Comparison of Prognostic Scores in Early Phase Clinical Trials: A 10-year Single Centre Australian Experience.

BACKGROUND/AIM: Early phase clinical trials (EPCTs) assess the tolerability of novel anti-cancer therapeutics in patients with advanced malignancy. Patient selection is important given the modest clinical benefit and time commitments for trials. Prognostic scores have been developed to facilitate identification of high-risk patients. This study aimed to compare five prognostic scores to predict survival for patients on an EPCT. PATIENTS AND METHODS: We performed a retrospective review of patients enrolled in EPCT at Liverpool Hospital, Sydney, from 2013 to 2023. Demographic, biochemical, and survival data were collected from electronic medical records. The score from five prognostic scoring systems (Royal Marsden hospital, MD Anderson Cancer centre, Gustave Roussy Immune, MD Anderson Immune Checkpoint Inhibitor and Princess Margaret Hospital Index) were calculated. Overall survival was measured using the Kaplan-Meier method and predictive discrimination was assessed using Harrell's c-index. RESULTS: A total of 218 patients across 36 EPCTs were included. The median overall survival was 9.8 months with 22% of patients dying in less than 90 days. Seventeen to thirty-four percent of patients were categorised as high-risk. The MDACC score obtained the highest predictability for overall survival for the whole cohort (c-index=0.67, 95%CI=0.62-0.72) and the immunotherapy-based cohort (c-index= 0.65, 95%CI=0.59-0.71). However, all scores performed similarly with a significant overlap in the confidence intervals. CONCLUSION: Our retrospective audit confirms the utility of prognostic scores to predict survival in an Australian EPCT cohort, with similar predictive discrimination across various scoring systems. Integration of these prognostic tools into EPCT screening processes may optimise benefits and reduce risks associated with EPCTs.

Providing a scaffold for considering theoretical frameworks in evidence implementation projects: the JBI approach to evidence implementation.

ABSTRACT: There are many theories, models, and frameworks that have been proposed in the field of implementation science. Despite this, many evidence implementation or practice improvement projects do not consider these theories, models, or frameworks in their improvement efforts. The JBI approach is one example of an implementation theory, model, or framework. This approach has been developed particularly with health care professionals in mind and is designed to clearly guide pragmatic evidence implementation efforts based on the best available evidence. In this paper, we discuss how the JBI approach to evidence implementation can interact with and support theory-informed, pragmatic evidence implementation projects.

From Pediatric to Adult Brain Cancer: Exploring Histone H3 Mutations in Australian Brain Cancer Patients.

Genetic histone variants have been implicated in cancer development and progression. Mutations affecting the histone 3 (H3) family, H3.1 (encoded by HIST1H3B and HIST1H3C) and H3.3 (encoded by H3F3A), are mainly associated with pediatric brain cancers. While considered poor prognostic brain cancer biomarkers in children, more recent studies have reported H3 alterations in adult brain cancer as well. Here, we established reliable droplet digital PCR based assays to detect three histone mutations (H3.3-K27M, H3.3-G34R, and H3.1-K27M) primarily linked to childhood brain cancer. We demonstrate the utility of our assays for sensitively detecting these mutations in cell-free DNA released from cultured diffuse intrinsic pontine glioma (DIPG) cells and in the cerebral spinal fluid of a pediatric patient with DIPG. We further screened tumor tissue DNA from 89 adult patients with glioma and 1 with diffuse hemispheric glioma from Southwestern Sydney, Australia, an ethnically diverse region, for these three mutations. No histone mutations were detected in adult glioma tissue, while H3.3-G34R presence was confirmed in the diffuse hemispheric glioma patient.

Surgical experience and identification of errors in laparoscopic cholecystectomy.

BACKGROUND: Surgical errors are acts or omissions resulting in negative consequences and/or increased operating time. This study describes surgeon-reported errors in laparoscopic cholecystectomy. METHODS: Intraoperative videos were uploaded and annotated on Touch SurgeryTM Enterprise. Participants evaluated videos for severity using a 10-point intraoperative cholecystitis grading score, and errors using Observational Clinical Human Reliability Assessment, which includes skill, consequence, and mechanism classifications. RESULTS: Nine videos were assessed by 8 participants (3 junior (specialist trainee (ST) 3-5), 2 senior trainees (ST6-8), and 3 consultants). Participants identified 550 errors. Positive relationships were seen between total operating time and error count (r2 = 0.284, P < 0.001), intraoperative grade score and error count (r2 = 0.578, P = 0.001), and intraoperative grade score and total operating time (r2 = 0.157, P < 0.001). Error counts differed significantly across intraoperative phases (H(6) = 47.06, P < 0.001), most frequently at dissection of the hepatocystic triangle (total 282; median 33.5 (i.q.r. 23.5-47.8, range 15-63)), ligation/division of cystic structures (total 124; median 13.5 (i.q.r. 12-19.3, range 10-26)), and gallbladder dissection (total 117; median 14.5 (i.q.r. 10.3-18.8, range 6-26)). There were no significant differences in error counts between juniors, seniors, and consultants (H(2) = 0.03, P = 0.987). Errors were classified differently. For dissection of the hepatocystic triangle, thermal injuries (50 in total) were frequently classified as executional, consequential errors; trainees classified thermal injuries as step done with excessive force, speed, depth, distance, time or rotation (29 out of 50), whereas consultants classified them as incorrect orientation (6 out of 50). For ligation/division of cystic structures, inappropriate clipping (60 errors in total), procedural errors were reported by junior trainees (6 out of 60), but not consultants. For gallbladder dissection, inappropriate dissection (20 errors in total) was reported in incorrect planes by consultants and seniors (6 out of 20), but not by juniors. Poor economy of movement (11 errors in total) was reported more by consultants (8 out of 11) than trainees (3 out of 11). CONCLUSION: This study suggests that surgical experience influences error interpretation, but the benefits for surgical training are currently unclear.

Automated analysis of intraoperative phase in laparoscopic cholecystectomy: A comparison of one attending surgeon and their residents.

OBJECTIVE: This study compares the intraoperative phase times in laparoscopic cholecystectomy performed by an attending surgeon and supervised residents over 10-years to assess operative times as a marker of performance and any impact of case severity on times. DESIGN: Laparoscopic cholecystectomy videos were uploaded to Touch Surgery™ Enterprise, a combined software and hardware solution for securely recording, storing, and analysing surgical videos, which provide analytics of intraoperative phase times. Case severity and visualisation of the critical view of safety (CVS) were manually assessed using modified 10-point intraoperative gallbladder scoring system (mG10) and CVS scores, respectively. Attending and residents' times were compared unmatched and matched by mG10. SETTING: Secondary analysis of anonymized laparoscopic cholecystectomy video, recorded as standard of care. PARTICIPANTS: Adult patients who underwent elective laparoscopic cholecystectomy a single UK hospital. Cases were performed by one attending and their residents. RESULTS: 159 (attending=96, resident=63) laparoscopic cholecystectomy videos and intraoperative phase times were reviewed on Touch Surgery™ Enterprise and analyzed. Attending cases were more challenging (p=0.037). Residents achieved higher CVS scores (p=0.034) and showed longer dissection of hepatocystic triangle (HCT) times (p=0.012) in more challenging cases. Residents' total operative time (p=0.001) and dissection of HCT (p=0.002) times exceeded the attending's in low-severity matched cases (mG10=1). Residents' total operative times (p<0.001), port insertion/gallbladder exposure (p=0.032), and dissection of HCT (p<0.001) exceeded the attending's in matched cases (mG10=2). Residents' total operative (p<0.001), dissection of HCT (p<0.001), and gallbladder dissection (p=0.010) times exceeded the attendings in unmatched cases. CONCLUSIONS: Residents' total operative and dissection of HCT times significantly exceeded the attending's unmatched cases and low-severity matched cases which could suggest training need, however, also reflects an expected assessment of competence, and validates time as a marker of performance.

Empowering nurses to increase engagement in advance care planning in a medicine transitional care unit: a best practice implementation project.

INTRODUCTION AND OBJECTIVE: Advance care planning (ACP) communication and documentation are often inadequate, leading to care that is inconsistent with patients' preferences and moral dilemmas for family members. Nurses are patient advocates optimally positioned to initiate ACP but many feel that they lack the training and skills to navigate these conversations. The objective of this project was to increase nurses' capacity to engage in ACP. METHODS: This project used the JBI audit and feedback method to implement evidence into practice. The JBI Practical Application of Clinical Evidence System and Getting Research into Practice audit tools were used to incorporate ACP into nursing workflow. Eight audit criteria were created based on a JBI evidence summary. Compliance was measured by reviewing ACP notes from electronic health records and online survey responses. A baseline audit was followed by educational presentations and development of posted materials. Three follow-up audits examined sustainability. RESULTS: Compliance with the best practice recommendation for nurses to engage in ACP discussions increased from 55% to 80%. There was improvement from zero ACP notes at baseline (0% compliance) to 12 ACP notes in the final audit. Of these notes, 42% included all best practice elements and 92% included patients' treatment preferences. CONCLUSIONS: Development of an integrative nursing education plan for ACP empowers nurses to engage in vital conversations. Informing nurses of their scope of practice, defining terms and expectations, and encouraging them to attempt and document conversations will benefit patients. Future initiatives would benefit from incorporating practical opportunities without real-life implications and providing continued support to cohorts.

A phase 1 dose-escalation study of the poly(ADP-ribose) polymerase inhibitor senaparib in Australian patients with advanced solid tumors.

BACKGROUND: Senaparib is a novel, selective poly(ADP-ribose) polymerase-1/2 inhibitor with strong antitumor activity in preclinical studies. This first-in-human, phase 1, dose-escalation study examined the safety and preliminary efficacy of senaparib in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors were enrolled from three centers in Australia, using a conventional 3 + 3 design. Dose-escalation cohorts continued until the maximum tolerated dose or a recommended phase 2 dose was determined. Patients received one dose of oral senaparib and, if no dose-limiting toxicity occurred within 7 days, they received senaparib once daily in 3-week cycles. The primary end points were safety and tolerability. RESULTS: Thirty-nine patients were enrolled at 10 dose levels ranging from 2 to 150 mg. No dose-limiting toxicities were observed in any cohort. Most treatment-emergent adverse events were grade 1-2 (91%). Seven patients (17.9%) reported hematologic treatment-emergent adverse events. Treatment-related adverse events occurred in eight patients (20.5%), and the most frequent was nausea (7.7%). Two deaths were reported after the end of study treatment, one of which was considered a complication from senaparib-related bone marrow failure. Pharmacokinetic analysis indicated that senaparib the accumulation index was 1.06-1.67, and absorption saturation was 80-150 mg daily. In 22 patients with evaluable disease, the overall response rate was 13.6%, and the disease control rate was 81.8%. The overall response rate was 33.3% for the BRCA mutation-positive subgroup and 6.3% for the nonmutated subgroup. CONCLUSIONS: Senaparib was well tolerated in Australian patients with advanced solid tumors, with encouraging signals of antitumor activity. The recommended phase 2 dose for senaparib was determined to be 100 mg daily. GOV ID: NCT03507543.

Converting an inpatient nursing unit to a pandemic-response unit: Lessons learned.

The University of California, San Francisco (UCSF) Hospital Epidemiology and Infection Prevention and the Department of Nursing used lessons-learned during COVID-19 as a foundation to create a framework to be used as a guide for converting an inpatient unit to a pandemic-response unit. This article provides details of this framework and other lessons learned that can be applied to other pandemic pathogens.

The bi-directional relationship between post-traumatic stress disorder and obstructive sleep apnea and/or insomnia in a large U.S. military cohort.

OBJECTIVES: Determine if a bi-directional relationship exists between the development of sleep disorders (obstructive sleep apnea [OSA] and/or insomnia) and existing post-traumatic stress disorder (PTSD), and vice versa; and examine military-related factors associated with these potential relationships. DESIGN: Longitudinal analyses of a prospective representative U.S. military cohort. PARTICIPANTS: Millennium Cohort Study responders in 2011-2013 (Time 1 [T1]) and 2014-2016 (Time 2 [T2]) without insomnia or OSA at T1 (N = 65,915) or without PTSD at T1 (N = 71,256). MEASUREMENTS: Provider-diagnosed OSA, self-reported items for insomnia, provider-diagnosed PTSD, and current PTSD symptoms were assessed at T1 and T2. Adjusted multivariable models identified military-related factors associated with new-onset PTSD in those with OSA and/or insomnia, and vice versa. RESULTS: Self-reported history of provider-diagnosed PTSD without current symptoms at T1 was associated with new-onset OSA only and comorbid OSA/insomnia at T2, while current PTSD symptoms and/or diagnosis was associated with new-onset insomnia only. OSA/insomnia at T1 was consistently associated with newly reported PTSD symptoms or diagnosis except that insomnia only was not associated with newly reported provider-diagnosed PTSD. Military-related risk factors significantly associated with the bi-directional relationship for new-onset PTSD or OSA/insomnia included prior deployment with higher combat exposure and recent separation from the military; being an officer was protective for both outcomes. CONCLUSIONS: In this large military cohort, findings suggest that PTSD and OSA and/or insomnia are bi-directionally predictive for their development, which was sometimes revealed by health care utilization. Relevant military-related risk factors should be considered in efforts to prevent or treat PTSD and/or sleep disorders.

Combat exposure and behavioral health in U.S. Army Special Forces.

Although combat has been found to be associated with adverse health outcomes, little is known about the impact of specific combat exposures, particularly among specialized personnel. This study examined the association of different types of combat exposures with behavioral health outcomes, and whether these associations differed by Army occupational specialization: General Purpose Forces infantrymen (n = 5,361), Ranger Qualified infantrymen (n = 308), and Special Forces personnel (n = 593). Multivariable regression models estimated the association of combat severity, type of combat event (fighting, killing, threat to oneself, death/injury of others), and type of killing with mental health disorders, trouble sleeping, and problem drinking. Combat severity, each type of combat event, and killing noncombatants were associated with adverse health outcomes after adjusting for covariates and other combat exposures. Except for trouble sleeping, these associations did not differ by occupational specialization, though the prevalence and odds of outcomes were generally lower for Special Forces personnel.

JBI series paper 3: The importance of people, process, evidence, and technology in pragmatic, healthcare provider-led evidence implementation.

In this paper, we describe and discuss evidence implementation as a venture in global human collaboration within the framework of "people, process, evidence, and technology" as a roadmap for navigating implementation. At its core implementation is not a technological, or theoretical process, it is a human process. That health professionals central to implementation activities may not have had formal training in implementation, highlights the need for processes and programs that can be integrated within healthcare organization structures. Audit with feedback is an accessible implementation approach that includes the capacity to embed theory, frameworks, and bottom-up change processes to improve the quality of care. In this third paper in the JBI series, we discuss how four overarching principals necessary for sustainability (Culture, Capacity, Communication, and Collaboration) are combined with evidence, technology, and resources for evidence-based practice change. This approach has been successfully used across hundreds of evidence implementation projects around the globe for over 15 years. We present healthcare practitioner-led evidence-based practice improvement as sustainable and achievable in collaborative environments such as the global JBI network as a primary interest of the practicing professions and provide an overview of the JBI approach to evidence implementation.

Neoadjuvant Intravenous Oncolytic Vaccinia Virus Therapy Promotes Anticancer Immunity in Patients.

Improving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases or metastatic melanoma were treated with a single intravenous infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec-associated side effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells. Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with IFNα secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anticancer immunity. In the 2 patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of presurgical oncolytic vaccinia virus-based therapies to stimulate anticancer immunity and increase the chances to cure patients with cancer.