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Lymphoma

HD-MT With/Without IT-MT and WBRT for Primary CNS Lymphoma

KEY TAKEAWAYS The study aimed to evaluate the efficacy and safety of HD-MT with or without IT-MT and WBRT for PCNSL. The results showed no significant difference in efficacy between HD-MT alone or with IT-MT plus radiotherapy, with manageable side effects. Primary...

Sep 19, 2024

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Belzutifan Shows PFS Benefits Over Everolimus in ccRCC

KEY TAKEAWAYS

  • The study aimed to investigate the efficacy of belzutifan vs everolimus in improving PFS and ORR in patients with ccRCC.
  • The primary endpoints were to determine PFS and OS.
  • Researchers noted that belzutifan showed PFS and ORR benefits over everolimus but did not significantly improve OS.

Compared to everolimus, Belzutifan significantly improved progression-free survival (PFS) and objective response rate (ORR) in patients with advanced clear cell renal cell carcinoma (ccRCC), who had previously received immune checkpoint and antiangiogenic agents.

Brian I. Rini and the team aimed to assess the comparative efficacy of belzutifan versus everolimus in this patient population.

They conducted a comprehensive analysis of adults with advanced ccRCC who had undergone 1–3 prior systemic treatments, including at least 1 PD-(L)1 inhibitor and one VEGFR-TKI. Participants were randomized 1:1 to receive either belzutifan 120 mg or everolimus 10 mg daily until disease progression or unacceptable adverse events occurred.

The dual primary endpoints were PFS and overall survival (OS), evaluated per RECIST 1.1 by central review. The key secondary endpoint was the ORR, also assessed per RECIST 1.1 by central review. Duration of response (DOR) and safety were additional secondary endpoints. Formal statistical testing for PFS and ORR was not performed at the final analysis, as positive results for these endpoints had already been established at the first interim analysis.

About 746 patients were allocated to belzutifan (n=374) or everolimus (n=372). At the final analysis (data cutoff: April 15, 2024), the median follow-up was 35.8 months (range 26.9–49.2); 14.5% of patients remained on treatment with belzutifan compared to 1.4% with everolimus. Belzutifan maintained a PFS benefit over everolimus (median 5.6 months vs 5.6 months; HR 0.75; 95% CI 0.63–0.88), with estimated PFS rates at 12 months (33.7% vs 17.6%) and at 24 months (17.5% vs 4.1%) favoring belzutifan.

The median OS was 21.4 months with belzutifan compared to 18.2 months with everolimus (HR 0.92; 95% CI 0.77–1.10; P=0.18). Estimated OS rates were 67.9% vs 65.8% at 12 months and 45.2% vs 41.2% at 24 months. The ORR was consistent with prior reports (22.7% vs 3.5%). Median (range) DOR was 19.3 months (1.9+–40.1+) vs 13.7 months (3.8–29.5+).

Fewer patients discontinued belzutifan (6.2%) compared to everolimus (15.3%) due to any-cause adverse events. The median duration of therapy was longer with belzutifan (7.6 months vs 3.9 months). The rate of grade ≥3 treatment-related adverse events (TRAEs) was similar between the 2 arms (39.5% vs 40.0%).

The study concluded that belzutifan continued to demonstrate benefits in PFS and ORR compared to everolimus, although a significant improvement in OS was not observed. With over 2 years of minimum follow-up, the safety profile of belzutifan remained consistent with prior reports. The final analysis results of LITESPARK-005 support belzutifan as a viable treatment option for advanced ccRCC following PD-(L)1 inhibitor and VEGFR-TKI therapy.

The study was sponsored by the Merck Sharp & Dohme LLC.

Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/14

Clinical Trial: https://clinicaltrials.gov/study/NCT04195750

Rini B.I, Rodriguez C.S, Albiges L, et al. (2024). “Final analysis of the phase III LITESPARK-005 study of belzutifan versus everolimus in participants (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC).” Presented at ESMO 2024 (Abstract LBA74).

Single-Cell Insights into Ferroptosis in BCa TME

KEY TAKEAWAYS

  • The study explored how ferroptosis regulators in the TME affect BCa progression and immunotherapy.
  • The study identified ACSL4+CAFs as a potential therapeutic target and SDC1 as a valuable biomarker for BCa.

Ferroptosis, a form of programmed cell death, is pivotal in the onset and progression of bladder cancer (BCa). Despite its importance, the mechanisms regulating ferroptosis in the tumor microenvironment (TME) of BCa remain unclear.

Ziang Chen and the team aimed to evaluate the role of ferroptosis regulators in the TME and their effects on BCa progression and immunotherapy outcomes.

Researchers performed an inclusive analysis of single-cell RNA (scRNA) transcriptomic data from patients with BCa, utilizing non-negative matrix factorization (NMF) for dimensionality reduction and clustering to uncover novel ferroptosis-related cell subtypes within the BCa TME. This approach aimed to elucidate the biological characteristics of these TME cell subtypes.

The survival analysis and univariate Cox regression were then conducted to assess the prognostic significance of these subtypes. The study also explored the relationship between specific subtypes and immune infiltration, evaluating their implications for immunotherapy. A valuable and novel biomarker for BCa was identified, further supported by a series of in vitro experiments.

About the cancer-associated fibroblasts (CAFs), macrophages, and T cells, researchers subdivided these into 3-5 small subpopulations using NMF and explored their biological features. It was found that ferroptosis plays a significant role in the BCa TME. Bulk RNA-seq analysis further verified that ferroptosis influences BCa progression, prognosis, and immunotherapy response by regulating the TME.

Notably, ACSL4+CAFs were identified as a subtype with high-level infiltration, which predicted poorer prognosis, more complex immune infiltration, and reduced response to immunotherapy. Additionally, this CAF subtype was linked to cancer cells through the PTN-SDC1 axis, suggesting that SDC1 may be crucial in regulating CAFs in cancer cells.

In vitro experiments supported these findings, showing that SDC1 promotes BCa progression. Furthermore, FTH1+ macrophages were discovered to be closely related to SPP1+ macrophages and may also be involved in regulating the BCa TME.

The study highlighted the significant impact of ferroptosis on the BCa TME. The identification of novel ferroptosis-related TME cell subpopulations, particularly ACSL4+CAFs, provides potential therapeutic targets for BCa. Furthermore, the study identifies SDC1 as a promising prognostic biomarker for BCa.

This study was funded by the National Natural Science Foundation of China (No.81802569, 82373222, 82202255), the Leading Talent Program by Shanghai Municipal Health Commission (2022LJ008), Medical Innovation Research Special Project by Science and Technology Commission of Shanghai Municipality (22Y21900200), Clinical Scientific and Technological Innovation Project by Shanghai Hospital Development Center (SHDC12021104).

Source: https://pubmed.ncbi.nlm.nih.gov/39238647/

Chen Z, Hu J, Ou Y, et al. (2024). “Integrating single-cell transcriptomics to reveal the ferroptosis regulators in the tumor microenvironment that contribute to bladder urothelial carcinoma progression and immunotherapy.” Front Immunol. 2024;15:1427124. Published 2024 Aug 22. doi:10.3389/fimmu.2024.1427124

Exploring LIG1 Role in BLCA Progression and Prognosis

KEY TAKEAWAYS

  • The study aimed to investigate LIG1’s role in BLCA progression and prognosis.
  • Researchers noticed that LIG1 significantly drives BLCA progression, making it a promising prognostic biomarker.

Bladder cancer (BLCA) is a highly lethal disease that poses a severe threat to patients worldwide. LIG1, 1 of the 4 essential DNA ligases located at 19q13.2-13.3 in mammalian cells, plays a critical role in DNA replication and repair. Despite frequent deletions of LIG1 observed in tumor cells of various origins, its specific role in BLCA remains unclear.

This groundbreaking study seeks to explore the unexamined role of LIG1 in BLCA, focusing on its influence on cancer progression and its relationship with clinicopathological factors.

Through a comprehensive analysis integrating experimental approaches, machine learning, and single-cell sequencing, Ding-Ming Song and the team aimed to unravel the molecular mechanisms underlying LIG1’s function in BLCA.

They performed an inclusive analysis of gene expression data from BLCA and para-carcinoma tissues, retrieved from the GEO repository. Single-cell sequencing data were processed using the “Seurat” package. Differential expression analysis was conducted with the “Limma” package. The “WGCNA” package was applied to build scale-free gene co-expression networks.

A Venn diagram was then used to intersect genes from positively correlated modules identified by WGCNA with differentially expressed genes (DEGs), isolating overlapping genes for further analysis. Using the “STRINGdb” package, they constructed a protein-protein interaction (PPI) network, identifying hub genes through the Betweenness Centrality (BC) algorithm.

Subsequent KEGG and GO enrichment analyses revealed regulatory mechanisms and biological functions linked to these hub genes. A machine-learning diagnostic model was established with the “mlr3verse” R package. Mutation profiles of patients between the LIG1high and LIG1low groups were visualized using the BEST website. Survival analyses for these groups were also conducted through the BEST and GENT2 websites. Finally, functional experiments were performed to validate the role of LIG1 in BLCA progression.

The study identified a significant upregulation of LIG1 in BLCA specimens, with elevated LIG1 levels being closely associated with poorer overall survival outcomes. GO and KEGG functional enrichment analyses of hub genes highlighted LIG1’s involvement in essential processes, including DNA replication, cellular senescence, the cell cycle, and the p53 signaling pathway.

Additionally, the mutational landscape of BLCA displayed marked differences between the LIG1high and LIG1low groups. Immune infiltration analyses revealed that LIG1 plays a key role in immune cell recruitment and regulation within the BLCA microenvironment, influencing patient prognosis. Experimental validations further confirmed LIG1’s critical role in BLCA pathogenesis, reinforcing its functional significance in BLCA samples.

The study concluded that LIG1 is pivotal in advancing BLCA malignancy by enhancing proliferation, invasion, epithelial-mesenchymal transition (EMT), and other critical functions, positioning it as a potential risk biomarker.

The study received no funding.

Source: https://pubmed.ncbi.nlm.nih.gov/39234248/

Song DM, Shen T, Feng K, et al. LIG1 is a novel marker for bladder cancer prognosis: evidence based on experimental studies, machine learning and single-cell sequencing. Front Immunol. 2024;15:1419126. Published 2024 Aug 21. doi:10.3389/fimmu.2024.1419126

Durvalumab With NAC Improves Survival in MIBC

Durvalumab With NAC Improves Survival in MIBC

KEY TAKEAWAYS

  • The NIAGARA phase III trial assessed D’s effectiveness when combined with NAC in MIBC treatment.
  • The primary endpoints were to determine EFS & pCR, and the secondary endpoint was OS.
  • Perioperative D plus NAC significantly improved survival outcomes without affecting RC completion or safety.

The standard treatment for cisplatin-eligible patients with muscle-invasive bladder cancer (MIBC) involves neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC).

Thomas B. Powles and the team aimed to evaluate the efficacy of durvalumab (D) when combined with NAC, followed by RC and adjuvant D in patients with MIBC.

The NIAGARA phase 3 trial involved cisplatin-eligible patients with MIBC (cT2-T4aN0/1M0) scheduled for RC. Patients were randomly assigned (1:1) to receive either neoadjuvant D (1500 mg IV Q3W) plus NAC (cisplatin + gemcitabine IV Q3W) followed by RC and adjuvant D (1500 mg IV Q4W) for 8 cycles (D arm) or NAC plus RC alone.

Stratification factors were clinical tumor stage (cT2N0 vs >cT2N0), renal function (CrCl ≥60 mL/min vs ≥40 to <60 mL/min), and PD-L1 status (high vs low/negative). The primary endpoints were event-free survival (EFS) and pathologic complete response (pCR), with overall survival (OS) as a secondary endpoint.

The results showed that 1,063 patients were randomized, with 533 in the D arm and 530 in the comparator arm. The median EFS follow-up was 42.3 months (range 0.03–61.3). Patients in the D arm had significantly longer EFS (HR 0.68, 95% CI: 0.56-0.82, P<0.0001) and OS (HR 0.75, 95% CI: 0.59-0.93, P=0.0106) compared to the comparator arm.

It also showed that RC was completed in 88% of the D arm and 83% of the comparator arm. Post-RC, 82% of patients in the D arm started adjuvant D. Grade 3/4 treatment-related adverse events (TRAE’s) occurred in 41% of patients in each arm, with 15% discontinuing neoadjuvant treatment and 8% stopping adjuvant D due to adverse events. Treatment-related deaths were 0.6% in each arm.

The study concluded that perioperative D plus NAC significantly improved EFS and OS compared to NAC alone. Additionally, the addition of D did not affect the completion of RC and maintained a consistent safety profile.

The trial was sponsored by AstraZeneca.

Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/170

Clinical Trial: https://clinicaltrials.gov/study/NCT03732677

Powles TB, Van der Heijden MS, Galsky MD, et al. (2024). “A randomized phase III trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle-invasive bladder cancer (NIAGARA).” Presented at: ESMO 2024, (Abstract LBA5).

KRT23 Identified as Key Target in BLCA Immunotherapy

KEY TAKEAWAYS

  • The study aimed to investigate multiple immune checkpoint gene profiles in BLCA to identify potential immunotherapy targets like KRT23.
  • Researchers identified KRT23 as a key target for improving immunotherapy in BLCA.

In recent decades, significant progress has been made in treating bladder cancer (BLCA), particularly with the development of immune checkpoint inhibitors (ICIs). However, most studies have focused on individual ICIs, with limited research addressing the comprehensive gene expression profiles of multiple immune checkpoints. Understanding the broader landscape of immune checkpoint genes is crucial for optimizing immunotherapy strategies and improving patient outcomes.

Dongshan Chen and the team aimed to assess the expression profiles of multiple immune checkpoint genes in BLCA, explore their relationship with the tumor immune microenvironment, and identify key targets for enhancing immunotherapy, with a specific focus on KRT23.

They performed an inclusive analysis using RNA-sequencing profiling data and clinical information from patients with BLCA and normal human bladder samples, sourced from the Cancer Genome Atlas and Gene Expression Omnibus databases.

The data were analyzed to identify differential expression profiles of immune checkpoint genes (ICGs) following consensus clustering analysis. From 526 intersecting differentially expressed genes, LASSO Cox regression analysis was applied to develop an ICG signature, enabling further investigation of immune infiltration and potential therapeutic targets.

Based on the expression of ICGs, patients with BLCA were classified into 3 distinct subtypes, each exhibiting unique phenotypic and mechanistic characteristics. Furthermore, the developed ICG signature was identified as an independent predictor of outcomes in patients with BLCA and was closely associated with immune infiltration, ICG expression levels, and chemotherapy effectiveness.

The study concluded that a systematic and comprehensive analysis of immune checkpoint gene expression led to the establishment of the ICG signature, which revealed significant differences in ICG expression and the tumor immune microenvironment.

This information aids in risk stratification and supports the advancement of precision medicine for BLCA. Furthermore, KRT23 was identified as the most critical model gene, highlighting its potential as a promising target to enhance immunotherapy in patients with BLCA.

The study received no funds.

Source: https://pubmed.ncbi.nlm.nih.gov/39160525/

Chen D, Cao H, Zheng X, et al. (2024). “Immune checkpoint gene signature assesses immune infiltration profiles in bladder cancer and identifies KRT23 as an immunotherapeutic target.” BMC Cancer. 2024;24(1):1024. Published 2024 Aug 19. doi:10.1186/s12885-024-12790-w

Impact of QoL and Optimism on Prognostic Views in mRCC and mBC

KEY TAKEAWAYS

  • The study aimed to evaluate perceptions of treatment outcomes in patients with mRCC and mBC, focusing on the role of optimism and QoL.
  • Most patients with mRCC and mBC had inaccurate views on treatment outcomes, linked to higher QoL and optimism.

Durable complete response rates for metastatic renal cell carcinoma (mRCC) and metastatic bladder cancer (mBC) remain low despite advancements in therapy. Palliative care prioritizes life extension and improving quality of life (QoL) rather than a cure.

Hatice Bolek and the team aimed to examine how patients with mRCC and mBC perceive treatment outcomes and how QoL and optimism impact these perceptions.

Between March 15, 2023, and January 15, 2024, researchers conducted a multicenter, cross-sectional online survey targeting patients diagnosed with mRCC and mBC. The survey included structured questions assessing perceptions of disease cure, symptom improvement, daily activity performance, and life extension from treatment.

To measure optimism and QoL, the European Organization for Research and Treatment of Cancer 30.3 QoL questionnaire and the Life Orientation Test were used. The study revealed high optimism and inaccurate beliefs about cure among patients.

About 169 patients participated in the survey, with the majority rating their general health as good (72.2%) and excellent (13.6%). Patients who rated their health as good-excellent had higher median general QoL and optimism scores than those who rated it fair-poor. Overall, 85.2% of patients believed the possibility of a cure was very likely or likely.

Most participants thought treatment would relieve symptoms (30.2% very likely, 49.1% likely), improve daily activity performance (28.4% very likely, 55.6% likely), and extend life (32.5% very likely, 53.3% likely). Patients who responded very likely and likely to these questions had higher QoL and optimism scores than those who responded a little likely or not possible.

The study concluded that most patients with mRCC and mBC held inaccurate beliefs about treatment outcomes. Higher QoL and optimism were linked to greater inaccuracies in these perceptions.

Funding is provided by Roche, Novartis, BMS, Merck, AstraZeneca, Nektar, Johnson &Johnson, Lilly, Amgen, Incyte, Bayer, Yuhan, Henlius, Pfizer, Biontech, Genmab, Beigene, GSK.

Source: https://pubmed.ncbi.nlm.nih.gov/39208383/

Bolek H, Arslan C, Basaran M, et al. (2024). “Perceptions and Expectations: A Study on Prognostic Perception and Quality of Life in Patients With Metastatic Renal and Bladder Cancer.” JCO Glob Oncol. 2024;10:e2400201. doi:10.1200/GO.24.00201

Low HALP Scores Predict Bladder Cancer Recurrence After UTUC

KEY TAKEAWAYS

  • The study aimed to investigate how the HALP score affects pathologic results and bladder cancer recurrence in patients with UTUC.
  • Results showed that lower HALP scores are linked to advanced disease, higher grade, and increased bladder cancer recurrence risk.

Mehmet Yoldas and the team aimed to investigate how the haemoglobin, albumin, lymphocyte, and platelet (HALP) score impacts pathologic outcomes and bladder cancer recurrence (BCR) in patients who underwent surgery for upper urinary tract tumors (UTUCs).

Researchers calculated HALP scores for all patients. They compared demographic data, preoperative blood parameters, pathologic results, and bladder cancer recurrence status between patients with low and high HALP scores.

Results showed that haemoglobin (11.2±2.3 g/dL vs. 12.9±2.4 g/dL), albumin (4.0±0.8 g/dL vs. 4.4±0.9 g/dL), and HALP score (38.2±2.9 vs. 43.4±3.1) were significantly lower in the BCR (+) group compared with the BCR (-) group (P<0.001). The ROC curve indicated an optimal HALP score cut-off point of 40.8. Multivariate analyses demonstrated that the HALP score was effective for Tumour Grade, Tumour Stage, and BCR.

The study concluded that lower HALP scores are associated with more advanced stages, higher-grade pathologic outcomes, and an increased risk of BCR.

No funding information was available.

Source: https://pubmed.ncbi.nlm.nih.gov/39208822/

Yoldas M, Arikan Y, Kuvvet Yoldas T. (2024). “The Effect of the HALP Score on the Development of Bladder Cancer Recurrence in Patients Undergoing Radical Nephroureterectomy for Upper Urinary Tract Tumours.” Der Einfluss des HALP-Scores auf die Entwicklung eines Blasenkrebsrezidivs bei Patienten, die sich einer radikalen Nephroureterektomie aufgrund eines Tumors des oberen Harntrakts unterziehen. Aktuelle Urol. 2024;55(5):452-457. doi:10.1055/a-2359-7990

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