Multivariate Survival Analysis Research Articles

EPEN-07. A MULTICENTER STUDY OF POOR PROGNOSIS CHROMOSOME 1Q GAIN AND/OR 6Q LOSS IN POSTERIOR FOSSA A EPENDYMOMA SHOWS INCREASED PREVALENCE FROM 20% AT DIAGNOSIS TO 60% AT FIRST RECURRENCE

Abstract Ependymoma (EPN) posterior fossa group A (PFA) has the highest rate of recurrence and the worst prognosis of all EPN types. At relapse, it is typically incurable even with re-resection and re-irradiation. The biology of recurrent PFA EPN remains largely unknown, which hinders clinical advances. In this longitudinal large multicenter study, we examined matched samples of primary and recurrent disease from PFA EPN patients (n=95) to investigate the biology of recurrence. DNA methylomic data was used to measure copy number variants (CNVs), revealing progressive large scale chromosome gains and losses in successive recurrences. These CNV changes were dominated by chromosome 1q gain and/or 6q loss (1q+/6q-), both previously identified as high-risk factors in PFA EPN, which were present in ~20% at presentation but increased to ~60% at 1st recurrence. Because 6q testing is not routinely performed, this very high incidence at recurrence has not been previously reported. Evolution of chromosomal aberrations was further explored using CNV analysis of single-nuclei RNAseq on approximately 46,000 PFA EPN cells from 6 matched pairs of primary and 1st relapse tumors that harbored CNV changes at recurrence. No evidence of rare subclones in primary tumors was observed, suggesting that chromosomal rearrangement events occur after initial presentation. Cellular and molecular characteristics associated with CNVs were examined by single-nuclei RNAseq, bulk transcriptomic analysis and immunohistochemistry, revealing that 1q+/6q- PFA have a significantly higher mitotic index, increased proportions of proliferative epithelial progenitors and decreased differentiated neoplastic subpopulations. Multivariate survival analyses showed that cases with 1q gain or 6q loss at 1st recurrence were significantly more likely to recur than cases with no 1q or 6q change. The high prevalence of 1q+/6q- at recurrence and the associated shortened survival, suggest that both these abnormalities should be routinely tested for, and used for trial stratification.

Pathomorphological Manifestations and the Course of the Cervical Cancer Disease Determined by Variations in the TLR4 Gene.

Cervical cancer (CC) is often associated with human papillomavirus (HPV). Chronic inflammation has been described as one of the triggers of cancer. The immune system fights diseases, including cancer. The genetic polymorphism of pathogen recognition receptors potentially influences the infectious process, development, and disease progression. Many candidate genes SNPs have been contradictory demonstrated to be associated with cervical cancer by association studies, GWAS. TLR4 gene activation can promote antitumor immunity. It can also result in immunosuppression and tumor growth. Our study aimed to investigate eight selected polymorphisms of the TLR4 gene (rs10759932, rs1927906, rs11536898, rs11536865, rs10983755, rs4986790, rs4986791, rs11536897) and to determine the impact of polymorphisms in genotypes and alleles on the pathomorphological characteristics and progression in a group of 172 cervical cancer subjects with stage I-IV. Genotyping was performed by RT-PCR assay. We detected that the CA genotype and A allele of rs11536898 were significantly more frequent in patients with metastases (p = 0.026; p = 0.008). The multivariate logistic regression analysis confirmed this link to be significant. The effect of rs10759932 and rs11536898 on progression-free survival (PFS) and overall survival (OS) has been identified as important. In univariate and multivariate Cox analyses, AA genotype of rs11536898 was a negative prognostic factor for PFS (p = 0.024; p = 0.057, respectively) and OS (p = 0.008; p = 0.042, respectively). Rs11536898 C allele predisposed for longer PFS (univariate and multivariate: p = 0.025; p = 0.048, respectively) and for better OS (univariate and multivariate: p = 0.010; p = 0.043). The worse prognostic factor of rs10759932 in a univariate and multivariate Cox analysis for survival was CC genotype: shorter PFS (p = 0.032) and increased risk of death (p = 0.048; p = 0.015, respectively). The T allele of rs10759932 increased longer PFS (univariate and multivariate: p = 0.048; p = 0.019, respectively) and longer OS (univariate and multivariate: p = 0.037; p = 0.009, respectively). Our study suggests that SNPs rs10759932 and rs11536898 may have the potential to be markers contributing to the assessment of the cervical cancer prognosis. Further studies, preferably with larger groups of different ethnic backgrounds, are needed to confirm the results of the current study.

Clinical Significance of Intramural Metastasis as an Independent Prognostic Factor in Esophageal Squamous Cell Carcinoma

BackgroundAlthough intramural metastasis (IM) in esophageal cancer is considered a poor prognostic factor, there are only limited reports detailing its clinicopathologic characteristics and prognostic impact.Patients and MethodsWe retrospectively included patients with esophageal squamous cell carcinoma (ESCC) with esophagectomy at our institution between 2010 and 2016. We compared patients with intramural metastases (IMs) (IM group) versus those without IMs (non-IM group) to clarify the clinical significance of intramural metastasis in ESCC.ResultsA total of 23 (3.9%) out of all 597 patients were identified to have IM. The IMs were located on the cranial side in 13 (56.5%) and caudal side in 10 (43.5%) of the primary tumor, with two multiple cases. The IM group, compared with the non-IM group, was associated with higher percentage of cN-positive (91.3 versus 67.9%, P = 0.02), pN-positive (82.6 versus 55.9%, P = 0.04), and pM(lym)-positive (30.4 versus 12.5%, P = 0.02) cases. Five-year recurrence-free survival (RFS) was significantly worse in the IM group than the non-IM group (14.9 versus 55.0 %, P < 0.001). Multivariable analysis of recurrence-free survival identified pT (HR 1.74, 95% CI 1.36–2.23, P < 0.001), pN (HR 2.11, 95% CI 1.60–2.78, P < 0.001), histological classification (HR 1.68, 95% CI 1.21–2.35, P = 0.002), and pM(LYM) (HR 1.64, 95% CI 1.64–2.95, P < 0.001), along with presence of IM (HR 2.24, 95% CI 1.37–3.64, P < 0.001) to be independent prognostic factors. Lymphatic (65.2 versus 24.9%, P < 0.001) and hepatic (26.1 versus 6.8%, P = 0.005) recurrences were significantly more common in the IM group than in the non-IM group.ConclusionsIM was shown to be associated with dismal survival after surgery. A treatment strategy emphasizing more intensive systemic control should be considered for patients with ESCC with IM.

Clinical analysis of 2790 children with retinoblastoma: a single-center experience in China.

In this study, we aimed to analyze the clinical characteristics and prognosis of children with retinoblastoma (RB) in a single center in China with a large sample collection spanning 17years. The clinical data of 2790 children with RB treated in Beijing Tongren Hospital from 2005 to 2021 were collected, and a retrospective analysis was conducted. The median age of the participants was 28.3months. There were 3624 affected eyes, 12.4% of which were in groups A-C, 67.1% in groups D-E and 16.2% were not specified. The primary symptom observed in most cases was a white pupil, accounting for 66.5%, followed by strabismus (12.8%). The median follow-up time was 59.7months. The enucleation rate was 71.3% (703/986) in a single left eye and 72.5% (702/968) in a single right eye. The overall survival (OS) rate was 95.8% (2444/2552) because 237 patients dropped out, and 109 died. Kaplan‒Meier survival analysis showed that the median survival time (MST) was 125.92months [95% confidence interval (CI) = 124.83-127.01]. Cox multivariate survival analysis showed that trilateral RB (P = 0.017), metastasis site (P = 0.001), and combined distant tissue metastasis (P = 0.001) were independent prognostic factors for RB. The OS of 44 cases of familial RB was 93.2% (41/44), with an MST of 80.62months (95% CI = 67.70-93.54). The timing of eye protection treatment and enucleation should be comprehensively judged to avoid worsening prognosis due to operation time delay. More importantly, the promotion and popularization of diagnosis and treatment technologies are necessary to further improve RB prognosis.

Role of adjuvant chemotherapy (CT) in node negative 4-5 cm non-small cell lung cancer in elderly population.

e20615 Background: The role of adjuvant CT for 4-5 cm primary lung tumors without any regional lymph node involvement following surgical resection is somewhat controversial. While it is favored in most cases, it should be individualized depending on other pathological risk factors and the patient's performance status. In this study, we investigated the benefit of adjuvant CT in elderly patients with 4-5 cm tumor size following complete surgical resection. Methods: We utilized Surveillance, Epidemiology, and End Results Program (SEER) database to identify elderly patients (≥65 years) with 4 to 5 cm sized non-small cell lung cancer after complete surgical resection diagnosed from 2010-2015. The baseline characteristics among the patients who received and didn’t receive adjuvant CT were compared using relevant parametric/non-parametric tests. Kaplan Meir curve was generated for the univariate survival analysis, and the log-rank test was used for comparison. Multivariate survival analysis was done using the cox proportional hazards regression model. Results: The database included 2582 patients. Among them, 492 (19.1%) cases had received adjuvant chemotherapy while 2090 (80.9%) cases had not. The population that received chemotherapy was younger than those that did not (Median:75 years vs 71 years, p &lt; 0.001). The 5-year overall survival for patients who received chemotherapy was significantly higher than those who did not (53.9% vs 46.5%, P = 0.002). On the multivariate analysis adjusted for age, gender, race, income status, and type of surgery, cases with adjuvant chemotherapy had lower hazards as compared to those who had not received adjuvant chemo (Hazard Ratio (HR):0.86, confidence interval (CI): [0.75,0.99], P value = 0.04). Conclusions: Our study demonstrated a survival benefit with adjuvant CT for node-negative NSCLC of 4-5 cm size in the elderly population.

Association of circulating tumor DNA with survival in neoadjuvant-treated triple negative breast cancer independent of pathological complete response.

e12588 Background: Many patients with triple negative breast cancer (TNBC) still succumb to their disease after systematic treatment. It is crucial to identify those at high risk. Circulating tumor DNA (ctDNA) has recently become a promising marker to monitor tumor burden. Our study aimed to evaluate the clinical value of the presence and dynamic change of ctDNA to predict the tumor response and prognosis in TNBC patients treated with neoadjuvant chemotherapy (NAC). Methods: Cell-free DNA (cfDNA) was isolated from pre-NAC plasma samples and then analyzed by duplex sequencing. A Chi-square test or Fisher exact test were used for categorical variables. Kaplan‐Meier analysis with a Log‐rank test and the Cox proportional hazard regression model were used for the univariate and multivariable survival analysis. Survival prediction was assessed using a time-dependent receiver operating characteristic (ROC) curve and area under the ROC curve (AUC). Results: A total of 82 TNBC patients receiving NAC were enrolled. Baseline ctDNA detection indicated significantly worse survival. TP53 and genes involved in PI3K-Akt signaling pathway mutations were significantly associated with survival independent of the pathological complete response (pCR). A TP53 detection combined clinical model is highly predictive, with a time-dependent ROC of 0.936 for 3-year overall survival (OS), compared to the model including clinical variables only (AUC of the clinical predictor: 0.751, P= 0.028). Conclusions: Baseline ctDNA detection, TP53 mutations, and genes involved in PI3K-Akt signaling pathway mutation are all independent prognostic factors in TNBC patients receiving NAC. A TP53 detection combining model is highly predictive.

Impact of systemic immune-inflammation index in patients with limited-stage small cell lung cancer.

e20626 Background: The systemic immune-inflammation index (SII) has been suggested as a prognostic marker in several solid malignant neoplasms. However, there are few studies on the prognostic value of SII in patients with limited-stage SCLC. This study explored the impact of SII on overall survival (OS) and progression-free survival (PFS) in patients with limited-stage small cell lung cancer, and compared the predictive ability of SII and platelet/lymphocyte ratio (PLR) to find a better prognostic marker. Methods: In total, 572 patients with new diagnosis of limited-stage SCLC were included in this study. The optimal threshold of SII and PLR were determined using the outcome(OS)-based method by maximizing the log-rank test statistic and the survival differences.The predictive ability of SII and PLR were compared by drawing the continuous time-dependent receiver operating characteristic curves (time-dependent ROC). Logistic multivariable analysis was performed to identify factors associated with high SII. Propensity score matching (PSM) was used to balance confounders between groups and adjust observed selection bias. Kaplan-Meier methods and Cox proportional hazards models were used to assess the impact of pre-treatment SII on OS and PFS. Results: The median age of the whole group was 60.0 (25.0-81.0) years, and the median follow-up time was 56.5 (2.5-95.4) months. The optimal cutoff value of SII and PLR were 760.6 and 137.3, respectively. The area under the time-dependent ROC curves of SII and PLR in 1-, 2- and 3-year were 0.727, 0.708, 0.680 and 0.680, 0.669, 0.649, respectively. The high SII group was correlated with pleural effusion (P = 0.001), T stage (P = 0.009), N stage (P = 0.048), and pretreatment serum sodium (P = 0.003). The median OS and PFS of the whole group was 26.0 months (95%CI 23.8-28.2) and 13.0 months (95%CI 11.3 -14.7), and the 1-, 3-, 5-year OS rates and the 1-, 3-, 5-year PFS rates were 81.1%, 35.5%, 27.1% and 52.8%, 24.8%, 19.9%, respectively.There were 414 patients after PSM. In multivariable survival analysis, SII remained an independent prognostic factor for OS (HR1.792; 95%CI 1.416-2.268; P &lt; 0.001) and PFS (HR1.410; 95%CI 1.043-1.906; P = 0.025). Conclusions: Elevated SII is an independent adverse prognostic factor in patients with limited-stage SCLC and is superior to PLR in terms of prognostic ability.

SALVAGE RADIOTHERAPY IN RELAPSED/REFRACTORY LARGE B‐CELL LYMPHOMA AFTER CAR T‐CELL THERAPY FAILURE

Introduction: We sought to describe our experience with salvage radiation therapy (RT) relative to other therapies in patients with relapsed/refractory large B-cell lymphoma (LBCL) post-CD19-targeted chimeric antigen receptor (CAR T)-cell therapy failure. Methods: A multi-institutional retrospective study was conducted in a database of 352 consecutive LBCL patients who received axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) between 2017 and 2021. Patients who relapsed following CAR T-cell therapy and received salvage therapies (RT alone, systemic therapy alone, or combined modality therapy [CMT]) were identified and analyzed. A separate analysis was then conducted for patients who were treated with comprehensive versus focal RT. Results: A total of 120 patients with post-CAR T relapsed LBCL received salvage therapies (RT alone, 14 patients; CMT, 40 patients; systemic therapy alone, 66 patients). The median follow-up after CAR T-cell infusion was 10.2 months (interquartile range [IQR]: 5.2–20.9 months). Failure occurred in previously involved sites prior to CAR T-cell therapy in 78% of patients (n = 93). The median time from CAR T-cell therapy infusion to the start of salvage therapy was 3.4 months (IQR: 1.7–6.5 months). A total of 93 sites were irradiated among the 54 patients who received RT in the RT and CMT cohorts. The median dose/fractionation were 30 Gy (range 4–50.4 Gy) and 10 fractions (range 1–28 fractions). The 1-year local control (LC) rate for the 81 assessable sites was 84%. The median overall survival (OS) from the time of salvage therapy was not reached for the RT group, 10.5 months for the CMT group, and 6.6 months for the ST group (p = 0.4). The median OS from the start date of RT was significantly higher among patients who received comprehensive RT versus focal RT (19.1 months vs. 3.0 months, p ≤ 0.001); 26 of the 29 patients who received comprehensive RT had only a single site of disease, but survival for the 3 patients with >1 site of disease was not statistically different (p = 0.17). Receipt of bridging therapy and CAR T construct were not significantly associated with OS after CAR T infusion. On multivariate survival analysis, achieving PR or CR post-CAR T (HR = 0.5, 95% CI: 0.3–0.9, p = 0.01) was independently associated with superior OS. Keywords: aggressive B-cell non-Hodgkin lymphoma, cellular therapies, radiation therapy No conflicts of interests pertinent to the abstract.

Surgery with adjuvant chemotherapy versus chemoradiation for early-stage large cell neuroendocrine cancer (LCNEC) of the lung: A SEER plus based analysis.

e20616 Background: LCNEC of the lung is a rare and highly aggressive tumor with neuroendocrine differentiation. Given its rare occurrence and lack of data from large randomized trials, treatment recommendations are based on the extrapolation of data, primarily from small-cell lung cancer studies. We conducted this study to evaluate the survival difference among patients with LCNEC with an N1 disease between those who received surgery and adjuvant chemotherapy versus definitive chemotherapy and radiotherapy. Methods: We utilized Surveillance, Epidemiology, and End Results (SEER) plus 18 registries database to identify patients diagnosed with LCNEC with tumor stage of T1, T2, or T3 and nodal stage of N1. The study population included patients, 18 years and above, who underwent surgical resection followed by adjuvant chemotherapy and patients who received definitive chemo-radiotherapy for early stage LCNEC. Kaplan-Meier and log rank test were used to compare overall survival (OS) and Cancer specific survival (CSS). Multivariate survival analysis was done using the cox proportional hazards regression model. Results: A total of 178 patients were included, 57.3% (n = 102) were &lt; 65-year-old, 50.56% (n = 90) were male, mostly Caucasian 87.08% (n = 155) and identified as non-Hispanic 93.26% (n = 166). Out of them, 70.22% (n = 125) underwent surgery plus adjuvant chemotherapy and 29.78% (n = 53) underwent chemoradiation. Patients who underwent surgery with adjuvant chemotherapy had higher overall survival (OS) than chemoradiation (37 vs. 11 months respectively). 3-year (49.9% vs. 15.7%) and 5-year OS rates (36.7% vs. 10.4%) were also higher in the earlier group. On multivariate analysis after adjusting for age, gender, race and origin, patients who received chemoradiation had higher hazards as compared to those who received surgery and adjuvant chemotherapy (Hazard ratio: 2.91, 95% Confidence interval (CI):1.93,4.37, P value &lt; 0.001). When examining the cancer specific survival (CSS), similar results were observed with higher CSS in the surgery with adjuvant chemotherapy group (18 vs. 8 months) reaching a statistical significance of P &lt; 0.001 and higher hazards in chemoradiation group (Hazard ratio: 3.33, 95% Confidence interval (CI):2.09,5.28, P value &lt; 0.001). 3-year survival (26.47% vs. 2.7 %) and 5-year CSS rates (11.76% vs. not reached) were also pronounced in the patients treated with surgery with adjuvant chemotherapy. Conclusions: Our study demonstrates that patients with early stage LCNEC (T1-3 N1) disease treated with surgery and adjuvant chemotherapy had statistically significant overall and cancer specific survival rates compared to those treated with chemoradiation.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Diffuse Large B- cell Lymphoma (DLBCL) is characterized by genetic and clinical heterogeneity. Different loci within the human leukocyte antigen (HLA) region have been implicated in susceptibility and disease control of DLBCL. Methods: HLA typing was performed using Sequence-Specific Oligonucleotide (SSO) and Sequence-Specific Primer (SSP) in 60 DLBCL patients and 250 healthy adult donors from local Bone Marrow registry. Statistical analysis was conducted with version 29.0 of IBM SPSS. The phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 between patients and controls were compared with the 2-sided Fisher’s exact test. Results with p-value < 0.05 were considered statistically significant. Odds Ratios (OR) with 95% Confidence Intervals were calculated to further strength the results. Additionally, a follow-up analysis was performed by calculating Bonferroni-adjusted p-values (pc). Thereafter HLA polymorphisms that showed statistically significant difference were included in univariate and multivariate survival analysis together with the patients clinical-biological characteristics (age, stage, LDH, R-IPI). The R programming language, version 4.2.2 and specifically the “survivalAnalysis” package version 0.3.0. were used to investigate the associations of each factor with the Overall Survival (OS) and the Progression Free Survival (PFS). Results: DLBCL patients displayed a lower frequency of HLA-C*12 (6.7% vs. 34.7%, p = 0.001, pc = 0.00001, OR = 0.13, 95% CI [0.05, 0.38]), HLA-DRB1*16 (15% vs. 29.7%, p = 0.02, pc = 0.04, OR = 0.42, 95% CI [0.19, 0.89]) and HLA-DRB1*03 (58.3% vs. 77.5%, p = 0.02, pc = 0.01, OR = 0.40, 95% CI [0.22, 0.74]) compared to healthy individuals. In univariate analysis only advanced stage, high LDH and low versus high R-IPI had statistically significant impact on OS (p values 0.007, 0.003 and 0.002 respectively) and PFS (p-values 0.001, 0.002 and <0.001 respectively). Interestingly the Cox regression analysis used to evaluate the impact of LDH together with the HLA-DQB1*03 polymorphism on OS showed that although normal LDH is a good prognostic factor with HR = 0.33 95% CI [0.17 – 0.65] p-value = 0.001), the combination of normal LDH with DQB1*03 with HR 2.07 95% CI [1.06–4.07] indicates a significantly increased risk of death (p-value = 0.034). Regarding PFS the LDH- DQB1*03 model displayed also statistical significancy (p = 0.001) in a similar way with DQB1*03 increasing the risk of death while keeping LDH within normal ranges. Conclusions: Our results suggest that DLBCL patients express certain genetic types of HLA in lower frequency compared to healthy individuals. Antigens represented less frequently may act protectively in the development of the DLBCL. However, the presence of rarely represented HLA types failed to prove any positive impact on OS and PFS indicating the complexity of DLBCL pathogenesis. Keywords: aggressive B-cell non-Hodgkin lymphoma, diagnostic and prognostic biomarkers No conflicts of interests pertinent to the abstract.

Impact of the Affordable Care Act and Medicaid Expansion on Insurance Coverage and Outcomes in Patients with HIV‐associated Aggressive B‐cell Non‐Hodgkin Lymphomas

Introduction: HIV-associated lymphomas affect a uniquely disadvantaged group of patients, who were often denied insurance based on preexisting conditions until the Affordable Care Act (ACA) was signed in 2010. We investigated the impact of ACA and its Medicaid expansion in 2014 which covered the low-income strata, on outcomes among patients with HIV-associated aggressive B-cell non-Hodgkin lymphomas (HIV-aB-NHL). Methods: We used the National cancer database (NCDB) to identify HIV-associated aB-NHL patients aged 18–64 years from 2004 to 2017. We defined the pre-ACA period up to 2013 and the post-ACA period after 2014. States were grouped as Medicaid expansion adopted or not adopted. To reduce bias from advancements in anti-retroviral and chemo-immuno-therapies, we compared survival outcomes between 2010 to 2013 and 2014 to 2017. Kaplan-Meier method and a parametric Weibull model were used for survival analysis. Results: We identified 10,795 eligible patients with HIV-associated aB-NHL, comprised of 1802 Hispanics (16.7%), 3915 non-Hispanic blacks [NHB (36.3%)], 4727 Non-Hispanic Whites [NHW (43.8%)] and 351 other minorities (3.2%). The predominant diagnoses were diffuse large B-cell lymphoma (63.3%) and Burkitt lymphoma (20.1%). The figure shows the distribution of insurance status at diagnosis in Medicaid expansion (n = 4611) and non-expansion (n = 3091) states before and after the implementation of ACA stratified by race. Hispanics were more likely to be from residential zip codes in the lower educational quartile. A higher proportion of patients were seen at academic medical centers in expansion states across all races, and this further improved post-ACA. There was a significant improvement in survival seen among NHB (p < 0.01) post-ACA though the trend in Hispanics was not significant (P = 0.36). A multivariable survival analysis using the Weibull model adjusting for age, sex, insurance status, Charlson-Deyo comorbidity index, income, race, and Medicaid expansion status found statistically significant improvement in the states that adopted Medicaid expansion (HR 0.88, p < 0.01) though NHB race predicted poor survival (HR 1.49, p < 0.01). Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cancer Health Disparities Conflicts of interests pertinent to the abstract. L. D. Anderson Consultant or advisory role: Celgene, BMS, Amgen, GSK, Janssen, Karyopharm, Beigene, AbbVie, Cellectar, and Sanofi Y. F. Madanat Consultant or advisory role: BluePrint Medicines, GERON, OncLive, Sierra Oncology, Stemline Therapeutics and Novartis G. Kaur Honoraria: BMS and Cellectar F. T. Awan Consultant or advisory role: Genentech, Astrazeneca, Abbvie, Janssen, Pharmacyclics, Gilead sciences, Kite pharma, Celgene, Karyopharm, MEI Pharma, Verastem, Incyte, Beigene, Johnson and Johnson, Dava Oncology, BMS, Merck, Cardinal Health, ADCT therapeutics, Epizyme, Caribou Biosciences, Cellecter Bisosciences Research funding: Pharmacyclics P. Ramakrishnan Geethakumari Consultant or advisory role: Kite Pharma, Bristol Myers Squibb, Rafael Pharma, Pharmacyclics LLC, ADC Therapeutics and Cellectar Biosciences

The role of adjuvant chemotherapy (CT) for early stage resectable node negative small cell lung cancer with size of ≤ 2 cm post-surgical resection: A SEER plus based statistical analysis.

e20643 Background: Small cell lung cancer (SCLC) is a poorly differentiated neuroendocrine tumor accounting for 15% of all lung cancers. Surgical resection followed by adjuvant platinum-etoposide is recommended for patients with limited-stage SCLC (T1 N0M0). In this study, we sought to evaluate the survival benefit of adjuvant chemotherapy for patients with ≤2 cm size SCLC following surgical resection. Methods: We utilized Surveillance, Epidemiology and End Results (SEER) plus 18 registries to identify adult patients (≥18 years) diagnosed with small cell cancer of the lung with tumor size of ≤ 2 cm from 2010 to 2018. The study population comprised of patients who underwent surgical resection followed by adjuvant chemotherapy and patients who received surgical resection alone. Kaplan-Meier and long rank tests were used to compare overall survival between the two groups. Multivariate survival analysis was done using the Cox proportional hazards regression model. Results: 419 patients were identified, with 203 (48%) receiving adjuvant CT while 216 (52%) not receiving adjuvant CT. The population who received adjuvant chemotherapy was younger than those who did not (Median years: 67 years vs 71 years, p &lt; 0.001). The 5-year overall survival rate was significantly higher for those receiving adjuvant CT (49% vs 40.9%, P value &lt; 0.001). On multivariate analysis after adjusting for age, gender, race, and origin, adjuvant chemotherapy was associated with better overall survival (HR:0.67; 95% CI 0.54 - 0.88, p = 0.003). Conclusions: Our study demonstrates that adjuvant CT should be used for early-stage small cell lung cancer irrespective of tumor size following surgical resection.

Expression of NAMPT in Patients with Multiple Myeloma and Its Correlation with Clinical Manifestation

To analyze the expression level of nicotinamide phosphoribosyltransferase (NAMPT ) in bone marrow of multiple myeloma (MM) patients and its correlation with clinicopathological features, clinical efficacy and prognosis. RT-qPCR and Western blot were used to detect the expression of NAMPT mRNA and protein in bone marrow mononuclear cells from 85 newly diagnosed MM patients (including 17 relapsed MM patients) and 15 healthy donors, and explore the correlation of the expression of NAMPT gene with clinicopathological features and efficacy. Kaplan-Meier method was used to analyze the effects of NAMPT on progression-free survival (PFS) and overall survival (OS), and univariate and multivariate survival analysis were performed. The median expression level of NAMPT mRNA in bone marrow of newly diagnosed and relapsed MM patients was significantly higher than that of healthy donors (P <0.001). The expression of NAMPT mRNA in relapsed MM patients was significantly higher than that in newly diagnosed MM patients (P <0.001), which was consistent with the expression of NAMPT protein. ISS staging, lactate dehydrogenase and C-reactive protein levels, p53 deletion and the proportion of myeloma cells were increased in high NAMPT expression group compared with low NAMPT expression group (P <0.001). Compared with complete remission group, NAMPT mRNA expression was significantly up-regulated in partial remission group, progression group and relapsed group (P <0.001). The median OS and PFS of patients in high NAMPT expression group was 27.3 and 14.9 months, respectively, which was significantly shorter than 39.1 and 27 months in low NAMPT expression group (P =0.048, P <0.001). Both univariate and multivariate analysis showed that NAMPT expression was correlated with PFS and OS. The expression level of NAMPT in newly diagnosed and relapsed MM patients is significantly higher than that in normal controls, and its up-regulation is related to the adverse clinical characteristics, efficacy and prognosis of MM patients. NAMPT is an independent prognostic risk factor of MM.

P-53 Prognostic factors in metastatic pancreatic carcinoma: A multivariate analysis and predictive score of survival

P-53 Prognostic factors in metastatic pancreatic carcinoma: A multivariate analysis and predictive score of survival

Outcomes in premenopausal patients with HR+/HER2- breast cancer and lymph node micro-metastasis based on the 21-gene recurrence score.

571 Background: Postmenopausal patients with hormone receptor positive, HER2-negative (HR+/HER2-) early breast cancer (EBC) and 21-gene OncotypeDX (ODX) recurrence scores (RS) &lt;26 do not benefit from chemoendocrine therapy (‘CET’) compared to endocrine monotherapy (‘E’). The TAILORx and RxPONDER trials demonstrated this was consistent in node-negative and node-positive disease, respectively. In premenopausal patients, however, guidelines for those with low RS diverge between disease involving 0 (pN0) vs. 1-3 (pN1a-c) lymph nodes. Additionally, treatment decisions are less clear for patients with micro-metastasis (pN1mi), who comprised only about 10% of patients in RxPONDER. This study used the National Cancer Database (NCDB) to assess treatment patterns and survival outcomes in premenopausal patients with EBC and lymph node micro-metastasis. Methods: A cohort of patients aged &lt;50, diagnosed between 2004-2019 with HR+/HER2- EBC and who underwent ODX testing, was recruited from the NCDB. (A) Firstly, we described demographic and clinical characteristics of a sub-cohort with micro-metastasis using univariate statistics. (B) We confirmed the prognostic value of ODX in this sub-cohort with multivariate Cox regression analysis of overall survival (OS). (C) We explored patterns of practice amongst the total cohort with ODX &lt;26 with chi-squared testing for differences in CET use by nodal status. (D) To elucidate the predictive value of this assay, we performed Kaplan-Meier models comparing OS for those with RS &lt;26 receiving E vs. CET, controlling granularly for nodal status: (i) pN1a-c, (ii) pN1mi, and (iii) pN0. Results: Of n=72,068 patients aged &lt;50 with HR+/HER2- EBC and ODX data, 6.1% (n=4,402) had micro-metastasis. (A) The median age of this subgroup was 45 (IQR 41-47) years. Most tumors were grade II (n=2,472, 57.7%) with ductal histology (n=3,500, 80.3%). 73.4% of pN1mi cases had RS &lt;26, while 26.6% had RS ≥26. (B) Multivariate Cox regression – adjusting for comorbidity, race and chemotherapy use – confirmed significance in this pN1mi cohort of RS ≥26 prognosticating poorer OS compared to RS 0-15 (HR 4.42, 95% CI 2.35-8.31, p&lt;0.001). (C) 29.0% (n=1,033) of patients with pN1mi and ODX &lt;26 underwent CET, greater than 15.2% (n=6,568) with pN0 and less than 47.3% (n=2,884) with pN1a-c staging (p&lt;0.001). (D) A benefit in OS (p=0.017) was observed in cases with RS&lt;26 and pN1a-c using CET (5-year OS: 99%) vs. E (5-year OS: 97.5%), but not in pN1mi (p=0.49) or pN0 (p=0.57) disease. Conclusions: The management of premenopausal patients with HR+/HER2- EBC, isolated micro-metastasis, and ODX &lt;26 is unclear. Our large registry study found the addition of chemotherapy to endocrine therapy was associated with improved survival in cases with ODX&lt;26 involving 1-3 lymph nodes, but not in node-negative or micro-metastatic disease. Prospective trials are needed to confirm these findings.

Effect of Early versus Delayed Use of Norepinephrine on Short-Term Outcomes in Patients with Traumatic Hemorrhagic Shock: A Propensity Score Matching Analysis.

Guidelines recommend norepinephrine (NE) for the treatment of fatal hypotension caused by trauma. However, the optimal timing of treatment remains unclear. We aimed to investigate the effect of early versus delayed use of NE on survival in patients with traumatic haemorrhagic shock (HS). From March 2017 to April 2021, 356 patients with HS in the Department of Emergency Intensive Care Medicine of the Affiliated Hospital of Yangzhou University were identified using the emergency information system and inpatient electronic medical records for inclusion in the study. Our study endpoint was 24 h mortality. We used a propensity score matching (PSM) analysis to reduce bias between groups. Survival models were used to evaluate the relationship between early NE and 24 h survival. After PSM, 308 patients were divided equally into an early NE (eNE) group and a delayed NE (dNE) group. Patients in the eNE group had lower 24 h mortality rates than those in the dNE group (29.9% versus 44.8%, respectively). A receiver operating characteristic analysis demonstrated that a cut-off point for NE use of 4.4 h yielded optimal predictive value for 24 h mortality, with a sensitivity of 95.52%, a specificity of 81.33% and an area under the curve value of 0.9272. Univariate and multivariate survival analyses showed that the survival rate of patients in the eNE group was higher (p < 0.01) than those in the dNE group. The use of NE within the first 3 h was associated with a higher 24 h survival rate. The use of eNE appears to be a safe intervention that benefits patients with traumatic HS.

Hsp90 is a potential risk factor for ovarian cancer prognosis: an evidence of a Chinese clinical center

BackgroundThe potential treatment effects of heat shock protein 90 (Hsp90) inhibitors in ovarian cancer (OC) are controversial. This research aims to investigate the relationship between the level of Hsp90 in peripheral blood and the prognosis of OC patients, as well as the clinicopathological indicators.Materials and methodsWe retrospectively collected the clinicopathological indicators of OC patients who were admitted to the Department of Obstetrics and Gynecology of the First Affiliated Hospital of Anhui Medical University from 2017 to 2022. Hsp90 level in patient blood was detected by enzyme-linked immunosorbent assay, and the correlation between Hsp90 level and OC prognosis was systematically investigated. Kaplan–Meier method was used to draw the survival curve, and the average survival time and survival rate were calculated. The log-rank test and Cox model were used for univariate survival analysis, and the Cox proportional hazards model was applied for multivariate survival analysis. Based on the TCGA dataset of OC obtained by cBioPortal, Pearson’s correlation coefficients between Hsp90 level values and other mRNA expression values were calculated to further conduct bioinformatics analysis. GSEA and GSVA analysis were also conducted for gene functional enrichment. The expression of Hsp90 in OC tissues were evaluated and compared by Immunohistochemical staining.ResultsAccording to the established screening criteria, 106 patients were selected. The enzyme-linked immunosorbent assay results showed that 50.94% OC patients with abnormal Hsp90 level. According to the outcome of Kaplan–Meier curves, the results revealed that the abnormal level of Hsp90 was suggested to poor prognosis (P = 0.001) of OC patients. Furthermore, the result of multivariate Cox proportional hazards regression model analysis also predicted that abnormal Hsp90 level (HR = 2.838, 95%CI = 1.139–7.069, P = 0.025) was linked to poor prognosis, which could be an independent prognostic factor for the prognosis of OC patients. Moreover, top 100 genes screened by Pearson’s value associated with Hsp90, indicating that Hsp90 participated in the regulation of ATF5 target genes, PRAGC1A target genes and BANP target genes and also enriched in the metabolic processes of cell response to DNA damage stimulus, response to heat and protein folding.ConclusionHsp90 level is positively associated with OC mortality and is a potential prognostic indicator of OC.

Racial and socioeconomic disparities in glioblastoma outcomes: A single-center, retrospective cohort study.

Glioblastoma (GBM) is the most common malignant primary brain tumor. Emerging reports have suggested that racial and socioeconomic disparities influence the outcomes of patients with GBM. No studies to date have investigated these disparities controlling for isocitrate dehydrogenase (IDH) mutation and O-6-methylguanine-DNA methyltransferase (MGMT) status. Adult patients with GBM were retrospectively reviewed at a single institution from 2008 to 2019. Univariable and multivariable complete survival analyses were performed. A Cox proportional hazards model was used to assess the effect of race and socioeconomic status controlling for a priori selected variables with known relevance to survival. In total, 995 patients met inclusion criteria. Of these, 117 patients (11.7%) were African American (AA). The median overall survival for the entire cohort was 14.23months. In the multivariable model, AA patients had better survival compared with White patients (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.2-0.69). The observed survival difference was significant in both a complete case analysis model and a multiple imputations model accounting for missing molecular data and controlling for treatment and socioeconomic status. AA patients with low income (HR, 2.17; 95% CI, 1.04-4.50), public insurance (HR, 2.25; 95% CI, 1.04-4.87), or no insurance (HR, 15.63; 95% CI, 2.72-89.67) had worse survival compared with White patients with low income, public insurance, or no insurance, respectively. Significant racial and socioeconomic disparities were identified after controlling for treatment, GBM genetic profile, and other variables associated with survival. Overall, AA patients demonstrated better survival. These findings may suggest the possibility of a protective genetic advantage in AA patients. To best personalize treatment for and understand the causes of glioblastoma, racial and socioeconomic influences must be examined. The authors report their experience at the O'Neal Comprehensive Cancer Center in the deep south. In this report, contemporary molecular diagnostic data are included. The authors conclude that there are significant racial and socioeconomic disparities that influence glioblastoma outcome and that African American patients do better.

Polypill protects MAFLD patients from cardiovascular events and mortality: a prospective trial.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a novel term that distinguishes patients at risk of adverse clinical outcomes with higher accuracy than those with non-alcoholic fatty liver disease (NAFLD). Cardiovascular mortality is the leading cause of death in MAFLD. The current literature lacks large-scale prospective studies that address preventive approaches for cardiovascular health in MAFLD. We investigated whether MAFLD patients benefit from a fixed-dose combination therapy (Aspirin, hydrochlorothiazide, atorvastatin, valsartan), known as a Polypill. Analysis was performed (stratified based on MAFLD status) of a clinical trial that included 1596 individuals randomly allocated to an intervention (polypill) or a control (usual care) group. Patients were followed up for five years for any adverse drug reaction, major cardiovascular events, and mortality. Univariable and multivariable survival analyses were performed, and the interaction level was assessed by R programming. Patients who consumed the polypill had significantly lower hazard ratios of major cardiovascular events incidence (HR 0.56, 95% CI 0.41-0.78) and cardiovascular mortality (HR 0.41, 95% CI 0.2-0.86) compared to the control group. Polypill showed significantly better results in lowering cardiovascular events in MAFLD patients than in the general population. (p-value for interaction: 0.028). Moreover, comparing those patients who had high adherence to the Polypill, with the control group, further enhanced the results. Major cardiovascular events are prevented in MAFLD patients who consume the Polypill. MAFLD patients benefit from the Polypill more than the general population.

Clinical outcomes after pulmonary vein isolation for atrial fibrillation in men versus women; insights from a contemporary large-scale population study

Abstract Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation (AF) is associated with an increased risk of stroke and mortality. Pulmonary vein isolation (PVI) is the most effective treatment to reduce AF burden and is associated with a reduced risk of stroke and death. Differences in long-term clinical outcomes following PVI between sexes are debatable. Purpose We aimed to explore the sex differences in outcomes following PVI in a contemporary population of AF patients. Methods This is a historical population-based study including all adult patients of the largest health maintenance organization in Israel who were first diagnosed with AF between January 1st, 2010, and January 1st, 2020. Patients with congenital heart disease, significant mitral stenosis, or who underwent valvular surgery were excluded. The primary outcomes were stroke and all-cause death after PVI. Early (30-day) outcomes were compared using logistic regression, and late (3-year) outcomes were assessed using multivariable survival analyses with Cox regression. Results Of 94,612 patients diagnosed with incident AF during the study period, 4593 (4.85%) underwent PVI, of whom 1892 (38.2%) were women. Women were older (65±12 vs. 63±13) and less likely to be smokers (15.0% vs. 33.0%). Women had higher body-mass-index (30.26±6.58 vs. 29.14±4.86) and higher rates of hypertension (66.4% vs. 63.2%) but had lower rates of known coronary or peripheral vascular disease and congestive heart failure (p&amp;lt;0.05 for all). The CHA2DS2-VASc score was higher among women compared to men [median 3 (IQR 2-4) vs. median 2 IQR (1-3), p&amp;lt;0.001). Compared to men, women were treated more often with beta-blockers (74.5% vs. 69.4%), non-dihydropyridine calcium channel blockers (6.5% vs. 3.0%), and class 1c antiarrhythmic drugs (19.4% vs. 12.8%; p&amp;lt;0.001 for all), but were treated less with amiodarone (14.2% vs. 18.1%, p&amp;lt;0.001). In the 30 days following CA, stroke occurred in 8 (0.2%) patients, and 26 (0.6%) patients died (p&amp;gt;0.1 for both). Three-year mortality was lower in women than in men (6.2%% vs. 8.6%, p=0.003), while stroke rates were similar in women (1.0%) and men (1.5%, p&amp;gt;0.1). In multivariable survival models, adjusting for potential confounders, women had a lower risk of mortality [aHR 0.72 95%CI (0.56-0.92), p=0.009]. Conversely, the risk of stroke was similar in women and men [aHR 0.62 95%CI (0.33-1.12), p=0.114]. The results were similar in propensity-adjusted models accounting for all differences between men and women. Conclusions In this contemporary AF population, short-term stroke and mortality rates after PVI were very low and similar in men and women. The risk of long-term stroke following PVI was relatively low and similar across sex criteria. Women had a lower risk of long-term mortality than men following PVI despite undergoing the procedure at an older age and after adjusting for comorbidities and background medical therapy, suggesting possible sex differences in long-term mortality after PVI.