Inferior Response Research Articles

Machine learning-based selection of immune cell markers in osteosarcoma: prognostic determination and validation of CLK1 in disease progression

IntroductionOsteosarcoma (OS) is a malignancy of the bone that mainly afflicts younger individuals. Despite existing treatment approaches, patients with metastatic or recurrent disease generally face poor prognoses. A greater understanding of the tumor microenvironment (TME) is critical for enhancing outcomes in OS patients.MethodsThe clinical and RNA expression data of OS patients were extracted from the TARGET database. The single-cell RNA sequencing (scRNA-seq) data of 11 OS samples was retrieved from the GEO database, and analyzed using the Seurat package of R software. Copy number variation (CNV) was analyzed using the InferCNV software. The potential interactions between the different cells in the TME was analyzed with the CellChat package. A multi-algorithm-based computing framework was used to calculate the tumor-infiltrating immune cell (TIIC) scores. A prognostic model was constructed using 20 machine learning algorithms. Maftools R package was used to characterize the genomic variation landscapes in the patient groups stratified by TIIC score. The human OS cell lines MG63 and U2OS were used for the functional assays. Cell proliferation and migration were analyzed by the EdU assay and Transwell assay respectively. CLK1 protein expression was measured by immunoblotting.ResultsWe observed higher CNV in the OS cells compared to endothelial cells. In addition, there was distinct transcriptional heterogeneity across the OS cells, and cluster 1 was identified as the terminal differentiation state. S100A1, TMSB4X, and SLPI were the three most significantly altered genes along with the pseudo-time trajectory. Cell communication analysis revealed an intricate network between S100A1+ tumor cells and other TME cells. Cluster 1 exhibited significantly higher aggressiveness features, which correlated with worse clinical outcomes. A prognostic model was developed based on TIIC-related genes that were screened using machine learning algorithms, and validated in multiple datasets. Higher TIIC signature score was associated with lower cytotoxic immune cell infiltration and generally inferior immune response and survival rate. Moreover, TIIC signature score was further validated in the datasets of other cancers. CLK1 was identified as a potential oncogene that promotes the proliferation and migration OS cells.ConclusionA TIIC-based gene signature was developed that effectively predicted the prognosis of OS patients, and was significantly associated with immune infiltration and immune response. Moreover, CLK1 was identified as an oncogene and potential therapeutic target for OS.

Pretreatment plasma vitamin D and response to neoadjuvant chemotherapy in breast cancer: evidence from pooled analysis of cohort studies

Background: Biological evidence has revealed anti-tumor effect of vitamin D, but whether it could predict the response to neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients remains inconclusive. The aim was to investigate the association between pretreatment vitamin D level and response to NAC and subsequent survival outcomes in BC patients. Materials and Methods: We systematically searched the Medline, Embase, Cochrane Library and Web of Science databases and clinical trial registries to identify relevant articles from inception to October 8, 2024. Eligible studies investigating the associations between pretreatment plasma vitamin D and response to NAC in BC patients were selected according to the predefined criteria, with the study characteristics extracted by two reviewers. The primary outcome was pathological complete response (pCR), while overall pathological response and event-free survival (EFS) were adopted as secondary outcomes. Summary effect estimates of odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. Subgroup and sensitivity analyses were performed based on study characteristics and methodological quality. Results: Six retrospective cohort studies involving 1,291 BC patients were included. We observed a significant association between pretreatment vitamin D deficiency and 50% increased odds of non-pCR after NAC (OR=1.50, 95%CI 1.11-2.03, P=0.008) with no heterogeneity (I2=0%). We also identified a significant association of vitamin D with overall pathological response (OR=1.33, 95%CI 1.01-1.75, P=0.046). A similar association with EFS (HR=1.27, 95%CI 0.92-1.75, P=0.139) was also noted although the effect estimate was not statistically significant. Sensitivity analyses based on methodological quality showed consistent findings. Conclusion: Pretreatment vitamin D deficiency is associated with an inferior response to NAC in BC patients. Our meta-analysis advocates further prospective studies with large sample sizes before vitamin D supplementation could be administered to improve NAC response and subsequent prognosis of BC patients.

Enhanced interfacial charge transfer in WO3-Bi2WO6 heterostructures: Toward trace detection of mustard gas simulant

Developing reliable and portable sensors for detection of highly toxic mustard gas is extremely important for public security. However, gas sensors based on pristine metal oxide semiconductors often suffer from high working temperature, inferior response, and inadequate detection limit owing to their poor intrinsic conductivity and weak adsorption toward target gases, thereby hindering their wide application. Herein, hierarchical WO3-Bi2WO6 heterostructures were fabricated as sensing materials to comprehensively improve their sensing properties to 2-chloroethyl ethyl sulfide (2-CEES, a mustard gas simulant). The optimized sensor based on WO3-Bi2WO6-2 displayed short response time of 1.4 s and high sensing response (Ra/Rg = 63) to 50 ppm 2-CEES at 133 °C, together with an ultra-low detection limit of 10 ppb. The improvement of WO3-Bi2WO6-2 in sensing properties are synergistically attributed to the amount of heterojunction and surface adsorption sites, which were proved by DFT calculations and a series of characterizations. This work might pave the way for further developing heterostructure-based sensors for 2-CEES detection with superior sensing properties.

The intra-tumoral microbiome as a potential biomarker of response to external beam radiation therapy in cervical cancer

BackgroundWe aimed to determine the potential predictive value of the intra-tumoral microbiome as a marker of the response to external beam radiation therapy (EBRT) in cervical cancer (CC).MethodsA prospective longitudinal trial of 36 CC patients receiving pelvic radiotherapy was designed to investigate microbial characteristic signatures and diversity (alpha and beta) of multiple sites (tumor, vaginal, gut, urethral, and oral) in the superior response (SR) and inferior response (IR) groups of CC patients by 16S rRNA sequencing. Utilized the least absolute shrinkage and selection operator (LASSO) logistic regression method to analyze clinicopathological factors that potentially influenced the efficacy of EBRT. LEfSe analysis highlighted the microbiome features that best distinguished the categorized patient samples. Selected parameters were validated with Spearman correlation analysis, receiver operating characteristic (ROC) area under the curve (AUC) analysis and Kaplan-Meier survival analysis.ResultsFirstly, in our cohort, LASSO logistic regression analysis revealed no association between clinicopathological factors and EBRT efficacy. Subsequently, we employed 16S rRNA sequencing to compare microbiome differences across multiple sites and their correlations with major clinicopathological factors. We discovered that the intra-tumoral microbiome was independent of clinicopathologic features and represented the most direct and reliable reflection of the microbial differences between the SR and IR groups. We found lower alpha diversity in the tumor microbiome of SR group and identified the most relevant microbiome taxa (Bifidobacteriaceae, Beijerinckiaceae, and Orbaceae) associated with the efficacy of the response to EBRT in CC patients. We then conducted ROC analysis, finding that specific microbial taxa had an AUC of 0.831 (95% CI, 0.667–0.995), indicating the potential of these taxa as biomarkers for predicting EBRT efficacy. Kaplan-Meier survival analysis showed a better prognosis for patients with lower alpha diversity and higher relative abundance of Bifidobacteriaceae.ConclusionsOur data suggested that intra-tumoral specific microbiome taxa and lower alpha diversity may play an important role in the CC patient sensitivity to EBRT and offer novel potential biomarkers for predicting the response to EBRT efficacy.

P2.11B.06 BIRC5 Expression Correlated with Immunosuppressive Phenotype and Predicted Inferior Response to Immunotherapy in LUAD

P2.11B.06 BIRC5 Expression Correlated with Immunosuppressive Phenotype and Predicted Inferior Response to Immunotherapy in LUAD

Mechanical properties and multi-field ferroelastic response of Nb/Mn Co-doped CaBi4Ti4O15 high-temperature ferroelectric ceramics

CaBi4Ti4O15 (CBT) ceramics are promising piezoelectric materials that have been widely studied for high-temperature applications. Despite significant advancements in the electrical performance of CBT ceramics, the understanding of their mechanical behaviors remains limited, which is unfavorable for designing ceramics with high stability and reliability during high-temperature service. This work investigated the mechanical properties and fracture behaviors of Nb/Mn co-doped CaBi4Ti4O15 (CBTNM) with various doping levels, focusing on stress-strain responses and ferroelastic deformation behaviors under uniaxial compression and multi-field coupling conditions. HRTEM analysis reveals small-scale layered domain wall structures on the surface of plate-like grains. The fracture and compressive strengths of CBTNM ceramics initially decrease and then increase with an increase in doping content, and the underlying mechanisms are related to grain size, defects, and densification. CBTNM ceramics exhibit nonlinear stress-strain responses due to ferroelastic deformation under compressive loading, and the resultant irreversible domain switching strain increases with an increase in doping content, while poling can further increase the residual strain. Under multi-field loading conditions, CBTNM ceramics undergo more ferroelastic deformation events and exhibit larger residual strain. The micro-cracks, pores, complicated fracture modes, and degraded fracture surfaces with fragmental and rough features are mainly responsible for the lower elastic modulus and inferior mechanical response. This work enhances our understanding of the mechanical behaviors of high-temperature piezoelectric ceramics and provides guidance for designing high-performance piezoelectric materials for complex environmental applications.

Predictive nomogram of the clinical outcomes of colorectal cancer based on methylated SEPT9 and intratumoral IL-10+ Tregs infiltration

BackgroundGene methylation and the immune-related tumor microenvironment (TME) are highly correlated in tumor progression and therapeutic efficacy. Although both of them can be used to predict the clinical outcomes of colorectal cancer (CRC) patients, their predictive value is still unsatisfactory. Whether a combination risk model comprising these two prediction parameters performs better predictive effectiveness than independent factor is still unclear. Methylated Septin9 (mSEPT9) is an early diagnosis biomarker of CRC, in this study, we aimed to investigate mSEPT9-related biomarkers of immunosuppressive TME and identify the value of the combination risk model in predicting the clinical outcomes of CRC.MethodsImmunofluorescence staining was performed to clarify the correlation between intratumoral IL-10+ Treg infiltration and mSEPT9 in peripheral blood. Survival time, response to 5-fluorouracil (5-FU)-based chemotherapy and PD-1 blockade, and the probability of recurrence or metastasis were analyzed in study (197 CRC samples) and validation (195 CRC samples) sets to evaluate the efficacy of combination risk model. Potential mechanisms were explored by mRNA sequencing.ResultsHypermethylated SEPT9 in the peripheral blood of patients with CRC (stage I-III, and stage IV with resectable M1) before radical resection was positively correlated with high intratumoral IL-10+ Treg infiltration. The high-risk model revealed poor overall survival and progression-free survival, inferior therapeutic response to 5-FU-based chemotherapy and PD-1 blockade, and high probability of recurrence or metastasis. The underlying mechanisms may be associated with the increase in mSEPT9 and mediation of IL-10 via methionine metabolic reprogramming-induced infiltration of IL-10+ Tregs in the TME, which promotes tumor progression and resistance to 5-FU-based chemotherapy and PD-1 blockade.ConclusionsThe combination risk model of peripheral mSETP9 and intratumoral IL-10+ Treg infiltration in CRC can effectively predict prognosis, responsiveness to 5-FU-based chemotherapy and PD-1 blockade, and the probability of recurrence or metastasis. Therefore, this model can be used for precision treatment of CRC.

Targeting SNRNP200-induced splicing dysregulation offers an immunotherapy opportunity for glycolytic triple-negative breast cancer

Metabolic dysregulation is prominent in triple-negative breast cancer (TNBC), yet therapeutic strategies targeting cancer metabolism are limited. Here, utilizing multiomics data from our TNBC cohort (n = 465), we demonstrated widespread splicing deregulation and increased spliceosome abundance in the glycolytic TNBC subtype. We identified SNRNP200 as a crucial mediator of glucose-driven metabolic reprogramming. Mechanistically, glucose induces acetylation at SNRNP200 K1610, preventing its proteasomal degradation. Augmented SNRNP200 then facilitates splicing key metabolic enzyme-encoding genes (GAPDH, ALDOA, and GSS), leading to increased lactic acid and glutathione production. Targeting SNRNP200 with antisense oligonucleotide therapy impedes tumor metabolism and enhances the efficacy of anti-PD-1 therapy by activating intratumoral CD8+ T cells while suppressing regulatory T cells. Clinically, higher SNRNP200 levels indicate an inferior response to immunotherapy in glycolytic TNBCs. Overall, our study revealed the intricate interplay between RNA splicing and metabolic dysregulation, suggesting an innovative combination strategy for immunotherapy in glycolytic TNBCs.

Combined-electrical optogenetic stimulation but not channelrhodopsin kinetics improves the fidelity of high rate stimulation in the auditory pathway in mice

Novel stimulation methods are needed to overcome the limitations of contemporary cochlear implants. Optogenetics is a technique that confers light sensitivity to neurons via the genetic introduction of light-sensitive ion channels. By controlling neural activity with light, auditory neurons can be activated with higher spatial precision. Understanding the behaviour of opsins at high stimulation rates is an important step towards their translation. To elucidate this, we compared the temporal characteristics of auditory nerve and inferior colliculus responses to optogenetic, electrical, and combined optogenetic-electrical stimulation in virally transduced mice expressing one of two channelrhodopsins, ChR2-H134R or ChIEF, at stimulation rates up to 400 pulses per second (pps). At 100 pps, optogenetic responses in ChIEF mice demonstrated higher fidelity, less change in latency, and greater response stability compared to responses in ChR2-H134R mice, but not at higher rates. Combined stimulation improved the response characteristics in both cohorts at 400 pps, although there was no consistent facilitation of electrical responses. Despite these results, day-long stimulation (up to 13 h) led to severe and non-recoverable deterioration of the optogenetic responses. The results of this study have significant implications for the translation of optogenetic-only and combined stimulation techniques for hearing loss.

Analysis of Histologic, Immunohistochemical and Genomic Features of Large B Cell Lymphoma Tumors May Predict Response to Polatuzumab Vedotin Based Therapy in Patients With Relapsed/Refractory Disease

BackgroundLarge B cell lymphoma (LBCL) is the most common form of lymphoma. Polatuzumab vedotin (polatuzumab) is an effective therapy for patients diagnosed with LBCL; however, only limited information regarding pathologic features detected by clinical laboratory assays is available to determine which patients are most likely to benefit from polatuzumab based therapies. Patients and MethodsWe collected data from real world patients with relapsed or refractory LBCL whose tumors underwent next generation sequencing and were treated with polatuzumab based therapy at a single large academic cancer center. Tumor and patient characteristics were analyzed to look for factors that predict response to polatuzumab based therapies. ResultsWe identified high grade B cell lymphoma (HGBL) -NOS or MYC/BCL2 histology and presence of MYC rearrangement as factors that predict inferior response to polatuzumab based therapy. Patients with germinal center B cell of origin (GCB COO) LBCL without these factors had a high response rate (73%) to polatuzumab based therapy. ConclusionIn a single center real world retrospective analysis of R/R LBCL patients with available genomic data, polatuzumab based therapy may be less effective in patients with HGBL-NOS or MYC/BCL2 histology and MYC rearrangements, but not in patients with GCB COO LBCL without these features. Routine performance of more comprehensive pathologic analysis of tumors may inform the use of polatuzumab based therapy in patients with LBCL.

Immune checkpoint inhibitor infusion times and clinical outcomes in patients with melanoma.

Circadian rhythms impact immune function; a previous study demonstrated that immunotherapy treatment times taking place later in the day correlated with poorer outcomes in patients with melanoma. However, this finding has not been replicated, and other infusion timing schemas are unexplored. The objective of this retrospective, cohort study was to determine if the time of immunotherapy infusion affects outcomes. Five hundred and sixteen participants age ≥18 years diagnosed with cutaneous, acral, mucosal, or unknown primary melanoma treated with >1 infusion of nivolumab, pembrolizumab, or combination ipilimumab/PD-1 inhibitors were included. Response rate, toxicity rate, overall survival (OS), and progression-free survival (PFS) were determined based on infusion timing. Patients with ≥1 late infusion (after 4pm) among their first 4 infusions had slightly poorer objective response rate compared with only pre-4pm infusions (39.7% vs 44.5%), but no significant associations with late infusions and PFS and OS (P = .23, .93, respectively). Multivariable analyses showed no statistically significant association with outcomes for patients with any post-4pm infusion among the first 4; median infusion time was also not associated with outcomes. However, considering all infusion times, we found inferior PFS (median 10.6 vs 38.9 months, P < .0001), and numerically inferior OS (median 54.6 vs 81.2 months, P = .19) in patients with ≥20% late infusions. Multivariable models had similarly inferior response and PFS for patients with ≥20% late infusions, and later median infusion times were associated with inferior response, PFS, and OS. Late immunotherapy infusion times were associated with inferior outcomes when considering all infusions, but not when considering initial (first 4) infusions.

Prognostic impact of body composition in hepatocellular carcinoma patients with immunotherapy

Objective This study aims to examine the possible relationship between body composition parameters, sarcopenia, and clinical outcomes in hepatocellular carcinoma (HCC) patients who received immune checkpoint inhibitor (ICI) treatment. Methods Three online databases, including Embase, PubMed, and the Cochrane Library, were thoroughly searched for literature describing the relationship between body composition parameters, sarcopenia, and outcomes of ICI-treated HCC patients from the start of each database to 21 January 2024. The Newcastle-Ottawa Scale was used to rate the quality of the studies. The assessed outcomes included hazard ratio (HR) for OS and PFS, as well as odds ratio (OR) for ORR and DCR. Results This analysis included a total of 15 articles with a combined patient cohort of 1543 individuals. The results demonstrated that HCC patients with low skeletal muscle index (SMI) had significantly inferior OS (HR: 1.68, p < 0.001), PFS (HR: 1.45, p < 0.001), ORR (OR: 0.64, p = 0.044), and DCR (OR: 0.58, p = 0.009) compared to those with high SMI. The presence of sarcopenia in HCC patients was significantly related to poorer OS (HR: 1.63, p < 0.001) and PFS (HR: 1.48, p < 0.001), as well as a lower ORR (OR: 0.64, p = 0.020) and DCR (OR: 0.58, p = 0.007) in comparison to those without sarcopenia. Subgroup analysis demonstrated that these findings were consistent with the multivariate analysis. Moreover, high subcutaneous adipose index (SAI) levels were associated with better OS (HR: 0.46, p = 0.001) and PFS (HR: 0.68, p = 0.021) than those with low SAI levels. Conclusion The presence of sarcopenia and low SMI in HCC patients undergoing treatment with ICIs was found to be related to inferior treatment response and reduced long-term effectiveness.

Genomic correlates of the response to first-line PD-1 blockade plus chemotherapy in patients with advanced non-small-cell lung cancer.

Programmed death 1 (PD-1) blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC). Yet not all NSCLC patients benefit from this regimen. This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC. We integrated clinical, genomic, and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone. We randomly assigned these patients into a discovery cohort (n=125), a validation cohort (n=82), and a control cohort (n=80). The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts. Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset. A genomic variation signature, in which one or more of the 15 candidate genes were altered, was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts. Its predictive value held in multivariate analyses when adjusted for baseline parameters, programmed cell death ligand 1 (PD-L1) expression level, and tumor mutation burden. Moreover, applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination. Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates, indicating an immune-desert tumor microenvironment. These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with advanced NSCLC.

Treatment outcome according to genetic tumour alterations and clinical characteristics in digestive high-grade neuroendocrine neoplasms

BackgroundChemotherapy has limited efficacy in advanced digestive high-grade neuroendocrine neoplasms (HG-NEN) and prognosis is dismal. Predictive markers for palliative chemotherapy are lacking, and prognostic markers are limited.MethodsDigestive HG-NEN patients (n = 229) were prospectively included 2013–2017. Pathological re-assessment revealed 188 neuroendocrine carcinomas (NEC) and 41 neuroendocrine tumours (NET G3). Tumour-DNA was sequenced across 360 cancer-related genes, assessing mutations (mut) and copy number alterations. We linked sequencing results to clinical information and explored potential markers for first-line chemotherapy efficacy and survival.ResultsIn NEC given cis/carboplatin and etoposide (PE), TP53mut predicted inferior response rate in multivariate analyses (p = 0.009) and no BRAFmut NEC showed response. In overall assessment of PE-treated NEC, no genetic alterations were prognostic for OS. For small-cell NEC, TP53mut were associated with longer OS (p = 0.011) and RB1 deletions predicted lack of immediate-progression (p = 0.003). In non-small cell NEC, APC mut were associated with immediate-progression and shorter PFS (p = 0.008/p = 0.004). For NET G3, ATRXmut, ARID1A- and ERS1 deletions were associated with shorter PFS.ConclusionCorrelations between genetic alterations and response/immediate-progression to PE were frequent in NEC but affected PFS or OS only when subdividing for cell-type. The classification of digestive NEC into large- and small-cell seems therefore molecularly and clinically relevant.

Investigation of Impact Properties under Instrumented Charpy Test

The Instrumented Charpy impact test is a promising method for determining a material’s impact response. Stainless steel has higher impact energy absorption capacity, high tensile, and yield strength compared to aluminum. Performance varies among grades; for instance, Aluminum 7075-T6 exceeds Aluminum 6061-T6 in tensile and yield strength. However, information regarding their energy capacity and impact signal pattern is lacking. This study investigated the impact properties using a Charpy machine, a data acquisition system, and a sensing element. Strain gauges were used to record the impact strain signal, enabling the analysis of impact duration, maximum strain, and the area under the curve. Specimens experimented include Stainless Steel 304, Aluminum Alloy 6061-T6, and Aluminum Alloy 7075-T6. The Charpy machine measures absorbed energy, while the theoretical impact energy is computed from software data. The area under the strain-time curve reflects the material energy absorption capacity. Stainless Steel 304 demonstrates superior energy absorbed, impact duration, and area under the curve, followed by Aluminum 6061-T6 and Aluminum 7075-T6. Despite higher tensile and yield strength, the inferior impact response of Aluminum 7075-T6 highlights the importance of factors like ductility, elongation, and alloy composition. Consequently, Aluminum 6061 is commonly used in the automotive industry, while Aluminum 7075 is preferred in aerospace applications.

Effectiveness of immune checkpoint inhibitor therapy on bone metastases in non-small-cell lung cancer.

Bone metastases (BoMs) are prevalent in patients with metastatic non-small-cell lung cancer (NSCLC) however, there are limited data detailing how BoMs respond to immune checkpoint inhibitors (ICIs). The purpose of this study was to compare the imaging response to ICIs of BoMs against visceral metastases and to evaluate the effect of BoMs on survival. A retrospective, multicentre cohort study was conducted in patients with NSCLC treated with nivolumab or pembrolizumab in Alberta, Canada from 2015 to 2020. The primary endpoint was the real-world organ specific progression free survival (osPFS) of bone versus visceral metastases. Visceral metastases were categorized as adrenal, brain, liver, lung, lymph node, or other intra-abdominal lesions. The secondary outcome was overall survival (OS) amongst patients with and without BoMs. A total of 573 patients were included of which all patients had visceral metastases and 243 patients (42.4%) had BoMs. High PD-L1 expression was identified in 268 patients (46.8%). No significant difference in osPFS was observed between bone, liver, and intra-abdominal metastases (p=0.20 and p=0.76, respectively), with all showing shorter osPFS than other disease sites. There was no difference in the osPFS of extra-thoracic sites of disease in patients with high PD-L1 expression. There was significant discordance between visceral disease response and bone disease response to ICI (p=0.047). The presence of BoMs was an independent poor prognostic factor for OS (HR 1.26, 95%CI: 1.05-1.53, p=0.01). Metastatic bone, liver, and intra-abdominal lesions demonstrated inferior clinical responses to ICI relative to other sites of disease. Additionally, the presence of bone and liver metastases were independent poor prognostic factors for overall survival. This real-world data suggests that BoMs respond poorly to ICI and may require treatment adjuncts for disease control.

Molecular Subtypes and the Role of TP53 in Diffuse Large B-Cell Lymphoma and Richter Syndrome.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy and a heterogeneous entity comprised of several biologically distinct subtypes. Recently, novel genetic classifications of DLBCL have been resolved based on common mutational patterns indicative of distinct pathways of transformation. However, the complicated and costly nature of the novel classifiers has precluded their inclusion into routine practice. In view of this, the status of the TP53 gene, which is mutated or deleted in 20-30% of the cases, has emerged as an important prognostic factor for DLBCL patients, setting itself apart from other predictors. TP53 genetic lesions are particularly enriched in a genetic subtype of DLBCL that shares genomic features with Richter Syndrome, highlighting the possibility of a subset of DLBCL arising from the transformation of an occult chronic lymphocytic leukemia-like malignancy, such as monoclonal B-cell lymphocytosis. Patients with TP53-mutated DLBCL, including those with Richter Syndrome, have a particularly poor prognosis and display inferior responses to standard chemoimmunotherapy regimens. The data presented in this manuscript argue for the need for improved and more practical risk-stratification models for patients with DLBCL and show the potential for the use of TP53 mutational status for prognostication and, in prospect, treatment stratification in DLBCL.

Impact of Extraosseous Extramedullary Disease on Outcomes of Patients with Relapsed-Refractory Multiple Myeloma receiving Standard-of-Care Chimeric Antigen Receptor T-Cell Therapy

The presence of extramedullary disease (EMD) has been associated with poor outcomes in patients with relapsed-refractory multiple myeloma (RRMM). Herein, we report the outcomes of RRMM patients who were treated with standard-of-care (SOC) chimeric antigen receptor (CAR) T-cell therapy and had active extraosseous EMD before the infusion. Data were retrospectively collected from patients at three US institutions with the intent to receive SOC CAR T. Responses were assessed per the International Myeloma Working Group criteria. A total of 152 patients proceeded with infusion, of whom 47 (31%) had EMD (EMD group) and 105 (69%) did not (non-EMD group). Baseline patient characteristics were comparable between the two groups. The EMD group had a higher incidence of high-grade CRS, steroid and anakinra use, and thrombocytopenia on day +30 compared to the non-EMD group. In addition, the EMD group had an inferior overall response rate (58% vs 96%, p < 0.00001), median progression-free survival (PFS) (5.1 vs 12.4 months; p < 0.0001), and overall survival (OS) (12.2 vs 27.5 months; p = 0.00058) compared to the non-EMD group. We further subdivided the non-EMD patients into those with paramedullary disease (PMD-only group, n = 26 [17%]) and those with neither EMD nor PMD (bone marrow-contained group or BM-only group, n = 79 [52%]). Patients with PMD-only had similar median PFS (11.2 vs 13.6 months, p = 0.3798) and OS (not reached [NR] vs 27.5 months, p = 0.6446) compared to patients with BM-only disease. However, patients with EMD exhibited inferior median PFS (5.1 vs 13.6 months, p < 0.0001) and OS (12.2 vs 27.5, p = 0.0008) compared to patients in the BM-only group. Treatment with SOC CAR T yielded meaningful clinical outcomes in real-world RRMM patients with extraosseous EMD, though responses and survival outcomes were suboptimal compared to patients without EMD. The presence of only EMD but not PMD was associated with significantly worse survival outcomes following the CAR T infusion.

HeredERA Breast Cancer: a phase III, randomized, open-label study evaluating the efficacy and safety of giredestrant plus the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with previously untreated HER2-positive, estrogen receptor-positive locally advanced or metastatic breast cancer

BackgroundHER2-positive, estrogen receptor-positive breast cancer (HER2+, ER+ BC) is a distinct disease subtype associated with inferior response to chemotherapy plus HER2-targeted therapy compared with HER2+, ER-negative BC. Bi-directional crosstalk leads to cooperation of the HER2 and ER pathways that may drive treatment resistance; thus, simultaneous co-targeting may optimize treatment impact and survival outcomes in patients with HER2+, ER+ BC.First-line (1L) treatment for patients with HER2+ metastatic BC (mBC) is pertuzumab, trastuzumab, and taxane chemotherapy. In clinical practice, dual HER2 blockade plus a fixed number of chemotherapy cycles are given as induction therapy to maximize tumor response, with subsequent HER2-targeted maintenance treatment given as a more tolerable regimen for long-term disease control. For patients whose tumors co-express ER, maintenance endocrine therapy (ET) can be added, but uptake varies due to lack of data from randomized clinical trials investigating the superiority of maintenance ET plus dual HER2 blockade versus dual HER2 blockade alone. Giredestrant, a novel oral selective ER antagonist and degrader, shows promising clinical activity and manageable safety across phase I–II trials of patients with ER+, HER2-negative BC, with therapeutic potential in those with HER2 co-expression.MethodsThis phase III, randomized, open-label, two-arm study aims to recruit 812 patients with HER2+, ER+ locally advanced (LA)/mBC into the induction phase (fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] plus a taxane) to enable 730 patients to be randomized 1:1 to the maintenance phase (giredestrant plus PH FDC SC or PH FDC SC [plus optional ET]), stratified by disease site (visceral versus non-visceral), type of LA/metastatic presentation (de novo versus recurrent), best overall response to induction therapy (partial/complete response versus stable disease), and intent to give ET (yes versus no). The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, safety, and patient-reported outcomes.DiscussionheredERA BC will address whether giredestrant plus dual HER2 blockade is superior to dual HER2 blockade alone, to inform the use of this combination in clinical practice for maintenance 1L treatment of patients with HER2+, ER+ LA/mBC.Trial registrationClinicalTrials.gov, NCT05296798; registered on March 25, 2022. Protocol version 3.0 (November 18, 2022). Sponsor: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124 4070, Basel, Switzerland.

Weight loss outcomes with semaglutide based on diabetes severity using the individualized metabolic surgery score

Semaglutide demonstrated inferior weight loss responses in patients with type 2 diabetes (T2D) compared to patients with obesity without T2D. The individualized metabolic surgery (IMS) score was validated to predict T2D remission after bariatric surgery. The parameters of the IMS are HbA1c (<7%), insulin use, T2D medications and T2D duration. We aim to assess weight loss outcomes of semaglutide based on IMS score in patients with obesity and T2D. This is a retrospective multicentered cohort study of patients with T2D and BMI≥ 27kg/m2 taking ≥1mg of semaglutide recruited from January 2020 to December 2022. We excluded patients with a history of bariatric surgery or taking other anti-obesity medications. IMS was calculated at baseline and patients weight change was recorded at baseline, 3, 6, 9 and 12 months. IMS was classified as mild (0-24.9 points), moderate (25-94.9 points), and severe (95-180 points). Analysis was performed based on IMS score quartiles and combination of Mild-Moderate vs Severe categories. We performed mixed linear regression models including age, sex, and baseline weight to assess associations between IMS categories with total body weight loss percentage (TBWL%). We included 297 patients (42% female, mean age 62±12 years) in the analysis. At 12 months, there was a stepwise decrease in weight loss outcomes when comparing patients by IMS quartiles (LS mean TBWL%± SE): 8.8±0.8% vs 6.9±0.8% vs 5.7±0.9% vs 5.0±0.8%. In the mixed linear model, patients in the mild-moderate category achieved significantly superior weight loss outcomes (LS mean TBWL± SE:-8.3±0.7%) than patients in the severe category (-5.5±0.6%; difference:-2.9, 95% CI:-5.2 to-0.5, p=0.006) at 12 months. There was no significant difference in glycemic improvement regardless of IMS severity at baseline. In our cohort, lower IMS severity was associated with more weight loss in patients with obesity and T2D. Further studies are needed to understand T2D severity and its effect on semaglutide outcomes. Beyond payment to the research staff by Mayo Clinic, this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.