Adverse Survival Outcomes Research Articles

Association between smoking status, toxicity and survival in the checkpoint inhibitor immunotherapy

IntroductionImmune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by enhancing T-cell-mediated immune responses against tumors. However, their use can lead to immune-related adverse events (irAEs), impacting patient outcomes.MethodsThis single-center, observational study investigates the relationship between immune-related adverse events (irAEs) and survival outcomes in 151 patients treated with ICIs, with or without chemotherapy, at the Department of Clinical Oncology and Chemotherapy in the Independent Public Hospital No. 4 in Lublin. Statistical analyses were performed using the log-rank test, and multivariable Cox proportional hazard model (p < 0.05).ResultsIrAEs were observed in 38% of patients, with the most common being thyroid dysfunction (11.9%) and dermal toxicity (6.6%). Individual toxicity groups presented similar median values of “pack-years”, suggesting that smoking did not have a direct impact on the degree of toxicity. No relationship between the number of “pack-years” and the time of occurrence of toxicity symptoms and the number of toxicity sites was found. Smoking status did not have a moderating effect on the toxicity parameter in survival analysis (OS) and progression free survival analysis (PFS). Pack-years of smoking significantly impacted both OS (HR = 1.01, p = 0.014) and PFS (HR = 1.01, p = 0.011).DisscusionThe results suggested that smoking, measured in pack-years, had no appreciable effect on the amount of toxicity experienced by patients and no correlation between smoking status, irAEs and efficiency of the treatment was found. Despite results not reaching statistical significance, other potential mechanisms by which smoking may influence cancer treatment cannot be ruled out.

Association between tumor deposits and liver and lung metastases at diagnosis of colorectal cancer: A SEER-based analysis

BackgroundTumor deposits are a unique histologic feature of colorectal cancer that is associated with adverse survival outcomes. The present study aimed to assess the association between tumor deposits and liver and lung metastases and to describe the characteristics of colorectal cancer associated with tumor deposits. MethodsThe Surveillance, Epidemiology, End Results (SEER) database was screened between 2010 and 2020 for patients with colorectal adenocarcinoma who underwent radical resection with data on tumor deposits. The primary outcome of the study was liver and lung metastases. The secondary outcome was the characteristics of patients with tumor deposits. ResultsA total of 205,294 patients (52% male, mean age 66.5 years) were included in the study. Tumor deposits were detected in 20,059 (9.7%) patients. Patients with tumor deposits were younger and presented more often with larger tumors, T3/T4 tumors, N+ tumors, stage IV disease, left-sided and rectal cancers, signet-ring cell carcinomas, high-grade adenocarcinomas, and perineural invasion. Multivariable binary regression analyses showed that tumor deposits were associated with 72% higher odds of liver metastases (odds ratio 1.72, 95% confidence interval 1.62–1.82, P < .001) and 68% higher odds of lung metastases (1.68, 1.51–1.86, P < .001). The odds of liver metastases increased by 3% (odds ratio 1.03, 95% confidence interval 1.03–1.04, P < .001) and the odds of lung metastases increased by 2% (1.02, 1.01–1.03, P < .001) for each tumor deposit detected. ConclusionsTumor deposit–positive colorectal cancers were larger, more often on the left side or in the rectum and presented with more advanced disease and unfavorable histology than tumor deposit–negative cancers. Tumor deposits were independently associated with 72% and 68% higher odds of liver and lung metastases, respectively.

Financial toxicity screening in an urban underserved patient population with cancer.

169 Background: Cancer-related financial hardship is associated with treatment delays, non-adherence and adverse survival outcomes. Racial/ethnic minorities and low-income households are disproportionately impacted by financial toxicity. The Comprehensive Score for Financial Toxicity (COST) measure is used to measure financial toxicity in research but has not been validated in low-income, racially diverse cancer patient populations. Methods: We conducted this study at a large urban medical center from January-August 2023. We included cancer patients on systemic therapy for at least 2 months with ECOG performance status 0-2. Participants completed the COST measure, the Functional Assessment of Cancer Therapy: General (FACT-G) and the European Organization for Research and Treatment of Cancer (EORTC) QOL to assess health-related quality of life (HRQOL). Cancer diagnosis/stage, demographic data, and social work/financial counseling interventions were abstracted. Factor analyses were conducted to determine the underlying factor structure of the COST measure responses and bivariate analyses were conducted to identify relationships between COST scores and other data. Results: 100 patients participated in the study; the average age was 65 and both sexes were equally represented. Most patients reported African American (67%) race/ethnicity. 72% of patients held less than a 4-year college degree, 22 % were unemployed and 55% reported a yearly household income of less than $35,000. Lung (46%) and gastrointestinal (38%) cancers were the most represented. 73% were enrolled in a government sponsored insurance program (Medicare, Medicaid). The average COST score among participants was 22 [range 0-44] and mean FACT-G and EORTC scores were 16.5 [range 0-28] and 59.6 [ range 0 – 100] respectively. Fifty-eight patients were referred to social work or financial counseling for financial interventions. Factor analysis revealed three predominant factors among the COST responses (Eigenvalues &gt; 1) including Factor 1: items 3, 7, 8, 9, 10, 11; Factor 2: item 4; Factor 3: item 5. COST was weakly associated with FACT-G and EORTC (Pearson range 0.27 – 0.37). The most highly correlated value was between the COST and EORTC physical wellbeing subscale (Pearson 0.38). The COST score was significantly associated with income, with higher incomes reporting less financial toxicity (p = 0.004). No significant differences in COST scores were noted across gender, race, or level of education. Conclusions: Low levels of financial toxicity were detected using the COST measure in a diverse, low-income cancer patient population despite many patients being referred to social work/financial counseling. Compared to similar studies, we found a weaker correlation between the COST measure and HRQOL. These findings suggest that the COST measure may need to be further adapted for use in underserved populations and patients with government sponsored insurance.

Identification of novel M2 macrophage-related molecule ATP6V1E1 and its biological role in hepatocellular carcinoma based on machine learning algorithms.

Hepatocellular carcinoma (HCC) remains the most prevalent form of primary liver cancer, characterized by late detection and suboptimal response to current therapies. The tumour microenvironment, especially the role of M2 macrophages, is pivotal in the progression and prognosis of HCC. We applied the machine learning algorithm-CIBERSORT, to quantify cellular compositions within the HCC TME, focusing on M2 macrophages. Gene expression profiles were analysed to identify key molecules, with ATP6V1E1 as a primary focus. We employed Gene Set Enrichment Analysis (GSEA) and Kaplan-Meier survival analysis to investigate the molecular pathways and prognostic significance of ATP6V1E1. A prognostic model was developed using multivariate Cox regression analysis based on ATP6V1E1-related molecules, and functional impacts were assessed through cell proliferation assays. M2 macrophages were the dominant cell type in the HCC TME, significantly correlating with adverse survival outcomes. ATP6V1E1 was robustly associated with advanced disease stages and poor prognostic features such as vascular invasion and elevated alpha-fetoprotein levels. GSEA linked high ATP6V1E1 expression to critical oncogenic pathways, including immunosuppression and angiogenesis, and reduced activity in metabolic processes like bile acid and fatty acid metabolism. The prognostic model stratified HCC patients into distinct risk categories, showing high predictive accuracy (1-year AUC = 0.775, 3-year AUC = 0.709 and 5-year AUC = 0.791). Invitro assays demonstrated that ATP6V1E1 knockdown markedly inhibited the proliferation of HCC cells. The study underscores the significance of M2 macrophages and ATP6V1E1 in HCC, highlighting their potential as therapeutic and prognostic targets.

1797P Association between baseline PD-L1 expression in circulating leukocytes, the presence of immune-related adverse events (irAEs) and survival outcomes in patients with extensive-stage small-cell lung cancer (ES-SCLC) from the CANTABRICO trial

1797P Association between baseline PD-L1 expression in circulating leukocytes, the presence of immune-related adverse events (irAEs) and survival outcomes in patients with extensive-stage small-cell lung cancer (ES-SCLC) from the CANTABRICO trial

Comparative Analysis of Gene Expression Profiles in Ovarian Clear Cell Carcinoma and High-Grade Serous Ovarian Cancer.

To evaluate disparities in gene expression profiles between Ovarian Clear Cell Carcinoma (OCCC) and High-Grade Serous Ovarian Carcinoma (HGSOC). A descriptive study. Place and Duration of the Study: The Second People's Hospital of Jingdezhen, Jiangxi, China, between 31st December 2017 and December 2023. Basic and clinical diagnostic information, along with genetic test reports, were compiled from all patients within the included groups. Differential gene expression between the two cohorts was scrutinised to elucidate its clinical significance. Comparative analysis revealed nine differentially expressed genes in OCCC relative to HGSOC, with six exhibiting significant disparities (p <0.05). These genes are implicated in pivotal cellular processes including the cell cycle, apoptosis, DNA damage repair, and the PI3K pathway. Notably, aberrant expression patterns, such as overexpression of MET and downregulation of PTEN and SMARCA4, correlated with adverse prognosis and survival outcomes in selected patients. Distinctive gene expression profiles between OCCC and HGSOC underscore disparate tumorigenic mechanisms, thereby laying a foundation for the tailored therapeutic interventions. Further elucidation of the identified differentially expressed genes is warranted to delineate their role in OCCC pathogenesis and prognostic significance. Ovarian clear cell carcinoma, High-grade serous ovarian cancer, Gene expression profiles, Homologous recombination repair.

Association between the occurrence of immune-related adverse events and survival outcomes in patients with cancer treated with perioperative immune checkpoint inhibitors: A systematic review and meta-analysis.

39 Background: Although multiple studies have revealed that the occurrence of immune-related adverse events (irAEs) is associated with better survival in patients with advanced cancer, the association in patients with early-stage disease in the perioperative setting remains unclear. We performed a systematic review and meta-analysis to evaluate this association in the neoadjuvant and adjuvant settings. Methods: We performed a database search in PubMed/MEDLINE and Embase to identify eligible articles up to March 2024. We included studies evaluating the association between the occurrence of irAEs and survival outcomes in patients with solid tumors receiving at least one ICI in the perioperative setting. Cancer type, ICI agent, the number of patients, and survival outcomes (hazard ratio [HR] with 95% confidence interval [CI]) were summarized. We performed a random-effect model meta-analysis of survival outcomes that contained HR and 95% CI information from more than two studies. Results: After screening 884 articles, we found 15 eligible articles of which four studies reporting only treatment-related adverse events without irAE information were excluded. Finally, 11 studies (Clinical trials: n=3, Cohort studies: n=8) analyzing the association between the incidence of irAEs and survival were identified. Melanoma, triple-negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), and urothelial carcinoma were evaluated in seven, two, one, and one study, respectively. While ten studies defined the irAE group as any-type and any-grade irAEs, one study defined the irAE group as any-type and grade 2-5 irAEs. OS was evaluated in five studies (four studies for melanoma), of which two studies suggested that the occurrence of irAEs was associated with longer OS. A meta-analysis of three studies showed a tendency of the association between the occurrence of any-type and any-grade irAEs and longer OS (Pooled HR=0.69, 95% CI 0.47-1.00, p = 0.05). RFS was evaluated in eight studies (seven for melanoma), of which seven studies indicated the association between the incidence of any-type irAEs (any-grade: 6 studies, grade 2-5: 1 study) and longer RFS. A meta-analysis of five studies revealed a significant association between the occurrence of any-type irAEs (any-grade: 4 studies, grade 2-5: 1 study) and longer RFS (Pooled HR=0.52, 95% CI 0.41 - 0.67, p &lt; 0.0001]); however, Funnel plot indicated a presence of publication bias. Conclusions: This study suggests an association between irAEs and longer survival from perioperative ICI therapy, particularly in patients with melanoma. The result should be cautiously interpreted given a possible presence of publication and immortal bias. Further prospective studies and individual patient data meta-analysis are needed to validate this result.

The Prognostic Significance of Histological Subtypes in Patients with Muscle-Invasive Bladder Cancer: An Overview of the Current Literature.

Bladder cancer (BC) is the tenth most commonly diagnosed malignancy worldwide. In approximately 25% of cases, it presents as a muscle-invasive disease, requiring a radical treatment. Traditionally, the mainstay of treatment has been radical cystectomy (RC), but in the last decade, bladder-sparing treatments have been gaining growing interest. In particular, trimodal therapy (TMT) seems to yield survival results comparable to RC with less morbidity and better quality of life (QoL) outcomes. In this scenario, we aimed at shedding light on the role of the histological subtypes (HS) of BC and their prognostic significance in muscle-invasive BC (MIBC), treated either surgically or with TMT. We performed a narrative review to provide an overview of the current literature on this topic. When compared with patients diagnosed with conventional urothelial carcinoma (UC) of the same disease stage, survival did not appear to be significantly worse across the reports. But when sub-analyzed for separate subtype, some appeared to be independently associated with adverse survival outcomes such as the micropapillary, plasmacytoid, small-cell, and sarcomatoid subtypes, whereas others did not. Moreover, the optimal management remains to be defined, also depending on the therapeutic susceptibility of each histology. From this perspective, multi-disciplinary assessment alongside the routine inclusion of such entities in randomized clinical trials appears to be essential.

Cutaneous Adverse Reactions and Survival Outcomes of Advanced Melanoma Treated with Immune Checkpoint Inhibitors in an Academic Medical Centre in Singapore.

Programmed cell death-1 (PD1) inhibitors, a form of immune checkpoint inhibitor, are efficacious for metastatic melanoma but are associated with cutaneous adverse reactions (CARs). Studies in Europe and North America showed that CARs are associated with an increased overall survival. However, studies from Asia showed mixed results. There is a paucity of data regarding the efficacy of PD1 inhibitors and the effect of CARs on overall survival from Southeast Asia. A retrospective study of patients in the National Cancer Centre Singapore who were diagnosed with melanoma between 2015 and 2020 was conducted. Patients were included in the study if they had stage IV melanoma (advanced melanoma). Sixty-two patients were included in the study. The median age was 62.5 years and acral melanoma was the commonest subtype. Forty-three patients received PD1 inhibitors. Comparing patients who did not receive PD1 inhibitors to patients who received PD1 inhibitors, the former had a median overall survival of 6 months (95% CI: 5.07, 6.93), whereas the latter had a median overall survival of 21 months (95% CI: 13.33, 28.67; p < 0.001) (Hazard ratio 0.32; 95% CI: 0.16, 0.63; p = 0.001). Amongst patients who received PD1 inhibitors, patients who developed CARs had a greater median overall survival of 33 months (95% CI: 17.27, 48.73) compared to 15 months (95% CI: 9.20, 20.80; p = 0.013) for patients who did not (HR 0.29; 95% CI: 0.098, 0.834; p = 0.022). This study provides insight into the outcomes of metastatic melanoma in Singapore, and adds to the body of evidence supporting the use of PD1 inhibitors in Asians.

Joint effect of atrial fibrillation and obesity on mortality in critically ill patients

BackgroundThe interplay between atrial fibrillation (AF) and obesity on mortality in critically ill patients warrants detailed exploration, given their individual impacts on patient prognosis. This study aimed to assess the associations between AF, obesity, and 1-year mortality in a critically ill population.MethodsUtilizing data from the Medical Information Mart for Intensive Care (MIMIC)-IV database, we conducted a retrospective analysis of adult patients admitted to the intensive care unit. The primary endpoint was 1-year mortality, analyzed through Cox regression with hazard ratio (HR) and Kaplan-Meier survival methods.ResultsThe study included 25,654 patients (median age 67.0 years, 40.6% female), with 39.0% having AF and 36.1% being obese. Multivariate COX regression analysis revealed that AF was associated with a 14.7% increase in the risk of 1-year mortality (p < 0.001), while obesity was linked to a 13.9% reduction in mortality risk (p < 0.001). The protective effect of obesity on mortality was similar in patients with (HR = 0.85) and without AF (HR = 0.86). AF led to a slightly higher risk of mortality in patients without obesity (HR = 1.16) compared to those with obesity (HR = 1.13). Kaplan-Meier survival curves highlighted that non-obese patients with AF had the lowest survival rate, whereas the highest survival was observed in obese patients without AF.ConclusionsAF significantly increased 1-year mortality risk in critically ill patients, whereas obesity was associated with a decreased mortality risk. The most adverse survival outcomes were identified in non-obese patients with AF.

Enhancing hepatocellular carcinoma management: prognostic value of integrated CCL17, CCR4, CD73, and HHLA2 expression analysis

PurposeHepatocellular carcinoma (HCC) is a critical global health concern, with existing treatments benefiting only a minority of patients. Recent findings implicate the chemokine ligand 17 (CCL17) and its receptor CCR4 as pivotal players in the tumor microenvironment (TME) of various cancers. This investigation aims to delineate the roles of CCL17 and CCR4 in modulating the tumor’s immune landscape, assessing their potential as therapeutic interventions and prognostic markers in HCC.Methods873 HCC patients post-radical surgery from 2008 to 2012 at Zhongshan Hospital, Fudan University were retrospectively examined. These individuals were stratified into a training cohort (n = 354) and a validation cohort (n = 519). Through immunohistochemical analysis on HCC tissue arrays, the expressions of CCL17, CCR4, CD73, CD47, HHLA2, and PD-L1 were quantified. Survival metrics were analyzed using the Cox model, and a prognostic nomogram was devised via R software.ResultsThe investigation confirmed the presence of CCL17 and CCR4 within the cancerous and stromal compartments of HCC tissues, associating their heightened expression with adverse clinical markers and survival outcomes. Notably, the interplay between CD73 and CCR4 expression in tumor stroma highlighted a novel cellular entity, CCR4 + CD73 + stromal cells, impacting overall and relapse-free survival. A prognostic nomogram amalgamating these immunological markers and clinical variables was established, offering refined prognostic insights and aiding in the management of HCC. The findings suggest that reduced CCR4 and CCR4 + CD73 + cell prevalence may forecast improved outcomes post-TACE.ConclusionThis comprehensive evaluation of CCR4, CCL17, and associated markers introduces a nuanced understanding of the HCC immunological milieu, proposing CCR4 + CD73 + stromal cells as critical to HCC pathogenesis and patient stratification.

Predictors of poor response to immune-checkpoint inhibitor (ICI) treatment among patient with hepatocellular carcinoma (HCC).

e16212 Background: No established risk factors or toxicity biomarkers exist for HCCs treated with ICI, even though they are commonly used in clinical practice. The outcomes in real-world practice are worse than those reported in clinical trials. This retrospective review aims to identify HCC patients at high risk of failing ICI therapy. Methods: HCC patients who received at least one ICI dose between 1/1/2017 and 5/30/2023 (before tremelimumab/durvalumab approval) at the Ohio State University were included in this study. The patient's baseline (BL) characteristics (at the first dose of ICI) were extracted with immune-related adverse event (irAE) details and survival outcomes. We examined BL characteristics significantly different in poor (progression-free survival (PFS) ≤ median (m)) and worst (PFS ≤ 25% percentile) responders, and poor (overall survival (OS) ≤ m) and worst (OS ≤ 25% percentile) survivors. Chi-square test and logistic regression were performed using JMP Pro 17 (SAS Institute Inc., Cary, NC). Results: Our cohort included 53 HCC patients. The median age was 66 years (range 40-86), with 81% male and 85% White (13% African American and 2% other). The median OS and PFS were 19 months (m) (95% confidence interval [CI], 8-26) and 5m (95% CI, 2-9), respectively. The poor responders (PFS ≤5m, N = 30) had patients with significantly higher alcohol history (AHx, 90% vs. 70%) and mean alpha-fetoprotein (AFP, 44, 155 vs. 811 ng/mL) levels, a higher proportion of Child-Pugh (CP) C (A/B/C %, 53/27/20 vs. 53/47/0), and negligible bevacizumab (bev, 77 vs. 24) use, all (p &lt; 0.05). The worst response group (PFS ≤2m, N = 16), furthermore, had significantly (p &lt; 0.05) higher Albumin-bilirubin (ALBI) grade (G) 3 patients (50% vs. 16%), higher mean total bilirubin (2 vs. 1,2 ng/mL), lower tyrosine-kinase inhibitor (TKI, 7% vs. 46%), and lower mean albumin (Ab, 3 vs. 3.4) levels. A significantly (p &lt; 0.05) higher fraction (fx) of poor survivors (OS ≤19m, N = 33) got ICI In the first or second line (85% vs. 45%) and did not receive any locoregional therapy (LRT, 66% vs. 35%). The worst survivors (OS ≤8m, N = 14) got ICI in the first line (100% vs. 59%, p = 0.04, and significantly (p &lt; 0.05) lower Alb (3 vs. 3,4) and higher AFP (90620 vs. 3104) levels. The irAE group (N = 10, 19%) had higher AFP (115289 vs. 3482, p = 0.01) and a lower distant metastasis rate (20% vs. 58%, p = 0.02), and none of them received bev (0% vs. 30, p = 0.04). Conclusions: Response to ICI depends on BL liver function (AHx, ALBI, CP, Alb) and combination therapy (bev). Survival depends on HCC management up to the administration of ICI (LRT and TKI).

Preoperative Plasma Insulin-Like Growth Factor-I and Its Binding Proteins-Based Risk Stratification of Patients Treated With Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

IntroductionWe evaluate the predictive and prognostic value of insulin-like growth factor-I (IGF-1), IGF binding protein-2 (IGFBP-2) and -3 (IGFBP-3) in patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). MethodsThis is a retrospective analysis of a multi-institutional database comprising 753 patients who underwent RNU for UTUC and had a preoperative plasma available. Logistic and Cox regression analyses were performed. The discriminative ability and clinical utility of the models was calculated using the lasso regression test, area under receiver operating characteristics curves, C-index, and decision curve analysis (DCA). ResultsLower preoperative plasma levels of IGFBP-2 and -3 independently correlated with increased risks of lymph node metastasis, pT3/4 disease, nonorgan confined disease, and worse recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) (all P ≤ .004). The addition of both IGFBP-2 and -3 to a postoperative multivariable model, that included standard clinicopathologic characteristics, improved the model's concordance index by 10%, 9%, and 8% for RFS, CSS, and OS, respectively. On DCA, addition of both IGFBP-2 and -3 to base models improved their performance for RFS, CSS, and OS by a statistically and clinically significant margin. Plasma IGF-1 was not associated with any of outcomes. ConclusionsWe confirmed that a lower plasma levels of IGFBP-2 and -3 both are independent and clinically significant predictors of adverse pathological features and survival outcomes in UTUC patients treated with RNU. These findings might help guide the clinical decision-making regarding perioperative systemic therapy and follow-up scheduling.

A retrospective study comparing the efficacy of microwave ablation and stereotactic body radiotherapy in colorectal cancer lung metastases.

The purpose of the present study was to assess and compare the efficacy of microwave ablation (MWA) and stereotactic body radiotherapy (SBRT) in the treatment of lung metastases from patients with colorectal cancer (CRC) and to identify the preferable treatment modality based on patient and tumor characteristics. Records of 118 patients with CRC with a total of 307 lung metastases who underwent SBRT or MWA between January 2015 and December 2022 were retrospectively analyzed, including the essential clinicopathological information on patients (age, sex and underlying diseases), diagnosis and treatment information [primary tumor site, levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9], imaging data [diameter of lung metastasis, location of the metastasis (i.e., whether or not the tumor was adjacent to the vessel or bronchus) and internal features] and follow-up data (postoperative therapy, complications or adverse effects and survival outcomes). For statistical analysis of the local tumor progression (LTP), disease-free survival and overall survival (OS) rates, Cox regression analysis, along with the Kaplan-Meier method adjusted using inverse probability of treatment weighting (IPTW), were performed. The median follow-up duration in the present study was 31.5 months. Multivariable Cox regression analysis revealed that the CEA level, metastasis diameter and internal features were independent predictors of OS. In the IPTW-adjusted analysis, no significant difference in the 1-year OS rate was observed between the SBRT and MWA groups (92.9 vs. 93.9%; P=0.483); however, a notable discrepancy in the treatment modalities was noted, leading to significant differences in the 2- and 3-year OS rates (65.9 vs. 57.6%, P=0.001, and 44.7 vs. 36.4%, P<0.001, respectively). A significant interaction effect for the treatment modality was observed for LTP (P=0.021). In conclusion, the present study revealed that SBRT and MWA have similar therapeutic effects in terms of prolonging the survival of patients with CRC with lung metastases; however, regarding the local control of lung metastases, MWA is associated with a number of significant advantages.

Chinese expert consensus on diagnosis and treatment of high risk multiple myeloma (2024)

High-risk multiple myeloma (HRMM) refers to patients with multiple myeloma whose overall survival time is less than 2-3 years under current standardized diagnosis and treatment. By combining various static and dynamic prognostic factors, risk stratification is performed to identify HRMM patients early and treat patients with personalized strategies, with the aim of significantly improving adverse survival outcomes in HRMM patients. Although the clinical value of HRMM has reached a consensus domestically in recent years, there still exist confusions and ambiguities in the definition, high-risk factors, risk stratification, and treatment of HRMM, necessitating standardization. In order to enhance the diagnostic and treatment capabilities of Chinese physicians in HRMM, the Professional Committee of Hematologic Malignancies of the Chinese Anti-Cancer Association (CACA) and the Multiple Myeloma Expert Committee of the Chinese Society of Clinical Oncology (CSCO) have organized relevant experts to develop this consensus. This consensus aims to clarify the definition of HRMM, high-risk factors, and risk stratification system, and provide treatment recommendations for HRMM, thereby improving the quality of life and prognosis of Chinese HRMM patients.

Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer

Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979.

Abstract PO4-27-03: Real-World Evidence: Impact of Margin Involvement on Overall Survival Following Breast Cancer Surgery – A Single-Center Analysis at Charité University Medical Center Berlin

Abstract Introduction: Limited data is available regarding the impact of margin involvement following surgery for early-stage breast cancer on distant recurrence and overall survival (OS). We therefore conducted a retrospective single-center analysis to provide further real-world evidence of margin status on OS. Methods: We systematically evaluated patients who underwent surgical intervention for early breast cancer or carcinoma in situ at Charité University Medical Center Berlin between 2006 and 2022. Our study cohort included individuals with a minimum follow-up period of 6 months and documented margin status. Patients with secondary tumors were excluded from this comprehensive analysis. Results: In our analysis, we included a total of 3767 patients, with a median follow-up duration of 72.2 months. Among these, 3443 patients underwent surgery for invasive breast cancer, while 324 patients underwent surgery for carcinoma in situ. The median overall survival (OS) for the entire cohort was 63.7 months. Specifically, patients who achieved clear margins after primary surgery exhibited a median OS of 63.5 months (n=3068), and those with free margins after secondary surgery had a median OS of 65.2 months (n=610). Conversely, patients with definitively involved margins experienced a shorter median OS of 58.6 months (n=89). The multivariate analysis revealed a statistical trend toward adverse survival outcomes for patients with definitive involved margins (Hazard Ratio 1.55; 95% CI: 0.93-2.56; p=0.090), with no statistically significant difference observed between clear margins following primary or secondary surgery. Notably, patients who underwent breast-conserving surgery demonstrated a significantly improved OS (HR 0.45; 95% CI 0.37-0.45; p&amp;lt; 0.001). Higher rates of margin involvement were observed in patients with hormone receptor-positive tumors and carcinoma in situ, while lower rates were noted in triple-negative breast cancer and after neoadjuvant chemotherapy. Implication: Our findings suggest that involved margins may be associated with a limited overall survival. Notably, patients who underwent breast-conserving therapy exhibited more favorable outcomes in our analysis, underscoring the oncologic safety of this procedure. Citation Format: Maximilian Heinz Beck, Karoline Weiler, Sophia Ossmann, Verena Kiver, Jens-Uwe Blohmer. Real-World Evidence: Impact of Margin Involvement on Overall Survival Following Breast Cancer Surgery – A Single-Center Analysis at Charité University Medical Center Berlin [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-03.

MAL, a potential immunotherapy target, is associated with poor prognosis in cancer patients.

The MAL gene encodes Myelin and Lymphocyte Protein, mainly expressed in T cells with immunomodulatory effects, showing the potential as a target for immunotherapy. However, the mechanism of MAL in the regulation of immune infiltration and its association with the prognosis in pan-cancer patients remain elusive. We used the TCGA, TIMER2.0, GTEx, UCSC, and TISCH databases and the R programming tool to explore the role of MAL in cancers. MAL was differently expressed in the majority of malignancies relative to the matched healthy controls. Patients with low MAL levels had adverse survival outcomes in the BRCA and LUAD cohorts. In all cancer types, MAL showed a significant correlation to specific immune-subpopulation abundance in particular T cells as well as B cells. MAL was also implicated in immunological pathways in BRCA and LUAD, suggesting the important role of MAL in cancer immune regulation. In conclusion, the pan-cancer study indicates that MAL with excellent prognostic value is a potential immunotherapy target in multiple cancers.

Abstract CT160: A phase I trial to evaluate allogeneic NKG2DL-targeting chimeric antigen receptor-grafted γδ T cells in subjects with advanced solid tumors or hematological malignancies (the ANGELICA Trial)

Abstract Background: Adoptive cellular therapy (ACT) has been transformative in the treatment of hematological malignancies. Limitations of ACTs include difficulty identifying suitable tumor antigens for solid tumors, the ability to target only one antigen per construct which commonly results in secondary resistance due to antigen escape, and largely autologous approaches which are challenging in heavily pre-treated patients with poor marrow function and those with rapidly progressive disease who may not receive their personalised cellular products in time. This is a phase I study evaluating a novel off-the-shelf allogenic mRNA-electroporated NKG2D ligand-targeting CAR-grafted γδ T cell therapy. NKG2DLs are a group of 8 types of stress-induced cancer antigens which are preferentially and widely expressed on tumor cells from diverse tissue origins but are not typically present on normal tissue. NKG2DL-targeting γδ T cells will be manufactured from peripheral blood mononuclear cells isolated from healthy donors enrolled on the donor protocol of the ANGELICA trial. ANGELICA is a phase I study evaluating the safety, tolerability and recommended phase 2 dose (RP2D) of NKG2DL-targeting CAR-grafted γδ T cells in patients with treatment refractory tumors. Methods: Patients will be enrolled in a 3+3 design. Dose escalation will be performed at 3 dose levels: 1x108, 3x108 and 1x109 per infusion (adjusted for body weight). Lymphodepletion with fludarabine 25mg/m2/day and cyclophosphamide 250mg/m2/day will given for 3 days and completed at least 2 days prior to the first cycle of treatment. Patients will receive 4 doses of weekly infusions for the first cycle, with up to 5 subsequent infusions every 2 months as maintenance. Patients will receive intravenous zoledronic acid 1mg prior to each cellular infusion and subcutaneous IL-2 1x106 IU/m2 within 2 hours of each cellular infusion as pre-clinical data demonstrated cancer cell sensitisation and prolonged γδ T cell survival with these adjuncts. Dose-limiting toxicities will be assessed over the first 8 weeks. Adverse events, response rates (RECIST v1.1), survival outcomes and immunomonitoring (immune cell phenotyping and serum cytokine analysis) will be assessed. The trial is currently enrolling healthy donors; enrolment of patients at the first dose level will begin in February 2024. NCT05302037 TABLE 1: NAND Dose Level and Schedule Dose Level Dose per infusion Infusion schedule Number of patients 1 Weight 65kg and above: 1x108.Weight less than 65kg: 1.5x106. Cycle 1: weekly x 4 infusions. Maintenance phase: 2-monthly x 5 infusions. 3-6 2 Weight 65kg and above: 3x108.Weight less than 65kg: 4.6x106. 3-6 3 Weight 65kg and above: 1x109.Weight less than 65kg: 1.5x107. 3-6 Citation Format: Joan Choo, Wee Kiat Tan, Lucas Luk, Jieming Zeng, Teck Guan Soh, Sou Yen Soon, Jedidah Lieow, Calista Wong, Mei Yan Pang, Sudipto Bari, Michelle Poon, Liang Piu Koh, Wee Joo Chng, Anand Jeyasekharan, Lip Kun Tan, Esther Chan, Raghav Sundar. A phase I trial to evaluate allogeneic NKG2DL-targeting chimeric antigen receptor-grafted γδ T cells in subjects with advanced solid tumors or hematological malignancies (the ANGELICA Trial) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT160.

Pan-cancer analyses suggest kindlin-associated global mechanochemical alterations

Kindlins serve as mechanosensitive adapters, transducing extracellular mechanical cues to intracellular biochemical signals and thus, their perturbations potentially lead to cancer progressions. Despite the kindlin involvement in tumor development, understanding their genetic and mechanochemical characteristics across different cancers remains elusive. Here, we thoroughly examined genetic alterations in kindlins across more than 10,000 patients with 33 cancer types. Our findings reveal cancer-specific alterations, particularly prevalent in advanced tumor stage and during metastatic onset. We observed a significant co-alteration between kindlins and mechanochemical proteome in various tumors through the activation of cancer-related pathways and adverse survival outcomes. Leveraging normal mode analysis, we predicted structural consequences of cancer-specific kindlin mutations, highlighting potential impacts on stability and downstream signaling pathways. Our study unraveled alterations in epithelial–mesenchymal transition markers associated with kindlin activity. This comprehensive analysis provides a resource for guiding future mechanistic investigations and therapeutic strategies targeting the roles of kindlins in cancer treatment.