Evolving or Immutable - Phase I Solid Tumor Trials in the Era of Precision Oncology.

Purpose In the era of precision oncology (PO), systemic therapies for patients (pts) with solid tumors have shifted from chemotherapy (CT) to targeted therapy (TT) and immunotherapy (IO). This systematic survey describes features of trials enrolling between 2010-2020, focusing on inclusion criteria, type of dose escalation scheme (DES) utilized, and use of expansion cohorts (ECs). Methods A literature search identified phase I studies in adults with solid tumors published January 1, 2000 - December 31, 2020 from 12 journals. We included only studies enrolling between 2010-2020 to better capture the PO era. Two reviewers abstracted data; a third established concordance. Results Of 10,744 studies, 10,195 were non-topical or enrolled prior to 2010; 437 studies were included. The most common drug classes were TT (47.6%), IO (22%), and CT (6.9%). In studies which reported race, patients were predominantly white (61.7%) or Asian (25.7%), followed by black (6.5%) or other (6.1%). Heterogeneity was observed in the reporting and specification of study inclusion criteria. Only 40.1% of studies utilized ECs, and among the studies which used ECS, 46.6% were defined by genomic selection. Rule-based DES were used in 89% of trials; a 3+3 design was used in 80.5%. Of all drugs tested, 37.5% advanced to phase II, while 10.3% garnered regulatory licensure (for an indication tested in phase I). Conclusion In the era of PO, TT and IO have emerged as the most studied agents in phase I trials. Rule-based DES, which are more relevant for escalating CT, are still chiefly utilized.

Efficacy and toxicity of anti-vascular endothelial growth receptor tyrosine kinase inhibitors in patients with neuroendocrine tumours - A systematic review and meta-analysis.

AIM: Although anti-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors (RTKIs) have been tested in patients with neuroendocrine tumours (NETs) over the last two decades, no study to date has benchmarked efficacy and toxicity of these drugs in this patient population. METHODS: All phase II and phase III studies of anti-VEGF RTKIs in patients with NETs, published between January 1, 2000 andJuly 31, 2021, across major trial databases, were searched in August 2021 for relevant studies. The primary objectives of the meta-analysis were to compare objective response rate (ORR) and progression-free survival (PFS) between patients with pancreatic NETs (pNETs) and extra-pancreatic NETs (epNETs), and the incidence rate ratio (IRR) of adverse events between patients receiving anti-VEGF RTKIs and control. RESULTS: 1611 patients were available for the meta-analysis; 1194 received anti-VEGF RTKIs. ORR in pNETs was 18% (95% confidence interval (CI) 13-25%), while ORR in epNETs was 8% (95% CI 5-12%); test for differences between pNETs and epNETs (x12 = 8.38, p < .01). Median PFS in pNETs was 13.9 months (95% CI 11.43-16.38 months), while median PFS in epNETs was 12.71 months (95% CI 9.37-16.05 months); test for differences between pNETs and epNETs (x12 = .35, p = .55). With regards to common grade 3/4 adverse events , patients who received anti-VEGF RTKIs were more likely to experience hypertension (IRR 3.04, 95% CI 1.63-5.65) and proteinuria (IRR 5.79, 95% CI 1.09-30.74) in comparison to those who received control. CONCLUSIONS: Anti-VEGF RTKIs demonstrate anti-tumour effect in both pNETs and epNETs, supporting their development in both populations. These agents also appear to be safe in patients with NETs.

Interventions Incorporating Therapeutic Alliance to Improve Medication Adherence in Black Patients with Diabetes, Hypertension and Kidney Disease: A Systematic Review.

Background: Black Americans have a disproportionately increased risk of diabetes, hypertension, and kidney disease, and higher associated morbidity, mortality, and hospitalization rates than their White peers. Structural racism amplifies these disparities, and negatively impacts self-care including medication adherence, critical to chronic disease management. Systematic evidence of successful interventions to improve medication adherence in Black patients with diabetes, hypertension, and kidney disease is lacking. Knowledge of the impact of therapeutic alliance, ie, the unique relationship between patients and providers, which optimizes outcomes especially for minority populations, is unclear. The role and application of behavioral theories in successful development of medication adherence interventions specific to this context also remains unclear. Objective: To evaluate the existing evidence on the salience of a therapeutic alliance in effective interventions to improve medication adherence in Black patients with diabetes, hypertension, or kidney disease. Data Sources: Medline (via PubMed), EMBASE (OvidSP), Cumulative Index of Nursing and Allied Health Literature (CINAHL) (EBSCOhost), and PsycINFO (ProQuest) databases. Review Methods: Only randomized clinical trials and pre/post intervention studies published in English between 2009 and 2022 with a proportion of Black patients greater than 25% were included. Narrative synthesis was done. Results: Eleven intervention studies met the study criteria and eight of those studies had all-Black samples. Medication adherence outcome measures were heterogenous. Five out of six studies which effectively improved medication adherence, incorporated therapeutic alliance. Seven studies informed by behavioral theories led to significant improvement in medication adherence. Discussion/Conclusion: Study findings suggest that therapeutic alliance-based interventions are effective in improving medication adherence in Black patients with diabetes and hypertension. Further research to test the efficacy of therapeutic alliance-based interventions to improve medication adherence in Black patients should ideally incorporate cultural adaptation, theoretical framework, face-to-face delivery mode, and convenient locations.

Paediatric chronic pain prevalence in low- and middle-income countries: A systematic review and meta-analysis.

BACKGROUND: Chronic pain is a leading cause of morbidity in children and adolescents globally, with a significant impact on quality of life. This is the first systematic review and meta-analysis on paediatric chronic pain in low- and middle-income countries (LMICs). METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched MEDLINE (via PubMed), Embase, CINAHL, PsycINFO, Web of Science, Cochrane Database of Systematic Reviews, and the WHO Global Index Medicus for all studies published prior to January 7, 2022. Articles published in all languages that included populations age 19 years and under living in LMICs were considered. Chronic pain was defined as persistent or recurrent pain that is present for ≥3 months, per the International Classification of Diseases (ICD-11) definition. Summary data were extracted from published reports and evaluated with mixed-effects regression analysis. PROSPERO Record ID: CRD42021227967. FINDINGS: Of the 2875 studies identified, 70 articles were reviewed, with 27 studies representing 20 LMICs eligible for analysis. The average prevalence for each pain type reported with 95% confidence interval is as follows: general/multi-site/any 20% (16-25), musculoskeletal (MSK) pain 9% (7-13), abdominal pain 7% (5-10), headache 4% (2-10), and fibromyalgia per American College of Rheumatology or Yunus and Masi criteria 3% (1-10). Overall, a pooled mean of 8% chronic pain was estimated across all studies. A significantly high level of heterogeneity was found across all studies (I2  >90%). Chronic headache (OR=1·65, 95% CI 1·39-1·96), abdominal pain (OR=1·36, 95% CI 1·22-1·51), and generalized/multi-site pain (OR=1·54, 95% CI 1·31-1·81) were significantly more prevalent in females than males. INTERPRETATION: The characterization of paediatric chronic pain in low- and middle-income countries suffers from a paucity of data and significant heterogeneity in the assessment methods. Understanding the global burden of chronic pain in this group should be prioritized. FUNDING: None.

Efficacy of virtual and asynchronous teaching of computer-assisted diagnosis of genetic diseases seen in clinics.

We studied if clinicians could gain sufficient working knowledge of a computer-assisted diagnostic decision support system (DDSS) (SimulConsult), to make differential diagnoses (DDx) of genetic disorders. We hypothesized that virtual training could be convenient, asynchronous, and effective in teaching clinicians how to use a DDSS. We determined the efficacy of virtual, asynchronous teaching for clinicians to gain working knowledge to make computer-assisted DDx. Our study consisted of three surveys (Baseline, Training, and After Use) and a series of case problems sent to clinicians at Vanderbilt University Medical Center. All participants were able to generate computer-assisted DDx that achieved passing scores of the case problems. Between 75% and 92% agreed/completely agreed the DDSS was useful to their work and for clinical decision support and was easy to use. Participants' use of the DDSS resulted in statistically significant time savings in key tasks and in total time spent on clinical tasks. Our results indicate that virtual, asynchronous teaching can be an effective format to gain a working knowledge of a DDSS, and its clinical use could result in significant time savings across multiple tasks as well as facilitate synergistic interaction between clinicians and lab specialists. This approach is especially pertinent and offers value amid the COVID-19 pandemic.

The Never-Ending Evolutionary Saga of Assessing and Demonstrating the Value of Information Services in a Biomedical Library.

Demonstrating added value can be very challenging, yet it is becoming important in academic libraries. The current literature primarily discusses citation analysis and usage reports to demonstrate return on investment for collections or impact on scholarly activity. However, value is not only in our collections but also in the library staff who support the institutional mission. Vanderbilt University's Annette and Irwin Eskind Family Biomedical Library and Learning Center has been experimenting with several methods to supplement the collections data with services performed by the staff. This article discusses the project's four phases as part of the goal to strategically demonstrate the biomedical library's added value to the university and medical center.

Comparison of Design, Eligibility, and Outcomes of Neuroendocrine Neoplasm Trials Initiated From 2000 to 2009 vs 2010 to 2020.

Importance: Neuroendocrine neoplasms (NENs) have historically been grouped homogenously in clinical trials, despite their heterogeneity. Given the adoption of a more advanced pathologic classification system and drug licensure of several targeted therapies over the last decade, information is needed on whether study characteristics of NEN studies have evolved. Objective: To assess changes in study design, eligibility, accrual, sponsorship, and outcomes between phase II or III NEN clinical trials that began enrollment from 2000 to 2009 vs 2010 to 2020. Design, Setting, and Participants: This quality improvement study used a systematic survey of completed studies published between January 1, 2000, and December 31, 2020. Therapeutic phase II and III NEN studies were identified through a database search of Medline (via PubMed), EMBASE (OvidSP), Cumulative Index of Nursing and Allied Health Literature (EBSCOhost), Web of Science (Clarivate), Cochrane Database of Systematic Reviews (Wiley), ClinicalTrials.gov (National Institutes of Health), EU Clinical Trials Register, and National Cancer Institute Clinical Trials. Data were analyzed between March and June 2021. Main Outcomes and Measures: Study characteristic proportions between the 2 enrollment periods. Results: Of 3243 identified studies, 119 studies met criteria for inclusion, of which 117 studies (54 studies that began enrollment between 2000-2009 and 63 studies that began enrollment between 2010-2020) included exact dates of enrollment and were compared. Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were less likely to include all NENs (13 studies [21%] vs 34 studies [63%]; P < .001) and more likely to include select NENs (eg, gastrointestinal neuroendocrine tumors, 25 studies [40%] vs 11 studies [20%]; P = .02; pancreatic neuroendocrine tumors, 32 studies [51%] vs 16 studies [30%]; P = .02). Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were more likely to specify tumor differentiation (59 studies [98%] vs 34 studies [63%]; P < .001) or Ki-67 index (23 studies [38%] vs 5 studies [9%]; P < .001) in inclusion criteria. Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were more likely to use progression-free survival (22 studies [35%] vs 9 studies [18%]; P = .04) rather than objective response rate (19 studies [30%] vs 27 studies [53%]; P = .01) as a primary or coprimary end point. Conclusions and Relevance: These findings suggest that NEN trials enrolling over the last decade were more focused on select tumor populations, compared with studies that began enrollment before 2010. Despite this shift, more than 20% of studies still included all NENs. Studying novel agents in specific disease populations may enhance drug development in the field.

Interventions Incorporating Therapeutic Alliance to Improve Hemodialysis Treatment Adherence in Black Patients with End-Stage Kidney Disease (ESKD) in the United States: A Systematic Review.

BACKGROUND: In the US, Blacks with end-stage kidney disease (ESKD) have a four-fold higher prevalence rate of hemodialysis treatment and higher subsequent rates of hemodialysis treatment nonadherence and hospitalization compared to their White peers. Nonadherence to prescribed dialysis therapy is an underestimated life-threatening behavior, because of its association with increased morbidity and mortality. Few studies have specified and systematically evaluated targeted methods of increasing hemodialysis treatment adherence among Black hemodialysis patients with added focus on therapeutic alliance, a rewarding patient-centered relationship between patients and providers, based on common goals and objectives. This review seeks to evaluate the state of the science to determine the salience of a therapeutic alliance for the development of effective interventions positively impacting hemodialysis treatment adherence among Black patients. METHODS: Medline (via PubMed), Embase (OvidSP), Cumulative Index of Nursing and Allied Health Literature (CINAHL; EBSCOhost), and PsycInfo (ProQuest) databases were used to search for abstracts with the keywords "dialysis", "therapeutic alliance", and "treatment adherence and compliance", including all underlying index terms and alternative variations of terms, in order to cover the entire scope of the field. Only randomized clinical trials and pre/postintervention studies published in the previous 10 years (2009-2019) and including a proportion of Black patients >25% were included for review. RESULTS: Only three intervention studies met these criteria, for a total aggregated sample of 130 - mean age 58.1 years and 53% female. None of these studies was composed exclusively of Black patients (range 62%-91.3%), nor did they present data specifically for Blacks. Despite the lack of robust data informing strategies to improve hemodialysis adherence among Blacks with ESRD, a limited number of intervention studies have reported positive effects on hemodialysis attendance. DISCUSSION/CONCLUSION: Further research is warranted to fill this significant gap in our understanding of theoretically based, therapeutic alliance-enhanced, and culturally tailored hemodialysis treatment-adherence interventions among Blacks.