatric cancer-related deaths, with around 63% survival for high-risk patients. Treatment remains limited for advanced disease, calling for the development of novel therapies. We investigated the anti-tumor effect of three imipridones (ONC201, ONC206, and ONC212), a promising new class of small molecules, in the treatment of neuroblastoma. Imipridones are potent anticancer drugs that have previously shown efficacy for a variety of adult and pediatric malignancies. ONC201 and ONC206 are antagonists of dopamine receptor D2 (DRD2), while ONC212 is an agonist of GPR132, both of which are overexpressed in many cancers. We performed drug treatment with ONC201, ONC206, and ONC212 on established MYCN-amplified SK-N-BE(2) and MYCN non-amplified SH-SY5Y pediatric neuroblastoma cell lines in vitro. Cell viability assays were performed 72 hours post-treatment to generate dose responses curves. The IC50s for ONC201, ONC206, and ONC212 were 17.82 uM, 547 nM, and 70 nM for SK-N-BE(2), and 997 nM, 314 nM, and 6 nM for SH-SY5Y. Imipridones demonstrated greater efficacy for the non-MYCN-amplified cell line. Using protein quantification studies and downstream target analysis on drug-treated cells, we investigated the mechanisms of how these therapies caused cell death. We showed that imipridones inactivate cell proliferation kinases Akt/ERK and induce cell death through the pro-apoptotic tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). They also induce tumor cell apoptosis by modifying the mitochondrial Clp protease complex, decreasing expression of chaperone subunit ClpX and activating mitochondrial proteolysis. Histone deacetylases (HDACs) play a role in controlling MYCN function, which is amplified in more aggressive neuroblastoma; HDAC activity and MYCN are also upregulated in chemotherapy-resistant neuroblastoma. Cell viability assays with HDAC inhibitors Vorinostat and Panobinostat demonstrated single-agent efficacy in vitro. The IC50s for Vorinostat and Panobinostat were 609 nM and 5.51 nM for SK-N-BE(2), and 884 nM and 6.13 nM for SH-SY5Y. However, further investigation is needed to determine synergy and mechanisms of synergy when histone deacetylase (HDAC) inhibitors are used in novel combinations with imipridones. Overall, our data reveals promise in imipridone therapy for neuroblastoma, and future studies are proposed to explore potential novel therapeutic combinations in this difficult-to-treat pediatric cancer. Citation Format: Claire Lin, Wen-I Chang, Joshua N. Honeyman, Lanlan Zhou, Varun V. Prabhu, Joshua Allen, Wafik El-Deiry. Imipridones show pre-clinical efficacy in MYCN-amplified and MYCN non-amplified neuroblastoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1823.

Abstract 76: Comprehensive genomic profiling as an approach to guide therapeutic planning in pediatric patients with high-risk solid tumors

Abstract Despite the great achievements in treating pediatric cancer patients in the last several decades, approximately one fifth of patients remains uncurable using standard therapeutic modalities and require search for innovative therapeutic approaches. Advances in sequencing techniques and bioinformatic data processing enabled identification of wide spectrum of molecular alterations including single nucleotide variants, copy number aberrations, fusion genes or changes in expression and methylation patterns, which could serve as therapeutic targets. Translation of comprehensive molecular profiling into clinical practice is still limited, however, multiple precision oncology initiatives have already explored feasibility of this approach. From September 2016 to December 2020, a total of 160 patients with high-risk solid tumors that were treated or consulted at Department of Pediatric Oncology of University Hospital Brno were subjected to molecular analysis of tumor tissue using whole-exome sequencing, targeted RNA sequencing, whole-transcriptome profiling and array-CGH. In 18 patients, 2 or more biopsies were analyzed due to relapse or progression of the disease. In the cohort, CNS tumors were the most prevalent (41%), followed by sarcomas (33%) and neuroblastoma (9%). All patients were presented at multidisciplinary molecular tumor board, where treatment recommendations were discussed. In 37% of patients (n = 59), therapeutic targets were identified. Most commonly identified targets included BRAF (n = 9), FGFR1 (n = 7), NF1 (n = 6), NRAS (n = 5) and PIK3CA (n = 4), making RAS/MAPK signaling most frequently altered pathway in the subgroup. Single nucleotide variants or small indels accounted for 65% of actionable findings, followed by fusion genes (12%), copy number aberrations (9%), CD274 expression (7%, confirmed by IHC staining for PD-L1 protein), and high tumor mutational burden (7%). Clinically relevant fusions were found in 25% of patients and 20% of identified fusions were targetable. 8 patients were eligible for immunotherapy based on either PD-L1 expression, or high tumor mutational burden (&amp;gt;10 mut/Mb). Using molecular-based approach in treating high-risk patients represents a promising strategy and helps to understand the complexity of pediatric malignancies though examining tumor biology at multiple levels. Implementing the concept of precision oncology into clinical practice could not only be beneficial in the context of chances for improved survival of high-risk patients, but might also be convenient for other patients, whose successful treatment comes at cost of various secondary complications due to intensive chemotherapy/radiotherapy approaches. Supported by Ministry of Health of the Czech Republic, grant nr. NV19-03-00562, NV19-03-00501, NV19-03-00559 and NU20-03-00240. All rights reserved. Citation Format: Petra Pokorna, Hana Palova, Tina Catela Ivkovic, Sona Adamcova, Michal Kyr, Vojtech Bystry, Robin Jugas, Karolina Trachtova, Dagmar Al Tukmachi, Tomas Merta, Jaroslav Juracek, Jiri Sana, Sona Mejstrikova, Marta Jezova, Peter Mudry, Zdenek Pavelka, Jaroslav Sterba, Ondrej Slaby. Comprehensive genomic profiling as an approach to guide therapeutic planning in pediatric patients with high-risk solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 76.