Publication Of Trials Research Articles

Epidemiology, survival and new treatment modalities for intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) is a rare biliary tract cancer with increasing incidence and poor survival rates. This study aims to evaluate the incidence and survival trends of iCCA patients over 20 years using a national cancer database, and assess the temporal association between survival and landmark clinical trials. Data was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Age-adjusted incidence rates (AAIRs) were calculated from 2000 to 2020. Overall survival was analyzed based on diagnosis time and disease stage. Subgroup analysis was performed for patients diagnosed between 2015 and 2020. Landmark clinical trials were reviewed to determine temporal changes in survival. In this analysis of 28,918 iCCA patients, the AAIR increased from 0.49 per 100,000 in 2000 to 1.38 in 2020 [annual percent change (APC) 6.94, 95% confidence interval (CI): 6.32 to 7.56], with a notable decline from 2019 to 2020. Incidence rates overall displayed an uptrend course across subgroups divided by sex, race, age, and disease stage. The age-adjusted median overall survival (mOS) improved from 5.28 months in 2000 to 9.3 months in 2013, then stabilized between 8.0-9.0 months after 2013. Using 2010 as a cutoff, when the ABC-02 trial was published, the decade-based mOS increased from 6.55 months in 2000-2010 to 9.06 months in 2010-2020. During 2015-2020, the overall mOS was 8.8 months, with mOS of 24.3, 12.1, and 5.4 months for local, regional, and distant stages, respectively. The study indicates a steady rise in iCCA incidence since 2000 across all subgroups. Survival rates improved since 2000 but stabilized after 2013, following the ABC-02 trial publication in 2010. The impact of more recent clinical trials on survival rates requires further analysis in the coming years.

Zero- and few-shot prompting of generative large language models provides weak assessment of risk of bias in clinical trials.

Existing systems for automating the assessment of risk-of-bias (RoB) in medical studies are supervised approaches that require substantial training data to work well. However, recent revisions to RoB guidelines have resulted in a scarcity of available training data. In this study, we investigate the effectiveness of generative large language models (LLMs) for assessing RoB. Their application requires little or no training data and, if successful, could serve as a valuable tool to assist human experts during the construction of systematic reviews. Following Cochrane's latest guidelines (RoB2) designed for human reviewers, we prepare instructions that are fed as input to LLMs, which then infer the risk associated with a trial publication. We distinguish between two modelling tasks: directly predicting RoB2 from text; and employing decomposition, in which a RoB2 decision is made after the LLM responds to a series of signalling questions. We curate new testing data sets and evaluate the performance of four general- and medical-domain LLMs. The results fall short of expectations, with LLMs seldom surpassing trivial baselines. On the direct RoB2 prediction test set (n = 5993), LLMs perform akin to the baselines (F1: 0.1-0.2). In the decomposition task setup (n = 28,150), similar F1 scores are observed. Our additional comparative evaluation on RoB1 data also reveals results substantially below those of a supervised system. This testifies to the difficulty of solving this task based on (complex) instructions alone. Using LLMs as an assisting technology for assessing RoB2 thus currently seems beyond their reach.

Percutaneous coronary revascularization versus medical therapy in chronic coronary syndromes: An updated meta-analysis of randomized controlled trials.

Coronary artery disease (CAD) is a main cause of morbidity and mortality. The effectiveness of coronary revascularization in chronic coronary syndromes (CCS) is still debated. Our recent study showed the superiority of coronary revascularization over optimal medical therapy (OMT) in reducing cardiovascular (CV) mortality and myocardial infarction (MI). The recent publication of the ORBITA-2 trial suggested superiority of percutaneous coronary revascularization (PCI) in reducing angina and improving quality of life. Therefore, we aimed to provide an updated meta-analysis evaluating the impact of PCI on both clinical outcomes and angina in CCS. Relevant studies were screened in PubMed/Medline until 08/01/2024. Randomized controlled trials (RCTs) comparing PCI to OMT in CCS were selected. The primary outcome was CV death. Secondary outcomes were MI, all-cause mortality, stroke, major bleeding and angina severity. Nineteen RCTs involving 8616 patients were included. Median follow-up duration was 3.3 years. Revascularization significantly reduced CV death (4.2% vs. 5.5%; OR = .77; 95% CI .62-.96, p = .02). Subgroup analyses favoured revascularization in patients without chronic total occlusions (CTOs) (p = .052) and those aged <65 years (p = .02). Finally, a follow-up duration beyond 3 years showed increased benefit of coronary revascularization (p = .04). Secondary outcomes analyses showed no significant differences, except for a lower angina severity in the revascularization group according to the Seattle Angina Questionnaire (SAQ) (p = .04) and to the Canadian Cardiovascular Society (CCS) classification (p = .005). PCI compared to OMT significantly reduces CV mortality and angina severity, improving quality of life in CCS patients. This benefit was larger without CTOs, in patients aged <65 years and with follow-up duration beyond 3 years.

Towards a minimum data set for the female stress urinary incontinence surgical literature: a collaborative work.

There has been a need for an acceptable common minimum data set in the scientific literature as regards the surgical treatment of female stress urinary incontinence (SUI). Such a data set, if widely adopted, would improve the quality of the literature and allow objective comparisons between and across interventions. The surgical treatment of female stress urinary incontinence has evolved considerably over the past few decades. The corresponding body of literature has grown exponentially describing the outcomes of hundreds of studies of these novel interventions. However, historically, the literature in this space has been of uneven quality. In order to improve the reporting of clinical studies, and ultimately patient outcomes, a standard minimum data set for trial design and publications was created by a collaborative group formed from leading scientific societies. The consensus document created from this novel collaboration between members of SUFU (Society of Urodynamics, Female Pelvic Medicine & Urogenital Reconstruction), AUGS (American Urogynecologic Society), and ICS (International Continence Society) provides clear guidance for the structure of clinical studies and reporting of results in the peer-reviewed literature. This has substantial potential ramifications for scientific journals, journal editors, peer reviewers, investigators, regulatory agencies, industry, clinicians, and patients.

Approach to radical hysterectomy for cervical cancer after the LACC trial and associated complications: a NSQIP study

BackgroundThe Laparoscopic Approach to Cervical Cancer (LACC) study results revolutionized our understanding of the best surgical management for this disease. Following its publication, guidelines state that the standard and recommended approach for radical hysterectomy is with an open abdominal approach. Nevertheless, the impact of the LACC trial on real-world changes in the surgical approach to radical hysterectomy remains elusive. ObjectiveWe aimed to study the trends and routes of radical hysterectomies and to evaluate post-operative complication rates before and after the LACC trial (2018). Study DesignThe National Surgical Quality Improvement Program registry was used to examine radical hysterectomies performed for cervical cancer between 2012-2022. We excluded vaginal radical hysterectomies and simple hysterectomies. The primary outcome measures were the trends in route of surgery [minimally invasive surgery (MIS) vs. laparotomy] and surgical complications rate, stratified by periods before and after the publication of the LACC trial in 2018 (2012-2017 vs. 2019-2022). The secondary outcome measure was major complications associated specifically with the different routes of surgery. ResultsOf the 3,611 patients included, 2,080 (57.6%) underwent laparotomy and 1,531 (42.4%) underwent MIS radical hysterectomy. There was a significant increase in the MIS approach from 2012 to 2017 (45.6% MIS in 2012 to 75.3% MIS in 2017, p<.001), and a significant decrease in MIS from 2018 to 2022 (50.4% MIS in 2018 to 11.4% MIS in 2022, p<.001).The rate of minor complications was lower in the period before the LACC trial [317 (16.9%) vs. 288 (21.3%), p=.002]. Major complications rate was similar before and after the LACC trial [139 (7.4%) vs. 78 (5.8%), p=.26]. The rates of blood transfusions and superficial surgical site infections were lower in the period before the LACC trial [137 (7.3%) vs. 133 (9.8%), p=.012 and 20 (1.1%) vs. 53 (3.9%), p<.001, respectively]. In a comparison of MIS vs. laparotomy radical hysterectomy during the entire study period, patients in the MIS group had lower rates of minor complications [190 (12.4%) vs. 472 (22.7%), p<.001] and the rate of major complications was similar in both groups [100 (6.5%) in the MIS group vs. 139 (6.7%) in the laparotomy group, p=.89]. In a specific complications analysis, the rates of blood transfusion and superficial surgical site infections were lower in the MIS groups (2.4% vs. 12.7%, and 0.6% vs. 3.4%, p<.001 for both comparisons) and the rate of deep incisional surgical site infections was lower in the MIS group (0.2% vs. 0.7%, p=.048). In a multiple logistic regression analysis, the route of radical hysterectomy was not independently associated with occurrence of major complications [aOR 95% CI 1.02 (0.63-1.65)]. ConclusionWhile the proportion of MIS radical hysterectomy decreased abruptly following the LACC trial, there was no change in the rate of major post-operative complications. In addition, hysterectomy route was not associated with major post-operative complications.

Clinical Trials Gone Missing—A Potential Source for Publication Bias in Dentistry

Background: The aim of this study was to examine publication bias associated with a failure to report research results of studies that were initially posted on the ClinicalTrials.gov registry and to examine factors associated with this phenomenon. Methods: A search was conducted in the ClinicalTrials.gov registry using six dental-related topics. Corresponding publications for trials completed between 2016 and 2019 were then searched using PUBMED, EMBASE and Google Scholar. For studies lacking matching publications, we emailed the primary investigator and received some additional data. For included studies, we recorded additional variables: industry funding, site setting (academic, private research facilities or private practice), design (single or multi-center), geographical location and commencement date vis a vis registration and publication dates. Results: A total of 744 entries were found, of which 7 duplicates were removed; an additional 67 entries just recently completed were removed. An additional 7 studies were in different fields and thus removed. Thus, 663 trials were included; of these, only 337 studies (50.8%) were published. The mean registration to publication interval was 29.01 ± 25.7 months, ranging from +142 to −34 months (post factum registration). Less than 1/3 of the studies were posted prior to commencement, of which much smaller proportions were published (37.3%). Studies that were posted after commencement (n = 462) had a much higher publication rate (56.7%), p &lt; 0.001. Multi-center studies and those conducted in commercial facilities had much higher, though non-significant, publication rates (56.5% and 58.3%, respectively). Conclusions: With only half of the studies registered being published, a major source for publication bias is imminent.

Discontinuation and non-publication of randomized controlled trials on cervical cancer or precancer.

Research waste is a considerable problem in clinical trials, with nonpublication being a significant contributor. We aimed to determine the prevalence of discontinuation and nonpublication of randomized controlled trials (RCTs) on cervical cancer or precancer. We searched ClinicalTrials.gov for registered RCTs investigating cervical cancer or precancer that started between January 2000 and December 2020. The primary and secondary outcomes were trial nonpublication and premature discontinuation, respectively. Publication status was determined by systematic searches of peer-reviewed journals using the PubMed and Scopus databases. A total of 113 RCTs met the inclusion criteria. Among the 85 trials completed before December 2020, 44 (51.8%) were prematurely discontinued and 40 (47.1%) were unpublished. A single-center design (61.4% vs. 34.1%, P=.012) and lack of external funding (59.1% vs. 36.6%, P=.038) were significantly associated with trial discontinuation. Large-scale (target sample size >400; 46.7% vs. 17.5%, P=.004) and externally funded trials (66.7% vs. 35.0%, P=.004) were more likely to be published. Multivariate logistic analysis revealed that a large sample size [odd ratio (OR): 4.125, 95% confidence interval (CI): 1.511-11.259, P=.006] and presence of external funding (OR: 3.714, 95% CI: 1.513-9.117, P=.004) were independent positive factors for trial publication. A significant proportion of RCTs related to cervical cancer or precancer were discontinued early or remain unpublished, resulting in a waste of research resources.

Current status of percutaneous coronary interventions in diabetics with multivessel disease - is it time to challenge FREEDOM?

Diabetes mellitus (DM) and coronary artery disease (CAD) are the leading causes of death in the world. Over the last two decades, clinical trials have indicated that DM patients with CAD have poorer cardiac outcomes than non-diabetic patients with CAD. The pivotal findings of the FREEDOM trial greatly impacted the way clinicians approached revascularisation in diabetic patients with multivessel disease (MVD). However, since the publication of the FREEDOM trial, much has changed both in percutaneous coronary intervention (PCI) technology, as well as in the management of diabetes. This review provides insights into advancements in stent technology, enhanced patient management strategies, improved clinical outcomes with newer hypoglycaemic agents, current approaches to antiplatelet therapy, and advances in lipid management in diabetic patients. The influence of patient-specific factors such as comorbidities and anatomical complexities on treatment decisions in diabetic patients with MVD is also discussed. The ongoing TUXEDO-2 India trial was designed to primarily compare the clinical outcomes of PCI with the new-generation ultrathin-strut Supraflex Cruz stent, compared to the second-generation XIENCE stent in the setting of contemporary optimal medical therapy in Indian diabetic patients with MVD. The secondary objective of this study is to compare clinical outcomes in the combined group from both study arms against a performance goal derived from the coronary artery bypass grafting (CABG) arm of the FREEDOM trial (historical cohort). The tertiary objective is to compare the efficacy and safety of ticagrelor versus prasugrel in diabetic patients with MVD. In view of recent advances in PCI and medical therapy since the FREEDOM trial, now is an appropriate time to revisit the results of CABG versus PCI in diabetic patients with MVD.

Myelomeningocele operated in utero and the incontinent bladder pattern: Mid-term follow up of a prospective study

In-utero myelomeningocele repair is the gold standard treatment after the publication of the MOMS trial. We have performed a retrospective analysis from our prospective in-utero myelomeningocele closure database (started in 2011), and selected only patients with the incontinent bladder pattern according to the Leal da Cruz categorization (Leal da Cruz, etal. J Urol 2015) to review mid-term clinical outcomes. We identified 30 patients with leaking pressure under 40 cmH20 (incontinent pattern) at first urodynamic evaluation (UE) from the whole cohort of 129 patients who underwent in-utero myelomeningocele closure. We selected patients with a minimum active follow-up of 48 weeks (4 years) to provide mid-term data. Patients were followed according to the same protocol with the proposal of yearly sonogram and UE. All clinical and radiological data were reviewed. We found 11 patients, with a mean age of 10.2 years old, median age at diagnosis of 19 weeks, surgery performed at 25.6 weeks and birth at 33.2 weeks. The mean follow-up was 81.73 months (6.81 years). Mean age at first urological evaluation was 5 months, and UE was 5.6 months. Febrile UTI incidence in the whole observation period was 27.3%. The average initial DLPP was 30 cmH2O. 71.4% of the patients had bladder capacity less than 50% of the expected age. Bladder compliance could not be determined in 63.7% of cases due to leakage. A total of 5.7 urodynamic studies per patient were performed. Surgery was recommended for 8 patients and done in 4 (36.3%). Surgery consisted of Macedo catheterizable reservoir and Macedo-Malone ACE, associated with urethral sling (2 patients) and bladder neck closure (2). It took an average of 5 UE before the final surgical decision was confirmed. Last urodynamic study showed persistent leakage and low DLPP in 3 patients, normal bladder pressure in 2 (under CIC and anticholinergics), and 1 patient changed his bladder pattern into a high risk group. All operated patients are fully continent (urinary >4hs) and fecal. Despite initially presenting a low risk for the most patients, we found surgery in 36.3% (4/11) and if we considered all cases with surgery indication proposed to treat urinary incontinence it would be even higher (72.7%).

Discussion of the classification of pediatric drug clinical trials in children's hospitals in China.

This study aimed to gain insights into pediatric clinical trials conducted in children's hospitals in China and provide valuable references for the development of children's hospitals and the research and development of pediatric drugs. A comprehensive search was performed on the Chinese Clinical Trial Registry (Chi CTR) and ChinaDrugTrials.org.cn to collect information on all clinical trials involving subjects under 18 years, including those conducted in children's hospitals. The retrieval period was extended until 31 December 2022. A total of 459 pediatric clinical trials were collected, comprising 299 from Chi CTR and 160 from the Drug Clinical Trial Registration and Information Publicity Platform (Information Platform). Post-marketing drug studies and phase III clinical trials accounted for the majority of research stages. These trials covered a wide range of diseases/systems, with a particular focus on respiratory system disorders, tumors, endocrine disorders, and nutritional or metabolic diseases. Chemical drugs constituted the most extensively studied category, while traditional Chinese medicine/natural drugs received comparatively less attention. Clinical trial activities were primarily geographically focused on the eastern coastal regions of China, with multicenter trials being the most predominant. Ethics committee approval was obtained for 427 studies. The pediatric clinical trials conducted by children's hospitals in China have shown an overall upward trend; however, there is limited research focusing on traditional Chinese medicine, along with significant regional and institutional imbalances. Furthermore, there is still room for improvement regarding ethical review processes. It is recommended that children's hospitals enhance their scientific research capabilities while optimizing resource allocation to meet medical service demands effectively. Additionally, fostering more research-focused children's hospitals will contribute to the high-quality development of children's health in China.

Omission of lymphadenectomy in patients with advanced epithelial ovarian cancer treated with primary or interval cytoreductive surgery after neoadjuvant chemotherapy: The CARACO phase III randomized trial.

LBA5505 Background: Lion trial demonstrated the lack of benefit of retroperitoneal pelvic and paraaortic lymphadenectomy (RPPL) in primary surgery in advanced epithelial ovarian cancer (AEOC) with clinically negative lymph nodes. As a consequence, the question of RPPL during interval cytoreductive surgery after neoadjuvant chemotherapy remains open. Methods: CARACO was a prospective multi-institutional phase III trial including patients with newly diagnosed AEOC FIGO III-IV, with no pre- and intra-operative suspicious lymph nodes, randomized intra-operatively to RPPL versus no-RPPL, stratified by surgical strategy (primary surgery, surgery after neoadjuvant chemotherapy). The primary endpoint was progression free survival (PFS). The target sample size was 450 evaluable patients, providing 80% power at 5% alpha based on the hypothesis of a 5 years PFS of 41%. Results: Between December 2008 and March 2020, 379 patients were randomly assigned to RPPL (n=181) or no-RPPL (n=187), 11 patients were excluded. Our required sample size was not reached because of a stop of inclusion after the publication of the Lion trial. The median number of removed lymph nodes in patients randomized to RPPL was 27 [IQR=19-36]. 75% of the patients were treated with neoadjuvant chemotherapy (244 patients treated with 3 or 4 cycles before interval surgery and 41 patients treated with 6 cycles before delayed surgery) and 83 patients treated with primary surgery followed with adjuvant platinum-based chemotherapy. The rate of surgery with no residual was 86% and 88% respectively in the No RPPL and the RPPL arm. Lymph node metastases were diagnosed in 49% of the patients in the RPPL arm, with a median of 3 involved lymph nodes [IQR=2-7]. After a median follow up of 9 years, median PFS in the no-RPPL arm and in the RPPL arm was 14.8 months and 18.5 months respectively (HR 0.98, 95%CI 0.78-1.22, p=0.86). Median OS was not significantly different: 48.9 months and 58.0 months in the No RPPL and RPPL arm respectively (HR 0.96, 95%CI 0.75-1.22 p=0.72). Results considering progression free and overall survival were not different in the subgroup of patients with a complete surgery or a neoadjuvant chemotherapy. Serious post-operative complications occurred more frequently in the RPPL arm: re-laparotomies 8.3% vs 3.2% [p=0.03], transfusion rate (34% vs 25%, p=0.05). Mortality within 60 days after surgery was similar between arms (1.1 vs 0.5% [p=0.54]) respectively. Conclusions: CARACO trial is the first randomized trial showing that systematic lymphadenectomy should be omitted in AEOC with clinically negative lymph nodes also in patients undergoing neoadjuvant chemotherapy and interval complete surgery. This surgical de-escalation allows to significantly reduce serious post operative morbidity. Clinical trial information: NCT01218490 .

ELDERLY ANKLE FRACTURE MANAGEMENT: PUTTING THE EVIDENCE INTO PRACTICE

IntroductionFollowing publication of the Ankle Injury Management (AIM) trial in 2016 which compared the management of ankle fractures with open reduction and internal fixation (ORIF) versus closed contact casting (CCC), we looked at how the results of this study have been adopted into practice in a trauma unit in the United Kingdom.MethodsInstitutional approval granted to identify eligible patients from a trauma database. 143 patients over 60 years with an unstable ankle fracture between 2017 and 2019 (1 year following publication of the AIM trial) were included. Open fractures, and patients with insulin-dependent diabetes or peripheral vessel disease were excluded (as per AIM criteria). Radiographs were reviewed for malunion and non-union. Clinical notes were reviewed for adverse events. Minimum follow up was 24 months.ResultsOf the 143 patients, 42 patients (29.4%) received a moulded cast with a return to theatre rate of 21.4%, malunion rate of 30.1%, and infection or wound problem rate of 4.8%. When the exact phrase “close contact cast” was specified in 21 patients (14.7%), there was a 19.0% return to theatre rate, 28.6% malunion rate, and a 4.8% infection or wound problem rate. 101 patients (70.6%) had ORIF with a return to theatre rate of 10.9%, malunion rate of 5.0%, and infection or wound problem rate of 13.9%.DiscussionOur results show a high rate of complication with cast management of unstable ankle fractures in this older population. This was improved where CCC was specified, but remains higher even than those published in the AIM trial. Whilst there is certainly a role for CCC in carefully selected patients, we would advise caution in the widespread adoption of a close contact casting technique.

Patient-Reported Outcomes in Phase 3 Clinical Trials for Blood Cancers: A Systematic Review

Published research suggests that patient-reported outcomes (PROs) are neither commonly collected nor reported in randomized clinical trials (RCTs) for solid tumors. Little is known about these practices in RCTs for hematological malignant neoplasms. To evaluate the prevalence of PROs as prespecified end points in RCTs of hematological malignant neoplasms, and to assess reporting of PROs in associated trial publications. All issues of 8 journals known for publishing high-impact RCTs (NEJM, Lancet, Lancet Hematology, Lancet Oncology, Journal of Clinical Oncology, Blood, JAMA, and JAMA Oncology) between January 1, 2018, and December 13, 2022, were searched for primary publications of therapeutic phase 3 trials for adults with hematological malignant neoplasms. Studies that evaluated pretransplant conditioning regimens, graft-vs-host disease treatment, or radiotherapy as experimental treatment were excluded. Data regarding trial characteristics and PROs were extracted from manuscripts and trial protocols. Univariable analyses assessed associations between trial characteristics and PRO collection or reporting. Ninety RCTs were eligible for analysis. PROs were an end point in 66 (73%) trials: in 1 trial (1%) as a primary end point, in 50 (56%) as a secondary end point, and in 15 (17%) as an exploratory end point. PRO data were reported in 26 of 66 primary publications (39%): outcomes were unchanged in 18 and improved in 8, with none reporting worse PROs with experimental treatment. Trials sponsored by for-profit entities were more likely to include PROs as an end point (49 of 55 [89%] vs 17 of 35 [49%]; P < .001) but were not significantly more likely to report PRO data (20 of 49 [41%] vs 6 of 17 [35%]; P = .69). Compared with trials involving lymphoma (18 of 29 [62%]) or leukemia or myelodysplastic syndrome (18 of 28 [64%]), those involving plasma cell disorders or multiple myeloma (27 of 30 [90%]) or myeloproliferative neoplasms (3 of 3 [100%]) were more likely to include PROs as an end point (P = .03). Similarly, compared with trials involving lymphoma (3 of 18 [17%]) or leukemia or myelodysplastic syndrome (5 of 18 [28%]), those involving plasma cell disorders or multiple myeloma (16 of 27 [59%]) or myeloproliferative neoplasms (2 of 3 [67%]) were more likely to report PROs in the primary publication (P = .01). In this systematic review, almost 3 of every 4 therapeutic RCTs for blood cancers collected PRO data; however, only 1 RCT included PROs as a primary end point. Moreover, most did not report resulting PRO data in the primary publication and when reported, PROs were either better or unchanged, raising concern for publication bias. This analysis suggests a critical gap in dissemination of data on the lived experiences of patients enrolled in RCTs for hematological malignant neoplasms.

Epidemiology, survival and new treatment modalities for intrahepatic cholangiocarcinoma (IHCC).

e16217 Background: Intrahepatic cholangiocarcinoma (IHCC), a rare biliary tract cancer, has been rising in incidence and is associated with poor survival. With the advent of new treatment modalities and various ongoing research, population-based perspective can be helpful to reflect the progress in managing this deadly disease and provide updated outcome information as a reference for comparison during upcoming clinical studies. We would like to provide a 20-year update on incidence and survival with reference to landmark trials, with a focus on survival outcomes of the recent 5 years for future insights. Recent and ongoing clinical trials will be discussed. Methods: This study extracted population data from the Surveillance, Epidemiology, and End Results (SEER) database. Age-adjusted incidence rate (AAIRs) and survival rate (SR) trends were calculated from January 2000 to December 2020 using 22 registries for the US population. Incidence and survival rates were collected from the SEER database, reported per 100,000 population and age adjusted to the 2020 US standard population. The annual percent change (APC) was used to report long term trends. Results: In this analysis of 19,948 IHCC patients, the AAIR increased from 0.49 per 100,000 in 2000 to 1.38 in 2020 (APC 6.94, 95% CI 6.32 to 7.56), with a notable decline from 2019 to 2020. Incidence rates overall displayed an uptrend course across subgroups divided by sex, race, age, and disease stage. The age-adjusted mOS climbed from 5.28 months in 2000 to 9.3 months in 2013, maintaining between 8.0-9.0 months after 2013. Using 2010 as a cutoff, when the ABC-02 trial was published, the decade-based mOS increased from 6.55 in 2000-2010 to 9.06 in 2010-2020, which remained statistically significant at 1-year, 3-year, and 5-year OS. During 2015-2020, the overall mOS was 8.8 months, with mOS of 24.3 months, 12.1 months, and 5.4 months for local, regional, and distant stages, respectively. Conclusions: These results indicate a steady rise in IHCC incidence since 2000, consistent across all subgroups. Survival rates have improved since 2000 but stabilized after 2013, following the publication of the ABC-02 trial published in 2010, which used systemic gemcitabine and cisplatin for unresectable iHCC. Updated survival data from 2015 onwards will serve as a reference of comparison for forthcoming clinical trials.

Pharmacokinetic Bioequivalence and Safety Assessment of Two Venlafaxine Hydrochloride Extended-Release Capsules in Healthy Chinese Subjects Under Fed Conditions: A Randomized, Open-Label, Single-Dose, Crossover Study.

Venlafaxine hydrochloride extended-release (ER) capsules are commonly used to treat depression and anxiety disorders. Evaluation of the bioequivalence of generic formulations with reference products is essential to ensure therapeutic equivalence. The objective of this study was to evaluate the bioequivalence, safety, and tolerability of Chinese-manufactured venlafaxine hydrochloride extended-release capsules compared with USA-manufactured EFFEXOR® XR in healthy Chinese volunteers under fed conditions. A randomized, open-label, single-dose, crossover study was conducted. Subjects were randomly assigned to receive the test formulation (one 150-mg ER capsule manufactured in China) or the reference formulation (one 150-mg ER capsule manufactured in the USA). The bioequivalence of the two drugs was assessed using the area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) and the maximum observed concentration (Cmax). A total of 28 subjects were enrolled and randomly assigned to receive a single dose of either the test or reference capsule. All the subjects completed the study and were included in the pharmacokinetic (PK) and safety analyses. The mean AUC0-t and Cmax of venlafaxine and its active metabolite O-desmethylvenlafaxine were comparable between the test and reference products with both parameters close to 100% and the corresponding 90% confidence intervals within the specified 80-125% bioequivalence boundary. Safety was also assessed between the two products and all adverse events (AEs) in this study were mild in severity. Both the test and reference venlafaxine hydrochloride ER capsules were bioequivalent and showed a similar safety and tolerability profile in the population studied. This study was registered at the Drug Clinical Trial Registration and Information Publicity Platform ( http://www.chinadrugtrials.org.cn/index.html ) with registration number CTR20211243, date: June 1, 2021.

The prevalence of RCTs in PARP and immune-checkpoint blockade combination trials: An appraisal of clinical evidence generation in oncology.

e23006 Background: PARP-inhibitors were developed to promote lethal genomic instability in cancers with homologous recombination repair (HRR) defects, ultimately receiving approval for patients with BRCA gene mutations. At the tumor microenvironment, DNA instability is linked to higher expression of immune activating signals such as PDL1. PDL1 is one of the primary targets for immune-checkpoint inhibitors (ICIs), receiving approval for numerous cancer types. In-vitro studies support mechanisms of possible synergy for PARP and ICIs in combination. Despite both therapy classes being available to oncologists for nearly a decade, the clinical benefit for these agents together remains unclear. Our study aims to appraise the global clinical trial landscape for trials testing combination PARP and PD1/PDL1 regimens. Methods: Search terms for all known approved or unapproved PD1/PDL1 and PARP inhibitors associated with trials registered on the National Library of Medicine’s website, clinicaltrials.gov, were included in the cohort as long as one interventional arm administered both agents. Qualitative and quantitative trial data features were collected from the Cancer Research Institute (CRI) Immuno-Oncology Intelligence Database and complemented with manually sourced information from trial registries and publications. Contribution of Effect (COE) was defined as trials with two or more arms that compare our combination regimen of interest to PARP or an ICI alone. The presence of randomization, eligibility for randomized-controlled trial (RCT) status as well as COE was determined by three reviewers separately with disagreements settled by committee decision. Results: In total, we found 188 clinical trials that enrolled 39,268 patients. A minority of 17 trials were phase I not considered as RCTs, leaving 37,827 patients across 171 trials for enrollment in phase II trials and beyond. Of these 171 trials, 80 (47 %) were single-arm studies without active comparator. Forty-nine (29%) used randomized assortment, 40 (23%) met criteria for an RCT and 33 (19%) met criteria for RCT with COE. In total, these 33 trials enrolled 14,803 patients. Of the 33, 17 (10%) enrolled patients with cancers that are approved for PARP blockade by the FDA and 11 (6%) employed genetic testing for HRR defects. Sponsorship ranged from 16 trials by industry, 6 by cooperative oncology group, 6 by academic institutions and 5 by the National Cancer Institute. Conclusions: Our study results highlight that the global clinical trial apparatus directs significant resources and patients towards trials with lower standards of evidence generation. Across sponsor types, there was a considerable number of trials that met the rigor of an RCT with COE. These findings show both promise and areas of improvement within the trial landscape to generate evidence relevant to the use of PARP and ICIs in combination.

A retrospective look: Industry partnership and transparency in phase III randomized clinical trials of breast cancer targeted therapies across two decades.

580 Background: To unveil industry involvement with respect to sponsorship, authorship, and demographic shifts in the trends of randomized clinical trials for breast cancer targeted therapies over the past two decades. Methods: All randomized phase III clinical trials focusing on targeted therapies for breast cancer were systematically identified from clinicaltrials.gov and reviewed using peer-reviewed publications. Trials that focused solely on chemotherapy and hormonal therapy were excluded. SAS Enterprise Guide v7.1 was used to analyze trial characteristics, authorship, and demographic details with Chi-square and Fisher’s exact tests. Results: From 2005-2023, 998 breast cancer treatment clinical trials were identified; 110 trials were included in the final analysis. Overall, 8.2% were limited to the U.S. and Canada while 67.3% were carried out internationally. 34.5% were led by cooperative (Co-op) groups vs 65.5% by pharmaceutical industries. 19.1% of trials were published in the New England Journal of Medicine (NEJM); all NEJM published trials reported positive results and 76.2% of were industry led. In contrast, of the 4.5% of trials featured in The Lancet, only 60% showed positive findings and 60% had major industry sponsorship. The most common industry partnerships were with Roche (27.3%), Novartis (12.7%), and Pfizer (7.3%) while the most common leading Co-op group was the National Cancer Institute (7.3%). To evaluate trends, trials were split into 3 time periods based on publication dates: 2005-2011, 2012-2017, and 2018-2023. The number of trial publications increased from 13 to 43 to 54. Of the 70% of trials that reported race/ethnicity data, the proportion of White patients decreased (84.5%, 78.8%, 79.3%; p&lt;0.001) and the proportion of Asian patients increased (8.9%, 18.4%, 16.7%; p&lt;0.001). However, enrollment of Black (6.6%, 2.8%, 4.0%; p&lt;0.001) and Hispanic (7.0%, 2.8%, 5.0%; p&lt;0.001) patients remained low. There were no statistically significant changes in international participation (46.2%, 69.8%, 70.4%; p=0.22), the proportion of exclusively industry-led (46.2%, 74.4%, 63.0%; p=0.15) or Co-op group-designed trials (61.5%, 35.7%, 26.4%; p=0.10). Industry-involved data collection increased from 23.1% to 64.2% to 73.6% (p=0.01) while industry sponsored data analysis (38.5%, 61.9%, 66.0%; p=0.49) and manuscript drafting (38.5%, 66.7%, 71.7%; p=0.09) did not significantly change. Conclusions: Over time, there was a notable rise in the number of phase III clinical trials for breast cancer targeted therapies. More than 70% of these trials now engage in international collaboration. Despite this progress, there remains an underrepresentation of Black and Hispanic participants in trial enrollment. Today, nearly 70% of trials have major industry sponsorship in study design, data analysis, and manuscript preparation.

The Glass Wall: Gendered Authorship Disparities in CD 19 and BCMA CAR-T Clinical Trials for Lymphoma and Myeloma

IntroductionExisting literature suggests that women are significantly underrepresented in the field of hematology-oncology. Women make up 35.6% of hematologists and data on females as site investigators for pivotal trials and authors in publications of pivotal trials in hematologic malignancies, specifically in the novel niche of Chimeric antigen receptor T cell (CAR-T), is sparse. MethodsWe examined the proportion of women in pivotal trials, screening a total of 2180 studies from PubMed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. 2180 initially searched records were filtered by date (2017-2023) and clinical trial status, yielding 149 records. Following a manual review, we included 15 studies that led to the approval of or anticipated approval of CD19 and BCMA CAR-T therapies in lymphoid and plasma cell malignancies. We examined overall number of female authors, number of lead female authors, and ratio of all authors to female authors in the 15 trials, which were all high impact, cited on average 1314 times. ResultsOf the 436 authors assessed, 132 were female, correlating to 29.5% female authorship. The only study with female authorship >50% was ELIANA, a 2017 pediatric study. 7 of the 15 studies had female lead authors; notably, 6 out of 7 of these studies were published in 2021 or later. ConclusionIn conclusion, our data suggests gender iniquities for female investigators exist in the field of immune effector cell therapy. We suggest further investigation and strategies to decrease gendered authorship disparities.

Prescribing trends of SGLT2 inhibitors among HFrEF and HFpEF patients with and without T2DM, 2013–2021

BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2i) are recommended for treatment of heart failure (HF), regardless of type 2 diabetes (T2DM) status. However, limited data exist on SGLT2i prescribing in HF patients without T2DM or across HF subtypes.MethodsThis was a serial, cross-sectional study of US MarketScan commercial and Medicare claims (2013–2021). Prevalence of SGLT2i was calculated by calendar year among HFrEF and HFpEF patients and stratified by T2DM status.ResultsAmong 218,066 HFrEF patients [mean (SD): 54.9 (8.92) years; 66.4% male], the prevalence of SGLT2i use increased from 0.3 to 18.6%, while among 150,437 HFpEF patients [56.5 (7.77) years; 47.6% male], it rose from 0.5 to 9.9%. These increases were driven by the subgroup with comorbid T2DM. SGLT2i prevalence use ratios among patients with T2DM compared to those without decreased from > 100 in 2018 to 3.8 in 2021 among HFrEF patients, and from 83.1 in 2018 to 17.5 in 2021, coinciding with the publication of landmark trials and corresponding changes in clinical guidelines.ConclusionsSGLT2i use rose rapidly following changes in guidelines but remained low among those without T2DM. By the end of the study, approximately 1 in 3 HFrEF and 1 in 5 HFpEF patients with T2DM were using an SGLT2i, compared to only 1 in 11 HFrEF and 1 in 85 HFpEF patients without T2DM. Future work identifying barriers with the uptake of GDMT, including SGLT2i, among HF patients is needed.

Integration of Clinical Trial Development in Hematology-Oncology Fellowship Training.

Several barriers to physicians becoming clinical investigators exist, including inexperience, lack of available mentors, and inconsistent instructive approaches with varying degrees of participation during training. These barriers cause fewer hematology-oncology fellows to pursue academic careers. A consensus is needed on structuring education in clinical investigation paired with active participation in development of a clinical trial guided by a mentor with the goal of increasing fellow interest in clinical research and pursuit of careers in academic medicine. The clinical trial development (CTD) program was initiated at Washington University School of Medicine in St. Louis in 2002 as a hands-on learning experience for hematology and oncology fellows in the design, implementation, and publication of clinical trials. Each fellow was required to identify a mentor and propose at least 1 prospective investigator-initiated clinical trial. At the time of data abstraction in July 2023, 118 fellows had participated in the CTD program and initiated protocols in a variety of areas according to their interests. Fellows were included in data abstraction if their fellowship began in 2002 through 2021; the program is ongoing, and the most recent class will graduate in 2024. Disease types were evenly distributed between solid tumor oncology (60 [51%]) or classic and malignant hematology (58 [49%]). Ninety-three fellows (79%) obtained institutional review board approval, and 60 (65%) published their results. Among graduating fellows, 67 (66%) secured an academic faculty appointment. Fellows with institutional review board-approved projects had significantly higher odds of obtaining an academic faculty appointment (odds ratio, 4.96; 95% confidence interval, 1.54, 15.98; P = .007).Next StepsNext steps will be to further evaluate the effect of the mentorship network on early career productivity of trainees that graduate and the feasibility of extending the program to another institution.