Results Of Trial Research Articles

Investigating the real-world outcomes of single- versus multi-agent preoperative chemoradiotherapy for locally advanced rectal cancer: NCDB analysis from 2004-2020.

61 Background: Fluorouracil-based chemoradiotherapy is the standard initial treatment for locally advanced rectal cancer, demonstrating improved pathological response and reduced local recurrences compared to radiation alone. Fluorouracil-based chemo-radiation therapy has no impact on distant recurrences. Oxaliplatin was tested in addition to fluorouracil-based chemo-radiotherapy in clinical trials to improve pathological complete response (pCR), distant recurrence-free survival, and overall survival. The trial results are conflicting. In this study, we aim to compare single-agent (SA) versus multi-agent (MA) chemotherapy using real-world data from the National Cancer Database (NCDB). Methods: The NCDB was used to identify 39,667 patients with rectal cancer who received concurrent chemoradiotherapy between 2004 and 2020. We compared patients who received SA chemotherapy with those who received MA concurrent chemotherapy. The primary outcomes of interest were overall survival and pCR. The groups were compared using univariate analysis and Cox proportional hazard models to adjust for potential confounding factors. Results: Of 39,667 patients with rectal cancer, 24,452 received single-agent (SA) chemotherapy and 14,215 received multi-agent (MA) chemotherapy. Patients in the SA group were of advanced age, had a greater number of comorbidities (as calculated by the Charleson-Dayo score), were treated within community facilities, had a higher income status, were covered by government insurance, were situated on the east coast, and had lower educational attainment compared to those in the MA group (p<0.05). SA group had higher T4 and N1 disease, however MA group had more N2 disease. Upon survival analysis, patient in MA group had higher survival (41.2 vs 38.9 months, p=0.005), however pCR was significantly higher in SA group (10.4% vs 6.4%, p<0.001). Conclusions: MA chemoradiotherapy for rectal cancer improves survival, with the SA regimen showing enhanced complete pathological response. Differences in baseline characteristics may explain the outcomes. While MA chemotherapy offers modest overall survival benefits, potential toxicity needs to be considered and confirmed in future studies. Comparison between single agent vs multi-agent chemo-radiotherapy group. Outcome Single-agent chemotherapy Multiagent chemotherapy Chi Squared p-value No readmission within 30 days of surgical discharge 22,727 (89.3 %) 12,921 (90.9 %) <0.001 30-day mortality after surgery 360 (1.5 %) 59 (0.5 %) <0.001 90-day mortality after surgery 716 (3.0 %) 158 (1.3%) <0.001 Median duration of surgical admission 6.0 5.0 <0.001 Median survival-vital = deceased (months) 38.9 41.2 0.005 Median survival-vital = alive (months) 66.9 52.0 <0.001 Pathological complete response (pCR) 2,644 (10.4%) 904 (6.4%) <0.001

Assessing Communication Impairments in a Rare Neurodevelopmental Disorder: The SCN2A Clinical Trials Readiness Study.

SCN2A-related disorders (SCN2A-RDs) entail severe impairments in multiple domains that could serve as nonseizure outcomes in clinical trials. This study evaluated the fitness for purpose of several clinical instruments with both standardized and alternative scoring and with some measures used out of their intended age range for assessing communication in SCN2A-affected participants. Parents of SCN2A-affected children were recruited through FamilieSCN2A Foundation outreach for a combined cross-sectional and longitudinal study. They completed assessments of their children at study entry and 6 and 12 months later. Assessments included the Vineland Adaptive Behavior Scale (VABS-3), Adaptive Behavior Assessment System (ABAS), Communication Matrix, and Communication and Symbolic Behavior Scale (CSBS). Analyses examined floor and ceiling effects, inter-rater and test-retest reliability, discrimination among different levels of functional impairment, and sensitivity to clinical aspects of SCN2A-RDs. Of 65 participants (28 females, median age 6.4 years, IQR 4.1-10.5), 56 (86%) had epilepsy. Eleven (17%) used speech as their primary communication mode; 84% were considered ineffective communicators. The mean Vineland composite standardized score (SS) was 34 (IQR 26-46). Cross-sectionally, standardized scores decreased with increasing age. There were substantial floor effects for receptive (75%) and expressive (83%) communication. SSs discriminated poorly between verbal vs nonverbal and communicative vs noncommunicative participants and were not sensitive to features reflecting epilepsy severity (e.g., epileptic spasms and number of current medications). By contrast, Vineland growth scale value (GSV) and ABAS, Matrix, and CSBS raw scores had minimal floor effects; most increased with age. These alternative scores distinguished clearly between participants with different levels of communication and were sensitive to aspects of epilepsy severity. Longitudinally, SSs decreased, but other scores remained relatively stable over a year. SCN2A-RD is characterized by severe-to-profound impairment with a SS <4 SDs of the norm-referenced mean. Owing to severe floor effects and their insensitivity to markers of communication function, age-standardized scores (e.g., Vineland SS) are not fit for purpose in clinical trials or other settings for evaluating nonseizure outcomes such as communication. GSVs and alternative scoring and assessments have much better measurement profiles in all these regards and should be considered in future precision medicine trials for SCN2A-RDs and other similar rare diseases.

The role of living donor liver transplantation in colorectal cancer liver metastases.

Despite technical and therapeutic advances, only 20-40% of patients with colorectal liver metastases (CRLM) have resectable disease. Historically, the remaining patients with unresectable, liver-only CRLM would receive palliative chemotherapy, with a median survival of 8 months. Liver transplantation has emerged as a viable option for selected patients with CRLM. This advancement stems from improved understanding of tumour genomics and biology and better patient selection criteria. The results of recent prospective clinical trials have further ignited enthusiasm for liver transplantation as a viable therapeutic option. Living donor liver transplantation (LDLT) offers several advantages over deceased donor liver transplantation (DDLT) for this disease, including reduced wait-time and optimized timing and coordination of oncologic therapy. On-going LDLT clinical trials have demonstrated favourable outcomes as compared with other liver transplantation indications. However, there is no established consensus or standardization in the implementation of LDLT for CRLM, beyond trials and centre-specific protocols. LDLT is an excellent therapeutic option in highly selected patients with CRLM. Refining prognostic factors and selection criteria will help to further optimize the utility and broaden the acceptance and implementation of LDLT for patients with CRLM.

Neoadjuvant Clinical Trials in Adults with Newly Diagnosed High-Grade Glioma: A Systematic Review.

High-grade gliomas are devastating cancers that remain incurable with standard surgical resection and radiochemotherapy. Although beneficial against neoplasms, radiation lowers lymphocyte counts, weakens immune activation, and recruits suppressive myeloid cells impairing immune responses. Tumor environments treated with radiation experience long-term immunosuppression, reducing immunotherapy effectiveness and contributing to recurrence. Investigating pre-radiation treatments in newly diagnosed patients could identify active agents, assess immunotherapy impact, and enable multiomic analyses without radiation-induced confounding factors. This literature review was conducted to describe the feasibility, safety, and outcomes of postsurgical, pre-radiation clinical trials for adults with newly diagnosed high-grade glioma. A systematic review was performed of the English-language literature reporting results of clinical trials for adults with newly diagnosed high-grade glioma administered postsurgical treatment prior to radiation therapy. A search was conducted in PubMed and references cited in research and review articles were also considered. From 1991 to 2024, 52 clinical trials were identified: 3 phase I, 38 phase II, 4 phase III, and 7 of unknown phase. Nine trials were randomized, 24 were multicenter trials, 21 investigated temozolomide-containing regimens, and 12 focused on inoperable tumors, involving a total of 2,737 patients. Pre-radiation neoadjuvant studies are feasible and may identify active drugs. This is particularly relevant in the era of personalized medicine with brain-penetrant drugs, targeted therapy, and immuno-oncology advancements. Investigating pre-radiation treatments in newly diagnosed high-grade glioma is a viable approach to rapidly identify active and inactive regimens while the immune system and tumor microenvironment remain intact.

FOLFIRI-ramucirumab (FOLFIRI-Ram) versus ramucirumab-paclitaxel (Ram-Pac) in the second line (2L) for patients with advanced upper gastrointestinal (UGI) cancer: A real-world propensity-score matched analysis of survival.

377 Background: The approach to 2L treatment of advanced UGI (gastric, esophageal, and gastroesophageal junction) cancers is guided primarily by the results of the RAINBOW trial, a global randomized phase III trial that demonstrated the benefit of Ram-Pac over paclitaxel. However, the onset of peripheral neuropathy limits its use in the palliative-intent setting. The RAMIRIS trial demonstrated the feasibility of 2L FOLFIRI-Ram compared to Ram-Pac, however it failed to meet the prespecified endpoint of ≥ 65% 6-month overall survival (OS). Despite this, FOLFIRI-Ram has emerged as an alternative 2L regimen and now endorsed in major society guidelines. Yet, comparative outcomes between FOLFIRI-Ram and Ram-Pac therapy in the real world are lacking. Methods: This study used the nationwide Flatiron Health electronic health record-derived deidentified database. During the study period (January 2011-June 2024), longitudinal patient-level data were derived from approximately 280 cancer clinics. Patients were eligible for inclusion if they had advanced unresectable or metastatic UGI cancer and received 2L treatment with either FOLFIRI-Ram or Ram-Pac. Demographics and lab values at the time of 2L initiation were extracted. Given anticipated imbalances in sample size, patients were matched 1:6 (FOLFIRI-Ram:Ram-Pac) for inclusion into the analytic dataset using a greedy match based on a logit model to predict propensity scores from key clinical and laboratory characteristics. The primary endpoint was OS from the start of 2L therapy, analyzed using the Kaplan-Meier method, log-rank test, and Cox proportional hazards model. A hybrid approach was used to construct a multivariate Cox model. Results: A total of 15,908 patients were included in the database, of whom 5189 received a 2L treatment. Of these, 631 patients received 2L Ram-Pac and 40 received 2L FOLFIRI-Ram. After matching, the final sample size was 240 patients who received Ram-Pac and 40 who received FOLFIRI-Ram. Baseline clinical and laboratory characteristics were well-balanced. The median OS from initiation of 2L FOLFIRI-Ram was 9.7 months (95% CI 6.9-12.3) and 7.6 months with 2L Ram-Pac (95% CI 6.3-9.2 months). The hazard ratio (HR) for death with FOLFIRI-Ram was 0.77 (95% CI 0.52-1.15, log-rank P=0.20) in reference to Ram-Pac. The adjusted HR death for FOLFIRI-Ram after adjustment for baseline albumin and white blood cell count was 0.87 (95% CI 0.58-1.30, p=0.49) in the final multivariate model. Conclusions: This real-world propensity-score matched analysis of patients with advanced UGI cancers receiving FOLFIRI-Ram or Ram-Pac supports the ongoing use of FOLFIRI-Ram in the 2L as an alternative to Ram-Pac. These data are consistent with results from the RAMIRIS study, however further prospective study is needed.

Aurora kinase B inhibitor AZD1152: repurposing for treatment of lupus nephritis driven by the results of clinical trials.

Lupus nephritis (LN) is one of the most common and severe complications of systemic lupus erythematosus (SLE). Multitarget therapy (MT) achieves a 20% higher complete remission (CR) rate compared to conventional therapy in LN management. Intrigued by its excellent clinical efficacy, we aimed to develop a single-agent therapy with comparable efficacy to MT, offering a simplified treatment regimen. AZD1152, an Aurora kinase B (Aurkb) inhibitor, was identified through transcriptomic analyses and the L1000 CMap drug repurposing database. The therapeutic efficacy of AZD1152 was evaluated in MRL/lpr mice. Transcriptome sequencing and functional assays were performed to elucidate its mechanisms of action. Aurkb expression and its clinical relevance were assessed in lupus-prone mice and patients with LN. AZD1152 significantly attenuated systemic immune activation and renal injury in MRL/lpr mice, demonstrating efficacy comparable to MT regimens in animal studies. AZD1152 treatment modulated immune-inflammatory pathways in the kidney. Aurkb expression was upregulated in T cells infiltrating the renal interstitium in LN. Additionally, Aurkb expression levels positively correlated with the activity index (AI) and serum creatinine (Scr) in patients with LN. Mechanistic studies revealed that AZD1152 exerts therapeutic effects primarily by inhibiting T-cell proliferation. This study presents a drug development strategy that integrates clinically validated LN therapies withdrug repurposing approaches. This strategy could accelerate drug development and clinical translation processes for LN. A full list of funding sources can be found in the acknowledgements section.

Real-world clinical outcomes of patients (Pts) with metastatic colorectal cancer (mCRC) who received trifluridine-tipiracil (FTD-TPI) monotherapy or FTD-TPI + bevacizumab (FTD-TPI+bev) combination therapy.

79 Background: FTD-TPI+bev has shown survival benefit when compared to FTD-TPI alone in pts with mCRC and was approved in the U.S. in 2023. However, there is a lack of real-world data on outcomes for pts who received FTD-TPI+bev as compared to pts who received FTD-TPI. Methods: This retrospective study used data abstracted from electronic medical records and claims in the ConcertAI RWD360 dataset. Adult pts with a diagnosis of mCRC and exposure to FTD-TPI were included. Pts were categorized as having received FTD-TPI or FTD-TPI+bev based on first exposure to FTD-TPI (index date). Kaplan-Meier analyses were used to describe the overall survival (rwOS), real-world time to discontinuation (rwTTD), and time to next treatment or death (rwTTNTD) from the index date. Multivariate Cox regression analyses were used to control for patient characteristics, including demographics, ECOG performance status (PS), comorbidities, sites of metastatic disease, time from mCRC to index date, lab results, and receipt of prior regorafenib. Results: This study included 3,680 pts. The FTD-TPI cohort included 3,151 pts (median age 62 years; male 56.3%; White 63.3%; any comorbidities 40.6%; ECOG PS 0-1 34.8%; 2+ metastatic sites 25.4%; median time from mCRC diagnosis to index date 699 days). The FTD-TPI+bev cohort included 529 pts (median age 60 years; male 53.9%; White 68.1%; any comorbidities 34.4%; ECOG PS 0-1 51.4%; 2+ metastatic sites 25.1%; median time from mCRC diagnosis to index date 609 days). Prior to index date, 18.5% and 6.9% of pts had been exposed to regorafenib in the FTD-TPI and FTD-TPI+bev cohorts, respectively. FTD-TPI+bev significantly increased rwOS (median 9.4 [95% CI 8.0-10.1] vs 6.4 [95% CI 6.1-6.6] months; p&lt;0.0001) and significantly decreased the risk of death (HR=0.68; p&lt;0.0001) in the adjusted model. Other significant factors for rwOS included 2+ metastatic sites (vs.1 site, HR=1.16; p=0.002) and no receipt of regorafenib prior to index date of FTD-TPI (HR=0.80; p&lt;0.0001). FTD-TPI+bev also significantly prolonged rwTTD as compared to FTD-TPI (median 3.5 [95% CI: 3.3-3.8] vs 2.4 [95% CI: 2.3-2.6] months; p&lt;0.0001) and decreased risk of discontinuation (HR=0.65; p&lt;0.0001) after adjusting for patient demographic and clinical characteristics. Additionally, the FTD-TPI+bev cohort had a significantly longer rwTTNTD as compared to the FTD-TPI cohort (median 5.0 [95% CI: 4.6-5.5] vs 3.9 [95%CI: 3.8-4.1] months; p&lt;0.0001) in the adjusted model (HR=0.73; p&lt;0.0001). Conclusions: This is the largest study to compare the clinical outcomes of pts receiving FTD-TPI and FTD-TPI+bev in the real-world setting. FTD-TPI+bev improved clinical outcomes including rwOS, rwTTD, and rwTTNTD, as compared to FTD-TPI in pts with mCRC. These findings align with the results of the SUNLIGHT trial.

Genetic mutations and cytotoxic chemotherapy response for advanced solid tumors: A detailed analysis using the C-CAT database in Japan.

130 Background: Chemotherapy regimens are selected based on information about the primary organ or its histological type and are administered based on the results of previous clinical trials. Even now, as cancer genomic research has progressed and precision medicine, which optimizes therapeutic interventions based on tumor genome profiling using next-generation sequencing(NGS), has become standard treatment, cytotoxic anticancer drugs still remain key drugs. We examined the real-world database of genomic and clinical information established by the national central datacenter, the Center for Cancer Genomics and Advanced Therapy (C-CAT) to systematically analyze the effects of mutations across multiple cancers and therapies. Methods: This study delineated the association between genetic mutations and the therapeutic efficacy of cytotoxic chemotherapy in advanced solid tumors in a real-world Japanese clinical context. We incorporated data from 15,474 patients enrolled in the C-CAT database between June 2019 and June 2022. We analyzed the overall response and time to next treatment (TNT) for genetic alterations and five categories of cytotoxic anticancer drugs in gastrointestinal cancers. Results: In the C-CAT data, gastrointestinal cancers were frequently registered, with colorectal cancer being the most common, followed by pancreatic cancer, esophageal/gastric cancer, and biliary tract cancer. For platinum-based drugs, in colorectal cancer, the presence of gene X was associated with not only a higher response rate but also a longer TNT (hazard ratio 0.82, p&lt;0.001). In the case of colorectal cancer and pancreatic cancer with KRAS gene mutations, the ORR was low, and the TNT was also short in the case of pancreatic cancer (hazard ratio 1.33, p&lt;0.001). Interestingly, when BRCA2 genes are mutant, TNT tended to be longer in many organs, suggesting that platinum-based drugs are effective across organs in carcinomas with BRCA2 mutations. Additionally, gene X showed differences in efficacy not only for platinum but also for antimetabolites and topoisomerase inhibitors. Moreover, KRAS mutation was observed in almost all pancreatic cancers and was a treatment-resistant mechanism for all platinum drugs and antimetabolites. Conclusions: This study demonstrated that the effects of cytotoxic anticancer drugs differ depending on genetic mutations. When determining chemotherapy regimens, considering not only the organ but also genetic mutations may enable more efficient drug selection.

Cohort-level patient-derived organoid assays and prediction of clinical trial outcomes in PDAC.

785 Background: Clinical trials are one of the major barriers in contemporary drug development. Improving the number of therapeutic solutions for patients whilst limiting the financial burden of healthcare systems will require dramatically improving clinical trial success rates. Functional assays based on patient-derived organoids (PDO) are a promising new tool for derisking clinical development of new therapies, but their use has been limited due to small cohort sizes and the absence of systematic validation studies. Methods: We have assembled a collection of 70 demographically relevant PDAC PDOs. Each PDO was screened with a 22-drug panel including standard of care, chemotherapies and targeted therapies. Using a best-in-class patient response prediction model we generate cohort scale estimations of overall response rates (ORR) and progression-free survival (PFS). The estimations are compared with data from published clinical trials to determine the validity of the approach. Results: The PDOs exhibit representative treatment histories in terms of number of lines of treatment (mean = 1.60) and treatment types (prior treatment types: folfirinox = 68.6%, gemcitabine = 50%). All the organoids’ mutational profile, past patient treatments and subsequent responses to future lines were analyzed and compared to the distributions observed in the clinic. The cohort-level drug efficacy on our PDO collection matches retrospective clinical trial ORRs reported in the literature. Furthermore, our preclinical assay predicts the relative performance of drugs in different clinical trial arms. Conclusions: We report that large-scale PDO-based assays predict clinical ORR and PFS with best-in-class accuracy. This work shows that well-characterized PDO collections can be used to improve the success rates of clinical studies for new potential treatments in PDAC.

Effects of disease aetiology on outcomes for unresectable HCC treated with lenvatanib or atezobev: A real world retrospective study.

554 Background: Hepatocellular Carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancer-death worldwide. 1 Standard of care first line treatment for unresectable HCC is Atezolizumab plus Bevacizumab (AtezoBev) 1 while the multi-kinase inhibitor Lenvatinib 2 is also available in the first line setting. No randomised studies have compared these treatments directly. Real world data suggests similar overall survival (OS) with AtezoBev possibly superior in patients with a viral hepatitis aetiology and Lenvatinib superior in NAFLD. 3,4,5,6,7 Methods: We evaluated patients treated with Lenvatinib or AtezoBev in a retrospective cohort of patients who commenced first-line treatment in the West of Scotland from 04/12/2015 to 28/11/2023. 102 received Lenvatinib and 52 AtezoBev. We collected data on progression free survival (PFS), OS, demographics and disease aetiology- classified primarily as viral hepatitis, acholic liver disease (ALD) or NAFLD. Results: AtezoBev patients had improved mOS compared with Lenvatinib (13.8 vs 9. 1 months, p = 0.04). No statistically significant differences were observed in mPFS (5.5 vs 3.5 months, p = 0.31). Of the three aetiologies considered, the only statistically significant (p&lt;0.05) difference between the treatments was OS in the NAFLD group (24.1 vs 9.1 months, p = 0.04). When considering patient demographic and disease factors, Child-Pugh score was most significant. Patients with Childs=5 liver disease had much longer OS and PFS compared with Childs≥6 disease. Similarly, patients with ECOG PS=0 had improved survival than PS≥1. There were no statistically significant (p&lt;0.05) differences between AtezoBev and Lenvatinib. Age, sex and social deprivation (SIMD) score had minimal effects on survival although high levels of social deprivation and male sex were over-represented in our population. Conclusions: In contrast to other real world analyses, our patients demonstrated improved mOS with Atezo/Bev vs Lenvatinib. 3 However, mPFS was similar for the two regimes. The difference in OS may be explained by differences in patient selection, with the Lenvatinib group disproportionately representing patients with a poorer performance status (PS&gt;0) and higher Childs-Pugh scores (CP&gt;5). Furthermore, patients in the AtezoBev group who progressed were often offered Lenvatinib second-line, possibly improving mOS, whereas Lenvatinib patients who progressed were offered either Sorafenib, a clinical trial or best supportive care. However, we cannot rule out a direct survival benefit from the use of AtezoBev vs Lenvatinib in the first line setting. The choice of first line therapy for HCC remains complex and must account for patient preferences such as convenience and side effect profile in addition to observed trial outcomes and the increasing body of real world evidence. 1. Finn RS et. al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N. Engl. J. Med. 2020 May 14;382(20):1894-1905. 2. Kudo, Masatoshi et. al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018. Volume 391, Issue 10126, 1163 – 1173. 3. Wang, BC. et. al. Lenvatinib Versus Atezolizumab Plus Bevacizumab in the First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Meta-Analysis of Real-World Studies. Targ. Oncol. 2024. 19, 203–212. 4. Casadei-Gardini A et. al. Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population. Eur. J. Cancer. 2023; 180:9-20. 5. Rimini M et. al. Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis. ESMO Open. 2022 Dec;7(6):100591. 6. Su CW et. al. Similar efficacy and safety between lenvatinib versus atezolizumab plus bevacizumab as the first-line treatment for unresectable hepatocellular carcinoma. Cancer Med. 2023. 12(6):7077-7089. 7. Rimini, M., et al. Survival outcomes from atezolizumab plus bevacizumab versus Lenvatinib in Child Pugh B unresectable hepatocellular carcinoma patients. J. Cancer. Res. Clin. Oncol. 2023. 149, 7565–7577.

Randomized trials: When scientific rigor meets field reality

Results from prospective randomized trial results are required to provide practice-changing level-1 evidence. However, if such a trial is not feasible, we should not accept that consequently practice could not change. We discuss hereby a pragmatically approach based on methodological alternatives.

Implications of Implementing Children's Oncology Group Risk Stratification to Patients With Rhabdomyosarcoma Treated on European Paediatric Soft Tissue Sarcoma Study Group Clinical Trial.

Prognostic factors are crucial in tailoring treatments for patients with rhabdomyosarcoma (RMS). The European paediatric Soft tissue sarcoma Study Group (EpSSG) and the Children's Oncology Group (COG) employ similar prognostic factors, but utilize them differently resulting in diverse stratification systems. This diversity may result in dissimilar treatment approaches for comparable patients and hinder the comparison of clinical trial results. We reclassified 1993 patients enrolled in the EpSSG RMS 2005 and MTS 2008 studies based on the risk stratification used in current EpSSG and COG trials, and compared the type and cumulative doses of chemotherapy recommended to the different risk groups. Alkylating agents were compared using the cyclophosphamide equivalent dose formula. Metastatic RMS with high-risk features were excluded because no standard recommended treatment exists. Patients were variably distributed across EpSSG and COG risk stratifications. Notably, 34.2% of EpSSG standard-risk patients fell into three different COG risk groups (very low, low, and intermediate), and 66.8% of the total population, classified as standard, high, and very high risk by EpSSG, would all be considered intermediate risk by COG. Consequently, only 57.3% of the study population would receive comparable intensive chemotherapy under both EpSSG and COG protocols. Disparities emerged, with 16.5% undergoing more intensive and 17.2% receiving less intensive treatment in COG protocols compared to EpSSG studies. Our study shows the complexities of the current RMS risk stratification systems, emphasizing the need for a global consensus. A unified approach would reduce the risk of disparate treatments for similar patients and facilitate more straightforward cross-study comparisons.

Quality Assurance of Depression Ratings in Psychiatric Clinical Trials.

Extensive experience with antidepressant clinical trials indicates that interrater reliability (IRR) must be maintained to achieve reliable clinical trial results. Contract research organizations have generally accepted 6 points of rating disparity between study site raters and central "master raters" as concordant, in part because of the personnel turnover and variability within many contract research organizations. We developed and tested an "insourced" model using a small, dedicated team of rater program managers (RPMs), to determine whether 3 points of disparity could successfully be demonstrated as a feasible standard for rating concordance. Site raters recorded and scored all Montgomery-Åsberg Depression Rating Scale (MADRS) interviews. Audio files were independently reviewed and scored by RPMs within 24 to 48 hours. Concordance was defined as the absolute difference in MADRS total score of 3 points or less. A MADRS total score that differed by 4 or more points triggered a discussion with the site rater and additional training, as needed. In a sample of 236 ratings (58 patients), IRR between site ratings and blinded independent RPM ratings was 94.49% (223/236). The lowest concordance, 87.93%, occurred at visit 2, which was the baseline visit in the clinical trial. Concordance rates at visits 3, 4, 5, and 6 were 93.75%, 96.08%, 97.30%, and 100.00%, respectively. The absolute mean difference in MADRS rating pairs was 1.77 points (95% confidence interval: 1.58-1.95). The intraclass correlation was 0.984 and an η2 = 0.992 (F = 124.35, P < 0.0001). Rigorous rater training together with real-time monitoring of site raters by RPMs can achieve a high degree of IRR on the MADRS.

Adjuvant capecitabine in resected biliary tract cancers: Real life data from a multicenter study (PRODIGE83-ACABi-PRONOBIL).

596 Background: Biliary tract cancers (BTCs) are rare and heterogeneous tumors with a poor survival even in early-stage patients treated with a curative surgery. Since 2019 the current standard of care in the adjuvant setting is oral chemotherapy (CT) with capecitabine for 6 months, as an option following BILCAP phase III trial results. Nevertheless, outside of this trial, real-world data are lacking. Methods: We conducted a French, retrospective, multicenter study from the ACABi-PRONOBIL cohort. Eligible patients had intrahepatic, perihilar, distal cholangiocarcinoma or gallbladder carcinoma treated by surgery with curative intent without prior therapy. Two groups were compared, patients who received capecitabine (Cape group) as adjuvant CT and patients without adjuvant treatment before 2017 (surveillance group). The primary endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS) and toxicity. Results: 324 patients were included, 200 in the Cape group and 124 in the surveillance group. The median OS was 43.5 months (CI95%= 35.4-48.0) and 44.6 months (CI95% 37.7-54.8) in the Cape and surveillance group, respectively. ECOG performance status ≥ 2, pT3 stage, vascular and node invasion were associated with a poorer OS. The DFS was 15.8 months (CI95%= 14.1-20.3) in the Cape group and 13.3 months (CI95%= 10.1-17.5) in the surveillance group. In inverse probability of treatment weighting (IPTW) analysis we observed a significant statistical association between Cape group and DFS (IPTW HR (CI95%) Cape group vs surveillance group = 0.76 (0.60-0.96), pvalue=0.0224) but not with OS. In the Cape group, 49% of patients had at least one dose reduction, 35% had to discontinue treatment due to toxicity (mainly gastrointestinal,13.3% of grade 3-4; and cutaneous, 27% of grade 3-4). Conclusions: In this retrospective analysis, adjuvant capecitabine appears to increase DFS without statistically significant impact on OS in patients undergoing surgery for BTC, confirming in real life the BILCAP study results.

Imiquimod Cream Preceded by Superficial Curettage vs Surgical Excision for Nodular Basal Cell Carcinoma: A Secondary Analysis of a Randomized Clinical Trial.

Interest in noninvasive treatment of basal cell carcinoma (BCC) has been increasing. For superficial BCC, it has been demonstrated that imiquimod cream, 5%, has high long-term efficacy, but for nodular BCC (nBCC), long-term evidence is sparse. To evaluate whether superficial curettage (SC) followed by imiquimod cream, 5%, is noninferior to surgical excision (SE) in nBCC after 5 years of treatment. In this secondary analysis of the noninferiority Surgery Versus Combined Treatment With Curettage and Imiquimod for Nodular Basal Cell Carcinoma (SCIN) randomized clinical trial, patients with a primary nBCC of 4 to 20 mm were assigned to either SC plus imiquimod, 5%, or SE between January 1, 2016, to November 30, 2017, at 2 outpatient dermatology departments in the Netherlands. The primary outcome of the SCIN trial was the 1-year probability of remaining free from treatment failure; the prespecified secondary trial outcomes were the probability after 5 years of follow-up, completed September 7, 2022. Both an intention-to-treat analysis and per-protocol analysis were planned. SC plus imiquimod vs SE. The 5-year probability of remaining free from treatment failure (ie, freedom from recurrence; with 95% CI) was estimated with Kaplan-Meier analysis using data on treatment response from 3 planned follow-up visits at 3 months and 1 and 5 years after the end-of-treatment date. Additional analyses accounting for death as competing risk were also performed. A total of 145 patients (77 [53.1%] male; median age, 68 [IQR, 31-89] years) with a primary, histologically proven nBCC were randomized to treatment with SC plus imiquimod (n = 73) or SE (n = 72). In total, 15 treatment failures occurred in the SC plus imiquimod group (5 treatment failures occurred between 1 and 5 years after treatment) and 1 in the SE group. The 5-year probability of remaining free from treatment failure was 77.8% (95% CI, 65.7%-86.0%) after SC plus imiquimod and 98.2% (95% CI, 88.0%-99.8%) after SE. The relative risk of treatment failure was 15.93 (95% CI, 2.10-120.64). The 95% CI does not exclude the noninferiority margin of 5.22. Death due to causes unrelated to BCC occurred in 20 patients, and the subhazard ratio from competing risk regression was 16.16 (95% CI, 2.18-119.72). This secondary analysis of a randomized clinical trial found that although it cannot be concluded that SC plus imiquimod is noninferior to SE, SC plus imiquimod was substantially less effective at 5 years after treatment. Most treatment failures occurred in the first year after treatment, and the probability of tumor-free survival 5 years after treatment with SC plus imiquimod was still 77.8%. The information in this trial can be used to counsel patients on the relative benefits and trade-offs of the different treatment options for nBCC. ClinicialTrials.gov Identifier: NCT02242929.

Utility of Progression Independent of Relapse Activity as a Trial Outcome in Relapsing-Remitting Multiple Sclerosis

Utility of Progression Independent of Relapse Activity as a Trial Outcome in Relapsing-Remitting Multiple Sclerosis

Effects of β-glucans on fatigue: a systematic review and meta-analysis.

Several clinical trials suggest that β-glucans may reduce feelings of fatigue, however the results of clinical trials are inconsistent. Additionally, no systematic reviews or meta-analyses have assessed the effects of β-glucans on fatigue. Therefore, this study investigates the effects of β-glucans on fatigue in healthy subjects through a systematic review and meta-analysis. PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from database inception to March 15, 2024. The inclusion criterion was a randomized controlled trial (RCT) investigating the effects of β-glucans on healthy subjects' fatigue, vigor, and mood state. To assess risk of bias, we employed the Cochrane risk of bias tool. A random-effects meta-analysis was conducted for the standardized mean difference (SMD). Sixteen RCTs with a total of 1,449 participants were included, and 12 studies provided data suitable for meta-analysis. Meta-analysis revealed that β-glucans significantly reduced feelings of fatigue (SMD = -0.32, 95% CI = -0.53 to -0.12; p = 0.0021), increased vigor (SMD = 0.46, 95% CI = 0.26-0.66; p < 0.0001), and improved mood state (SMD = 0.32, 95% CI = 0.11-0.53; p = 0.0026) compared to the placebo group. The results of the systematic review and meta-analysis indicate that β-glucans may be effective in reducing feelings of fatigue in healthy individuals. However, the number of studies included is insufficient, suggesting that further clinical trials are needed to validate this effect.

Rationale and design of the FAIR-HF2-DZHK05 trial: Ferric carboxymaltose assessment of morbidity and mortality in patients with iron deficiency and chronic heart failure.

While it is widely accepted that intravenous (IV) iron improves functional capacity, symptoms, and cardiovascular outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) diagnosed with iron deficiency (ID), three recently published cardiovascular outcome trials (AFFIRM-AHF, IRONMAN and HEART-FID) of IV iron supplementation in HF failed to demonstrate a significant benefit on their respective primary endpoints. Dosing of IV iron after the initial correction of baseline ID-by design or as a result of trial circumstances-was relatively low (i.e. <500 mg/year). The primary objective of the FAIR-HF2 trial is to evaluate the treatment effect of ferric carboxymaltose (FCM) compared with placebo in ambulatory patients with HFrEF using a higher dose of IV iron during follow-up (i.e. >1000 mg/year). The second objective of the study is to create prospective evidence for patients fulfilling the new definition of ID for patients with HF, i.e. for those with a transferrin saturation <20%. FAIR-HF2 is an investigator-initiated, multicentre, randomized, double-blind, placebo-controlled trial that has recruited 1105 patients with chronic HF with a left ventricular ejection fraction of ≤45% and concomitant ID, defined as serum ferritin <100 ng/ml or serum ferritin 100-299 ng/ml with a transferrin saturation <20%. Patients were consented and randomized to receive either IV FCM (treatment) or saline (placebo). During an estimated median follow-up of over 2 years, patients underwent a placebo-controlled repletion and maintenance phase, with an initial iron supplementation of up to 2000 mg, followed by 500 mg every 4 months unless stop criteria of haemoglobin >16 mg/dl or serum ferritin >800 ng/ml are met on repeat visits. The trial will evaluate three primary hypotheses: (i) time to first event of cardiovascular death or hospitalization for HF, (ii) the rate of total (first and recurrent) HF hospitalizations (both analysed in the full study population), and (iii) the time to first event of cardiovascular death or hospitalization for HF in patients with a transferrin saturation <20% at baseline. The familywise type I error rate across the three primary endpoint hypotheses will be controlled using the Hochberg procedure (alpha 0.05). The FAIR-HF2 will evaluate the efficacy of FCM in patients with HFrEF in improving cardiovascular outcomes by utilizing a more aggressive approach towards iron supplementation ensuring prevention of transitional ID after initial repletion targets have been met.

Nutritional and functional outcomes in trials of nutrient-stimulated hormone-based therapy-A systematic mapping review.

Currently, trials are investigating the efficacy of nutrient-stimulated hormone-based therapies (NuSHs) in promoting weight loss in people living with overweight and obesity. However, the extent to which nutritional and functional outcomes are evaluated remains uncertain. Thus, we conducted a systematic mapping to assess the presence of nutritional and functional outcomes in randomized controlled trials (RCTs) investigating NuSHs. We conducted a systematic mapping search on the Cochrane Central Register of Controlled Trials (CENTRAL), which includes ClinicalTrials.gov and the International Clinical Trials Registry Platform for interventional trials of NuSHs registered from inception to December 31, 2023. We excluded non- and quasi-randomized trials, phase I trials, trials that did not include body weight as a primary or secondary outcome, trials with an intervention duration of less than 6months, and trials that did not specify a body mass index threshold in their eligibility criteria. Outcomes included: dietary intake, eating behavior, body composition, physical performance, muscle strength, bone health, and levels of vitamins, trace elements, albumin, prealbumin, and hemoglobin. The search identified 2284 trials, of which 417 were included in the analysis. The proportion of RCTs that included nutritional assessment other than body weight increased over time. Approximately, 20.4% reported measurements of body composition, 17.3% reported measurements of albumin/prealbumin/hemoglobin, and 17% reported assessment of dietary intake and eating behavior. Evaluations of bone health, physical performance, muscle strength, and measurements of vitamins/trace elements were reported in less than 5% of the total trials each. The present review has shown the sparse reporting of nutritional and functional outcomes in RCTs evaluating the impact of NuSHs.

Regenerative fibroblasts derived from autologous skin tissue for the treatment of Sjögren’s syndrome: a case report

BackgroundSjögren’s syndrome (SS) is a systemic autoimmune disease, with major symptoms including dry mouth and dry eyes, for which there is no effective treatment. Recent studies have demonstrated that mesenchymal stem cells (MSCs) are effective in the treatment of SS, but the efficacy of allogeneic MSCs is affected by variability among different cell donors, and they are easily cleared by the immune system of the recipient. Autologous MSCs are one of the ideal options for the treatment of SS; however, their function decreases with age. Regenerative fibroblast (rFib) is a type of new MSC obtained through chemical reprogramming technology from skin fibroblasts. In this study, we report the safety and efficacy of intravenous infusion of autologous rFib in a volunteer with SS.Case reportIn March 2021, the volunteer was diagnosed with SS due to positive anti-SSB antibodies, lymphocyte infiltration in the lip gland, dry eyes, and a large area of purpura in both lower limbs. From May 2021 to November 2022, she received allogeneic Umbilical cord mesenchymal stem cells (UCMSC) therapy (5.0 × 107 UCMSCs per time, totaling 10 infusions), but her condition did not improve. In May 2023, the rFib for the volunteer was prepared, meeting the quality standard of T/CSCB0003-2021 Human Mesenchymal Stem Cells. Between October 2023 and June 2024, the volunteer received a total of 12 intravenous transfusions of autologous rFib. After the treatments, the volunteer experienced no recurrence of purpura in both lower limbs. Symptoms of dry mouth, dry eyes, and fatigue were relieved. ESR, B lymphocytes, rheumatoid factor IgM, and IgA declined, while the proportion of NK cells increased, and most of the cytokines returned to normal levels. In vitro experiments showed that rFib could significantly inhibit the proliferation of T lymphocytes after PHA stimulation. No adverse effects were associated with the use of rFib in the volunteer during the clinical trial.SummaryThe results of this clinical trial indicate that intravenous injections of autologous rFib are both safe and effective for treating SS. Autologous rFib may be more suitable for treating autoimmune diseases than allogeneic MSCs.