Institute Clinical Trials Research Articles

The National Cancer Institute Clinical Trials Planning Meeting to Address Gaps in Observational and Intervention Trials for Cancer-Related Cognitive Impairment.

Cancer-related cognitive impairment (CRCI) is a broad term encompassing subtle cognitive problems to more severe impairment. CRCI severity is influenced by host, disease, and treatment factors and affects patients prior to, during, and following cancer treatment. The National Cancer Institute (NCI) Symptom Management and Health-Related Quality of Life Steering Committee (SxQoL SC) convened a Clinical Trial Planning Meeting (CTPM) to review the state of the science on CRCI and to develop both Phase II/III intervention trials aimed at improving cognitive function in cancer survivors with non-central nervous system (CNS) disease and longitudinal studies to understand the trajectory of cognitive impairment and contributing factors. Participants included experts in the field of CRCI, members of the SxQOL SC, patient advocates, representatives from all seven NCI Community Oncology Research Program (NCORP) Research Bases, and the NCI. Presentations focused on the following topics: measurement, lessons learned from pediatric and geriatric oncology, biomarker and mechanism endpoints, longitudinal study designs, and pharmacologic and behavioral intervention trials. Panel discussions provided guidance on priority cognitive assessments, considerations for remote assessments, inclusion of relevant biomarkers, and strategies for ensuring broad inclusion criteria. Three CTPM working groups (longitudinal studies and pharmacologic and behavioral intervention trials) convened for one year to discuss and report on top priorities and to design studies. The CTPM experts concluded sufficient data exist to advance Phase II/Phase III trials utilizing selected pharmacologic and behavioral interventions for the treatment of CRCI in the non-CNS setting with recommendations included herein.

Addressing the Evidence Gap in Aneurysmal Subarachnoid Hemorrhage: The Need for a Pragmatic Randomized Trial Platform.

Aneurysmal subarachnoid hemorrhage (aSAH) occurs less often than other stroke types but affects younger patients, imposing a disproportionately high burden of long-term disability. Although management advances have improved outcomes over time, relatively few aSAH treatments have been tested in randomized clinical trials (RCTs). One lesson learned from COVID-19 is that trial platforms can facilitate the efficient execution of multicenter RCTs even in complex diseases during challenging conditions. An aSAH trial platform with standardized eligibility criteria, randomization procedures, and end point definitions would enable the study of multiple targeted interventions in a perpetual manner, with treatments entering and leaving the platform based on predefined decision algorithms. An umbrella institutional review board protocol and clinical trial agreement would allow individual arms to be efficiently added as amendments rather than stand-alone protocols. Standardized case report forms using the National Institutes of Health/National Institute of Neurological Disorders and Stroke common data elements and general protocol standardization across arms would create synergies for data management and monitoring. A Bayesian analysis framework would emphasize frequent interim looks to enable early termination of trial arms for futility, common controls, borrowing of information across arms, and adaptive designs. A protocol development committee would assist investigators and encourage pragmatic designs to maximize generalizability, reduce site burden, and execute trials efficiently and cost-effectively. Despite decades of steady clinical progress in the management of aSAH, poor patient outcomes remain common, and despite the increasing availability of RCT data in other fields, it remains difficult to perform RCTs to guide more effective care for aSAH. The development of a platform for pragmatic RCTs in aSAH would help close the evidence gap between aSAH and other stroke types and improve outcomes for this important disease with its disproportionate public health burden.

Assessment of functional and radiological outcomes of suprapatellar and infrapatellar approaches of tibial nailing in patients with tibial shaft fracture: A randomized control study

BackgroundThe study aimed to assess functional and radiological outcomes of the suprapatellar approach (SPA) and infrapatellar approaches (IPA) of tibial nailing in patients with closed tibia shaft fractures. MethodAfter Institutional Ethical Committee (IEC) and Clinical Trials Registry- India (CTRI) approval, patients with Orthopaedic Trauma Association (OTA) fracture type 42 were enrolled from August 2021 and August 2022 at a level I trauma centre and randomized to SPA and IPA with informed consent. Demographics, American Society of Anaesthesiologists (ASA) physical grading, intraoperative fluoroscopy time, operative duration, bleeding, postoperative radiographic alignment, and union were compared among both approaches. Functional parameters like Lysholm knee score, Anterior knee pain (AKP), Visual Analog Scale (VAS) Score upon kneeling, Knee Injury and Osteoarthritis outcome score (KOOS), KOOS Patellofemoral score (KOOS PF), EuroQol (EQ5D5L), Forgotten joint score (FJS), Range of motion (ROM) of knee and any complications were assessed at 3,6 and 12 months postoperatively. ResultsPer protocol analysis of 50 patients (25 SPA, 25 IPA) done at the end of the study. SPA group had significantly lesser fluoroscopy time (91.28 ± 12.40s vs. 105.36 ± 9.23s, p < 0.001) and operative duration (mins) (123.80 ± 24.25 vs. 130.00 ± 18.20, p < 0.001) than IPA. No significant differences were noted in Lysholm knee score at three months (p = 0.094), six months (p = 0.406), and 12 months (p = 0.071). The SPA group showed significantly lower VAS Score upon kneeling at six months (p < 0.0001). Similarly, KOOS (p < 0.001), KOOS PF (p = 0.01), and EQ 5D5L (p = 0.03) were significantly better in the SPA group at six months postoperatively. Lower Coronal translation was found in SPA [0 (0–1.8) vs. 1.4 (0.9–1.8), p = 0.010]. Whereas, IPA had higher range of flexion at 3 months [130.0 (129.0–135.0) vs 123.1 (120.0–130.5), p = 0.047]. However, no significant differences were noted in blood loss, AKP, FJS, EQ-VAS, coronal angulation, sagittal malalignment, time to union, return to work and postoperative complications among the groups. ConclusionSPA has lesser surgery time, more straightforward anatomic fracture reduction, better fracture alignment, lesser radiation exposure for both patients and surgeons, quicker recovery time, and promotes early kneeling activities with similar long-term functional outcomes and union rates, and can be considered in routine clinical practice than conventional IPA.

Barriers to Clinical Trial Implementation Among Community Care Centers

While an overwhelming majority of patients diagnosed with cancer express willingness to participate in clinical trials, only a fraction will enroll onto a research protocol. To identify critical barriers to trial enrollment to translate findings into actionable practice changes that increase cancer clinical trial enrollment. This survey study included designated site contacts at oncology practices with teams who were highly involved with the Association of Community Cancer Centers (ACCC) Community Oncology Research Institute (ACORI) clinical trials activities, all American Society of Clinical Oncology (ASCO)-ACCC collaboration pilot sites, and/or sites providing care to at least 25% African American and Hispanic residents. To determine participation trends among health care practices in oncology-focused research, identify barriers to clinical trial implementation and operation, and establish unmet needs for cancer clinics interested in trial participation, a 34-question survey was designed. Survey questions were defined within 3 categories: cancer center demographic characteristics, clinical trial characteristics, and referral practices. The survey was distributed through email and was open from June 20 through October 5, 2022. Participation in and barriers to conducting oncology trials in different community oncology settings. The survey was distributed to 100 cancer centers, with completion by 58 centers (58%) across 25 states. Fifty-two centers (88%) reported that they conduct therapeutic clinical trials, of which 33 (63%) were from urban settings, 11 (21%) were from suburban settings, and 8 (15%) were from rural settings. Only 25% of rural practices (2 of 8) offered phase 1 trials, compared with 67% of urban practices (22 of 33) (P = .01). Respondents noted challenges in conducting research, including patient recruitment (27 respondents [52%]), limited staffing (27 [52%]), and nonrelevant trials for their patient population (25 [48%]). Among sites not offering therapeutic trials, barriers to research conduct included limited infrastructure, funding, and staffing. Most centers (46 of 58 [79%]) referred patients to outside centers for clinical trial enrollment, particularly in the context of late-stage disease and/or disease progression. Only 17 of these sites (37%) had established protocols for patient follow-up subsequent to outside referral. In this national survey study of barriers to clinical trial implementation, most sites offered therapeutic trials, but there were significant disparities in trial availability across care settings. Furthermore, fundamental deficiencies in trial support infrastructure limited research activity, including within programs currently conducting research as well as at sites interested in future clinical research opportunities. These results identify crucial unmet needs for oncology clinics to effectively offer clinical trials to patients seeking care.

Moving from conventional to adaptive risk stratification for oropharyngeal cancer.

Oropharyngeal cancer (OPC) poses a complex therapeutic dilemma for patients and oncologists alike, made worse by the epidemic increase in new cases associated with the oncogenic human papillomavirus (HPV). In a counterintuitive manner, the very thing which gives patients hope, the high response rate of HPV-associated OPC to conventional chemo-radiation strategies, has become one of the biggest challenges for the field as a whole. It has now become clear that for ~30-40% of patients, treatment intensity could be reduced without losing therapeutic efficacy, yet substantially diminishing the acute and lifelong morbidity resulting from conventional chemotherapy and radiation. At the same time, conventional approaches to de-escalation at a population (selected or unselected) level are hampered by a simple fact: we lack patient-specific information from individual tumors that can predict responsiveness. This results in a problematic tradeoff between the deleterious impact of de-escalation on patients with aggressive, treatment-refractory disease and the beneficial reduction in treatment-related morbidity for patients with treatment-responsive disease. True precision oncology approaches require a constant, iterative interrogation of solid tumors prior to and especially during cancer treatment in order to tailor treatment intensity to tumor biology. Whereas this approach can be deployed in hematologic diseases with some success, our ability to extend it to solid cancers with regional metastasis has been extremely limited in the curative intent setting. New developments in metabolic imaging and quantitative interrogation of circulating DNA, tumor exosomes and whole circulating tumor cells, however, provide renewed opportunities to adapt and individualize even conventional chemo-radiation strategies to diseases with highly variable biology such as OPC. In this review, we discuss opportunities to deploy developing technologies in the context of institutional and cooperative group clinical trials over the coming decade.

Increasing diversity in clinical trials: demographic trends at the National Cancer Institute, 2005-2020.

We described participant demographics for National Cancer Institute (NCI) clinical trials at the clinical center (NCI-CC participants) of the National Institutes of Health to identify enrollment disparities. We analyzed NCI-CC data from 2005 to 2020, calculated enrollment fractions, compared with the US cancer population represented by the Surveillance, Epidemiology, and End Results cancer incidence data (2018) and the Cancer in North America database (2018), and compared further with clinical trial disparities data from the NCI Community Oncology Research Program and National Clinical Trials Network (2005-2019), and from ClinicalTrials.gov (2003-2016). NCI-CC (38 531 participants) had higher enrollment fractions for older adults (8.5%), male (5.6%), non-Hispanic (5.1%), and Black or African American (5.3%) participants; lower women proportion across race and ethnicity; and fewer female sex-specific cancer (6.8%) than male sex-specific cancer (11.7%) participants. NCI-CC had lower median age than Surveillance, Epidemiology, and End Results (54.0 vs 65.4); more Black or African American participants (12.0% vs 11.1%); and fewer women (41.7% vs 49.5%), White (76.1% vs 80.5%), Asian or Pacific Islander (4.6% vs 6.0%), American Indian or Alaska Native (0.3% vs 0.5%), and Hispanic participants (7.1% vs 13%). NCI-CC had more Black or African American and Asian or Pacific Islander participants; fewer Hispanic participants than the NCI Community Oncology Research Program and National Clinical Trials Network; more Black or African American and Hispanic participants; fewer Asian or Pacific Islander participants than ClinicalTrials.gov data. Improvement was noted for NCI-CC (older adults, Black or African American, Asian or Pacific Islander, Hispanic participants). We found lower representation of older adults, women, Asian or Pacific Islander, American Indian or Alaska Native, and Hispanic participants vs the US cancer population and higher representation of Black or African American vs US cancer population and oncology clinical trials. Multifaceted efforts are underway to reduce disparities in cancer clinical trials at the NCI-CC.

Does Sugar Control Arrest Complications in Type 2 Diabetes? Examining the Rigour in Statistical Methods and Causal Inference in Clinical Trials.

BACKGROUND: In contrast to type 1 diabetes mellitus (T1DM), in type 2 (T2DM) the success of intensive glucose normalisation in arresting diabetic complications is marginal and inconsistent across multiple clinical trials. However, glucose regulation still largely remains the main target of treatment for T2DM in clinical practice. OBJECTIVES: We examine the possible causes of inconsistency across studies, the scientific rigour behind the design, conduct and inferences of 6 large institutional clinical trials targeting glucose normalisation and following up for diabetic complications and mortality. STUDY DESIGN: We enumerate the possible flaws in the design, statistical treatment of the results and possible logical traps in making inferences. Further, we evaluate whether the flaws can mislead the conclusions. We also suggest a more sound statistical treatment of the data and interpret results of the trials together in a coherent way. RESULTS: The clinical trials for intensive glucose control suffer from a number of common problems that have not been addressed. The most important being the failure to correct for multiple outcomes. This is recognised by some reviewers but no correction is attempted. The second is the interdependence of the outcomes, owing to which statistics based on the assumption of independence can be misleading. Simulations show that the apparent inconsistency or heterogeneity between trial results can be explained by the violation of assumed independence alone. Further, the problems with placebo control, failure to recognise alternative possibilities, inability to segregate clinical significance from statistical significance and misleading reporting formats point to conformity bias and publication bias. CONCLUSIONS: We find no support for the prevalent belief that glucose normalisation has any benefit in terms of reducing the frequency of any of the complications or mortality. It is time to reconsider the glucocentric line of treatment of T2DM. Rethinking some of the fundamental beliefs about the pathophysiology of diabetic complications and facilitating novel alternative lines of research is the need of the field.

Immune Profiling of Newly Diagnosed Multiple Myeloma (NDMM) Treated with Quadruplet Induction and Autologous Stem Cell Transplantation (ASCT) and Comparison with Achievement of Minimal Residual Disease (MRD) Negativity

Background Incorporation of anti-CD38 monoclonal antibodies (mAb) to the triplet backbone of proteasome inhibitor, immunomodulatory agent and corticosteroid has resulted in unprecedented depth of response including MRD negativity in transplant eligible NDMM. While numerous immunological mechanisms of modern quadruplet combinations are proposed, the modulation of the immunoprofiles bone marrow (BM) and peripheral blood (PB) with quadruplet therapy and ASCT are unknown. The baseline as well as longitudinal study of the composition and functionality of the immune microenvironment with treatment may have implications on disease response. Methods We prospectively collected clinically annotated patient (pt) samples from a phase II single institution clinical trial in transplant eligible NDMM (NCT04991103). Pts received quadruplet combination with daratumumab, bortezomib, lenalidomide and dexamethasone for six cycles followed by MRD adapted deferral of ASCT for pts who achieved MRD&amp;lt;10 -5. Pts deferring ASCT received three additional cycles of consolidation followed by maintenance. Pts who did not meet threshold for ASCT deferral received ASCT followed by maintenance therapy per protocol. We collected paired PB and BM samples at the time of screening (SCN), post-induction (I), and post-consolidation/ASCT (C). We purified and biobanked viable PB mononuclear cells (PBMCs). We thawed PBMCs, treated with FcR blocking Ab, stained with fluorochrome-labeled antibodies and a live/dead fixable stain, and then analyzed using the FACSymphony A5 SE flow cytometer. We identified immune cell subsets in PBMCs using FlowJo v10.2. We report data as percentage of each population within total live PBMCs. Results We collected 48 samples from 8 pts at three timepoints (SCN, I and C) and performed initial immunophenotyping analysis on the PBMCs. We observed no significant changes over time in the frequencies of peripheral CD45 +, CD3 +, NK T cells, monocytes or dendritic cells (not shown). We noted decreased frequencies of multiple B cell subsets, including naïve, transitional, memory and double negative cells (not shown), as well as CD56 +CD16 + NK cells (Fig. panel A) post-induction with no recovery following consolidation . While the frequencies of CD3 + T cells did not change with time, we observed a shift in the CD4:CD8 ratio, with an increase in the proportion of CD8 + T cells post-consolidation (Fig. panel B). Within the post-consolidation CD8 + T cell compartment, we noted increased frequencies of cells that presented with senescent (PD1 negCD57 +), exhausted (PD1 +CD57 neg) or anergic (PD1 +CD57 +) profiles. Consistent with this, the frequencies of terminally differentiated effector memory cells re-expressing CD45RA (TEMRA) CD8 + T cells increased at consolidation (Fig. panel C) and many of these cells exhibited an anergic profile (CD57 +PD1 +, Fig. panel D). Comparison of the baseline immune profiles and MRD levels post-induction revealed that the pt attaining MRD&amp;lt;10 -5 had the highest frequency of-NK cells as well as proportionally higher T CM/T EM and lower TEMRA/T Naive cells at diagnosis. This subject was able to defer ASCT per protocol and subsequently exhibited the lowest frequency of CD8 + TEMRA with an anergic phenotype (PD1 +CD57 +) post quadruplet consolidation. The subject with the least response to quadruplet induction and highest MRD post-induction had a high proportion of CD8 + T cells with an exhausted phenotype (PD1 +CD57 neg) at screening. Conclusion This is the first longitudinal analysis comparing MRD levels to the immune profiles of PB and BM cells derived from a cohort of NDMM patients prospectively treated with quadruplet induction and ASCT. We conclude that quadruplet induction negatively affects the NK cell and B cell compartment during induction and these compartments do not rapidly recover in the immediate post-transplant period. ASCT post quadruplet therapy is associated with preferential expansion of the effector CD8 + T cell compartments, including terminally differentiated TEMRA cells, which express markers associated with T cell exhaustion and anergy. Additional studies evaluating BM immune profile and T cell exhaustion are ongoing and shown at the meeting.

Does Sugar Control Arrest Complications in Type 2 Diabetes? Examining the Rigour in Statistical Methods and Causal Inference in Clinical Trials

BACKGROUND: In contrast to type 1 diabetes mellitus (T1DM), in type 2 (T2DM) the success of intensive glucose normalisation in arresting diabetic complications is marginal and inconsistent across multiple clinical trials. However, glucose regulation still largely remains the main target of treatment for T2DM in clinical practice. OBJECTIVES: We examine the possible causes of inconsistency across studies, the scientific rigour behind the design, conduct and inferences of 6 large institutional clinical trials targeting glucose normalisation and following up for diabetic complications and mortality. STUDY DESIGN: We enumerate the possible flaws in the design, statistical treatment of the results and possible logical traps in making inferences. Further, we evaluate whether the flaws can mislead the conclusions. We also suggest a more sound statistical treatment of the data and interpret results of the trials together in a coherent way. RESULTS: The clinical trials for intensive glucose control suffer from a number of common problems that have not been addressed. The most important being the failure to correct for multiple outcomes. This is recognised by some reviewers but no correction is attempted. The second is the interdependence of the outcomes, owing to which statistics based on the assumption of independence can be misleading. Simulations show that the apparent inconsistency or heterogeneity between trial results can be explained by the violation of assumed independence alone. Further, the problems with placebo control, failure to recognise alternative possibilities, inability to segregate clinical significance from statistical significance and misleading reporting formats point to conformity bias and publication bias. CONCLUSIONS: We find no support for the prevalent belief that glucose normalisation has any benefit in terms of reducing the frequency of any of the complications or mortality. It is time to reconsider the glucocentric line of treatment of T2DM. Rethinking some of the fundamental beliefs about the pathophysiology of diabetic complications and facilitating novel alternative lines of research is the need of the field.

Overall Survival Prediction in Stereotactic Radiosurgery Patients with Glioblastoma Via a Deep-Learning Approach

Accurate and automated early survival prediction is critical for glioblastoma (GBM) patients as their poor prognosis requires timely treatment decision-making. We have developed a deep learning (DL)-based GBM overall survival (OS) prediction model based on a multi-institutional public dataset using only pre-operative basic structural multi-parametric magnetic resonance images (MRIs). The purpose of this study is to evaluate this DL-based OS prediction model with an institutional stereotactic radiosurgery (SRS) clinical trial dataset. The task of this study is to classify GBM patients into 3 OS classes: long-survivors (>15 months), mid-survivors (between 10 and 15 months) and short-survivors (< 10 months). The proposed OS prediction model is an ensemble of a ResNet-based classifier and a K-NN classifier. The ResNet-based classifier is trained in a Siamese fashion to explore inter-class differences. During testing, training sample features are implemented with a K-NN classifier to ensemble with the ResNet-based classifier. A public dataset from Medical Image Computing and Computer Assisted Intervention (MICCAI) Brain Tumor Segmentation (BraTS) challenge 2020 (235 patients) were used for model establishing and initial validation. Then the validated model was evaluated on 19 GBM patients from an institutional SRS clinical trial. Each data entry consists of pre-operative basic structural multi-parametric MRIs and survival days, as well as patient ages for BraTS data and basic clinical characteristics for institutional data. GBM sub-regions, including contrast-enhancing tumor, peri-tumoral edema, and necrotic/non-enhancing tumor core, were segmented in the multi-parametric MRIs by an in-house DL model for both datasets. The OS prediction model was trained on 90% of the segmented BraTS data and validated on the rest 10%, then further evaluated on the institutional data. The model performance was assessed by prediction accuracy (ACC) and the area under the curve (AUC). For this 3-class OS classification task, our DL-based prediction model achieved an ACC of 65.22% and an AUC of 0.81 on the BraTS dataset compared with the top-ranked result from the BraTS challenge 2020 (Rank 1st: ACC 61.7%), and an ACC of 52.63% and an AUC of 0.69 on the institutional dataset. Further analysis of the institutional dataset found that the predicted OS class had a statistically significant correlation with treatment volume (p = 0.012) and age (p = 0.006), which matches the analysis that the patients' ground truth OS class is statistical significantly correlated with treatment volume (p = 0.045). Our DL-based OS prediction model for GBM using basic structural multi-parametric pre-operative MRIs has demonstrated promising performance in both public and institutional dataset with minimal manual processing requirements. This OS prediction model can be potentially applied to assist timely clinical decision-making.

A novel GATA2 distal enhancer mutation results in MonoMAC syndrome in 2 second cousins

AbstractMutations in the transcription factor GATA2 can cause MonoMAC syndrome, a GATA2 deficiency disease characterized by several findings, including disseminated nontuberculous mycobacterial infections, severe deficiencies of monocytes, natural killer cells, and B lymphocytes, and myelodysplastic syndrome. GATA2 mutations are found in ∼90% of patients with a GATA2 deficiency phenotype and are largely missense mutations in the conserved second zinc-finger domain. Mutations in an intron 5 regulatory enhancer element are also well described in GATA2 deficiency. Here, we present a multigeneration kindred with the clinical features of GATA2 deficiency but lacking an apparent GATA2 mutation. Whole genome sequencing revealed a unique adenine-to-thymine variant in the GATA2 –110 enhancer 116,855 bp upstream of the GATA2 ATG start site. The mutation creates a new E-box consensus in position with an existing GATA-box to generate a new hematopoietic regulatory composite element. The mutation segregates with the disease in several generations of the family. Cell type–specific allelic imbalance of GATA2 expression was observed in the bone marrow of a patient with higher expression from the mutant-linked allele. Allele-specific overexpression of GATA2 was observed in CRISPR/Cas9-modified HL-60 cells and in luciferase assays with the enhancer mutation. This study demonstrates overexpression of GATA2 resulting from a single nucleotide change in an upstream enhancer element in patients with MonoMAC syndrome. Patients in this study were enrolled in the National Institute of Allergy and Infectious Diseases clinical trial and the National Cancer Institute clinical trial (both trials were registered at www.clinicaltrials.gov as #NCT01905826 and #NCT01861106, respectively).

Circulating tumor DNA sequencing of pediatric solid and brain tumor patients: An institutional feasibility study

The potential of circulating tumor DNA (ctDNA) analysis to serve as a real-time “liquid biopsy” for children with central nervous system (CNS) and non-CNS solid tumors remains to be fully elucidated. We conducted a study to investigate the feasibility and potential clinical utility of ctDNA sequencing in pediatric patients enrolled on an institutional clinical genomics trial. A total of 240 patients had tumor DNA profiling performed during the study period. Plasma samples were collected at study enrollment from 217 patients and then longitudinally from a subset of patients. Successful cell-free DNA extraction and quantification occurred in 216 of 217 (99.5%) of these initial samples. Twenty-four patients were identified whose tumors harbored 30 unique variants that were potentially detectable on a commercially-available ctDNA panel. Twenty of these 30 mutations (67%) were successfully detected by next-generation sequencing in the ctDNA from at least one plasma sample. The rate of ctDNA mutation detection was higher in patients with non-CNS solid tumors (7/9, 78%) compared to those with CNS tumors (9/15, 60%). A higher ctDNA mutation detection rate was also observed in patients with metastatic disease (9/10, 90%) compared to non-metastatic disease (7/14, 50%), although tumor-specific variants were detected in a few patients in the absence of radiographic evidence of disease. This study illustrates the feasibility of incorporating longitudinal ctDNA analysis into the management of relapsed or refractory patients with childhood CNS or non-CNS solid tumors.

Local versus radical surgery for early rectal cancer with or without neoadjuvant or adjuvant therapy.

Local versus radical surgery for early rectal cancer with or without neoadjuvant or adjuvant therapy.

Does a New Modification of the Two-Step Injection Technique for Inferior Alveolar Nerve Block Reduce Pain Compared to the Conventional Technique? A Randomized Clinical Trial.

The ability to control pain is an essential part of dental procedures and the need for optimal pain control and reduction of discomfort is the primary concern of every dentist. This study aims to compare the pain and vital signs during inferior alveolar nerve block between conventional and a new modification of the two-step injection techniques. In this institutional single-blind randomized clinical trial, attendees of dental school at Mazandaran University of Medical Sciences from February to May 2022 were included. Inclusion criteria were 20-60 years old and healthy (ASA1) individuals who were willing to participate in this study. Individuals who were taking medications affecting their understanding of pain and patients with active infections at the injection site were excluded. These individuals were divided into two groups. First, superficial anesthesia was performed and afterward, conventional and two-step injection techniques were performed. For the two-step injection method, 6 mm of the needle was injected into the mucosa and one-third of the local anesthetic solution was released from the computer-controlled injection toolkit. Afterward, a 25 mm 30-gauge needle was reinserted into the previous hole delivering the remaining local anesthetic. The pain during injection was measured by a patient-reported numerical rating scale (NRS). Moreover, vital signs were monitored immediately before and after the injection. Kolmogorov-Smirnov test, Mann-Whitney U test, independent T-test, and Fisher's exact χ 2 test were performed for statistical analysis (α = 0.05). This study involved 32 adults aged between 20 and 50 years old with 1 : 1 female/male sex distribution. The pain score was significantly higher in the conventional injection technique compared to the two-step injection technique in all sex and age groups. There were no significant differences in vital signs between the conventional and two-step injection techniques. There was no significant difference in the mean pain scores of females and males, regardless of their injection techniques. Utilizing the two-step injection technique in patients for inferior alveolar block reduces pain during injection without altering patients' vital signs significantly. This trial is registered with IRCT20220106053646N1.

Difficulties in Defining Oligometastatic Prostate Cancer: Implications for Clinical Trial Accrual and Community Practice Adoption of Metastasis-Directed Therapy Approaches

Metastasis-directed therapy is widely utilized for oligometastatic prostate cancer patients, but standard imaging does not always identify metastases definitively and, even with PSMA PET, there may be equivocal findings. Not all clinicians have access to detailed imaging review, particularly outside of academic cancer centers, and PET scan access is also limited. We sought to understand how imaging interpretation impacted recruitment to a clinical trial for oligometastatic prostate cancer. IRB approval was obtained to review medical records from all patients screened for the institutional IRB-approved clinical trial for men with oligometastatic prostate cancer involving androgen deprivation plus stereotactic radiation to all metastatic sites, as well as radium223 (NCT03361735). Clinical trial inclusion required at least one bone metastatic lesion and no more than five total sites of metastasis, including soft tissue sites. Tumor board discussion records were reviewed, along with results from additional radiology studies ordered or confirmatory biopsies performed. Clinical characteristics such as PSA level and Gleason score were studied for association with likelihood of oligometastatic disease confirmation. At the time of data analysis, 18 subjects were deemed eligible and 20 were not eligible. The most common reasons for ineligibility were no confirmed bone metastasis in 16 patients (59%) and too many metastatic sites in 3 (11%). The median PSA of eligible subjects was 3.28 (range 0.4-45.5), whereas the median PSA of those found to be ineligible was 10.45 (range 3.7-26.3) when there were too many metastases identified, and 2.7 (range 0.2-34.5) when metastases were unconfirmed. PET imaging (PSMA or fluciclovine PET) increased the number of metastases, while MRI resulted in downstaging to non-metastatic disease. This research suggests that additional imaging (i.e., at least two independent imaging modalities of a possible metastatic lesion) or tumor board adjudication of imaging findings may be critical to correctly identify patients appropriate for enrollment in oligometastatic protocols. This should be considered as trials of metastasis-directed therapy for oligometastatic prostate cancer accrue and results are translated to broader oncology practice.

Trial Design Considerations to Increase Older Adult Accrual to National Cancer Institute Clinical Trials.

Although adults aged 65 years or older make up a strong majority of cancer patients, their underrepresentation in cancer clinical trials leads to the lack of representative data to guide evidence-based therapeutic decisions in this patient population. The Trial Design Working Group, convened as part of the workshop titled, Engaging Older Adults in the National Cancer Institute Clinical Trials Network: Challenges and Opportunities, recommended study designs and design elements that could improve accrual of older adults in National Cancer Institute-funded clinical trials. These include trials that are specifically designed to enroll older adults, trials that include a cohort of older patients (parallel cohort, stratified cohort, or embedded cohort), and trials with pragmatic design elements to facilitate enrollment of older adults. This manuscript provides brief descriptions of the recommended designs, examples of successful trials, and considerations for implementation of these designs. As with any clinical trial, the scientific questions and trial objectives should drive the study design, the selection of endpoints and intervention, and eligibility criteria. When designing trials that include older adults, the heterogeneity of fitness levels is an important consideration as fitness can influence accrual rates and outcomes. Appropriately incorporating geriatric assessments can help identify the optimal subset of older patients for inclusion and minimize selection bias. Incorporating pragmatic design elements to reduce the burden on trial participants as well as on accruing sites and retaining essential elements to ensure that the main goal of the trial can be accomplished can enhance enrollment without compromising the integrity of trials.

Integrating Geriatric Assessment Measures into National Cancer Institute Clinical Trials.

To improve the care of older adults with cancer, the traditional approach to clinical trial design needs to be reconsidered. Older adults are underrepresented in clinical trials with limited or no information on geriatric-specific factors, such as cognition or comorbidities. To address this knowledge gap and increase relevance of therapeutic clinical trial results to the real-life population, integration of aspects relevant to older adults is needed in oncology clinical trials. Geriatric assessment (GA) is a multidimensional tool comprising validated measures assessing specific health domains that are more frequently affected in older adults, including aspects related to physical function, comorbidity, medication use (polypharmacy), cognitive and psychological status, social support, and nutritional status. There are several mechanisms for incorporating either the full GA or specific GA measures into oncology therapeutic clinical trials to contribute to the overarching goal of the trial. Mechanisms include utilizing GA measures to better characterize the trial population, define trial eligibility, allocate treatment receipt within the context of the trial, develop predictive models for treatment outcomes, guide supportive care strategies, personalize care delivery, and assess longitudinal changes in GA domains. The objective of this manuscript is to review how GA measures can contribute to the overall goal of a clinical trial, to provide a framework to guide the selection and integration of GA measures into clinical trial design, and ultimately enable accrual of older adults to clinical trials by facilitating the design of trials tailored to older adults treated in clinical practice.

Preface: Engaging Older Adults in Cancer Clinical Trials Conducted in the National Cancer Institute Clinical Trials Network: Opportunities to Enhance Accrual

Preface: Engaging Older Adults in Cancer Clinical Trials Conducted in the National Cancer Institute Clinical Trials Network: Opportunities to Enhance Accrual

Infrastructure to Support Accrual of Older Adults to National Cancer Institute Clinical Trials.

As part of ongoing efforts to meaningfully improve recruitment, enrollment, and accrual of older adults into cancer clinical trials, the National Cancer Institute (NCI) sponsored a workshop with experts across the country entitled Engaging Older Adults in the NCI Clinical Trials Network: Challenges and Opportunities. Three working groups, including Study Design, Infrastructure, and Stakeholders, were formed, who worked together to offer synergistic improvements in the system. Here, we summarize the workshop discussions of the Infrastructure Working Group, whose goal was to address infrastructural challenges, identify underlying resources, and offer solutions to facilitate accrual of older adults into cancer clinical trials. Based on preconference work and workshop discussions, four key recommendations to strengthen NCI infrastructure were proposed: 1) further centralize resources and expertise; 2) provide training for clinical research staff; (3) develop common data elements; and 4) evaluate what works and does not work. These recommendations provide a strategy to improve the infrastructure to enroll more older adults in cancer clinical trials.

Through the Lens of Patient Partners: Challenges in Accrual of Older Adults to NCI Clinical Trials.

The workshop "Engaging Older Adults in Cancer Clinical Trials Conducted in the NCI Clinical Trials Network: Challenges and Opportunities" included a Patient Stakeholder Workgroup that explored the needs and concerns of older adults with cancer regarding clinical trials. To accomplish this, the workgroup conducted patient focus groups in which participants were interviewed, recorded conversations were analyzed and coded, and salient themes were identified. The focus groups identified general barriers to accrual such as complex consent forms, general communication, restrictive eligibility, nonreferrals, patient costs, cultural insensitivity, limited accessibility in community settings, and transportation issues. They also identified the influence of knowledgeable information presenters, improved care, family or caregiver support, and the desire to help others as drivers or reasons to participate in clinical trials. The workshop concluded that multi-level interventions could be used to increase the accrual of older adults to National Cancer Institute clinical trials as well as others.