Escalation Process Research Articles

Georgia

In response to a request from the National Bank of Georgia (NBG), the Monetary and Capital Markets Department (MCM) of the International Monetary Fund (IMF) conducted a Technical Assistance (TA) mission between March 17 and April 20, 2022, which sought to support the operationalization of the bank recovery and resolution framework, building on recommendations from the 2021 Financial Sector Assessment Program (FSAP) for Georgia. In collaboration with the authorities, the mission identified several priority actions, including (i) reinforcing the NBG’s internal procedures for reviewing banks’ recovery plans; (ii) strengthening its resolution function and developing playbooks for the main resolution tools; (iii) clarifying the current crisis management escalation process; (iv) revising the credit hierarchy; (vi) introducing bank-specific targets for loss-absorbing capacity; (vii) performing a stock taking of contractual clauses in banks’ current subordinated and senior debt issuances; and (viii) undertaking further efforts to advance resolution planning.

Incorporating historical information to improve dose optimization design with toxicity and efficacy endpoints: iBOIN-ET.

In modern oncology drug development, adaptive designs have been proposed to identify the recommended phase 2 dose. The conventional dose finding designs focus on the identification of maximum tolerated dose (MTD). However, designs ignoring efficacy could put patients under risk by pushing to the MTD. Especially in immuno-oncology and cell therapy, the complex dose-toxicity and dose-efficacy relationships make such MTD driven designs more questionable. Additionally, it is not uncommon to have data available from other studies that target on similar mechanism of action and patient population. Due to the high variability from phase I trial, it is beneficial to borrow historical study information into the design when available. This will help to increase the model efficiency and accuracy and provide dose specific recommendation rules to avoid toxic dose level and increase the chance of patient allocation at potential efficacious dose levels. In this paper, we propose iBOIN-ET design that uses prior distribution extracted from historical studies to minimize the probability of decision error. The proposed design utilizes the concept of skeleton from both toxicity and efficacy data, coupled with prior effective sample size to control the amount of historical information to be incorporated. Extensive simulation studies across a variety of realistic settings are reported including a comparison of iBOIN-ET design to other model based and assisted approaches. The proposed novel design demonstrates the superior performances in percentage of selecting the correct optimal dose (OD), average number of patients allocated to the correct OD, and overdosing control during dose escalation process.

What Goes Around Comes Around: How Perpetrators of Workplace Bullying Become Targets Themselves

In this study, we investigated whether and how perpetrators of bullying become targets themselves. Building on the notion of bullying as an escalation process and the Conservation of Resources Theory, we hypothesized that following enactment of bullying, people would experience increased relationship conflicts with colleagues, diminishing their sense of control and making them more likely to become exposed to bullying themselves. We tested this idea using longitudinal sequential mediated Structural Equation Modelling in a sample of 1420 Belgian workers. Our results confirmed that enactment of bullying lead to more exposure to bullying 18 months later. Relationship conflicts partially mediated this effect, meaning that bullying enactment can lead to increased tensions with others at work, increasing one’s vulnerability to bullying exposure. Although perceived control also mediated the enactment-exposure relationship, relationship conflicts did not lead to perceived loss of control, suggesting a missing link in this relationship. Furthermore, the effect from perceived control to exposure to bullying was small and did not replicate in post-hoc analyses. Our findings suggest that people may experience a backlash from others in their work environment following engagement in bullying behavior at work and invite further exploration of the processes that may account for this relationship.

Using pulse oximeters in care homes for residents with COVID-19 and other conditions: a rapid mixed-methods evaluation

Background There are over 15,000 care homes in England, with a total of approximately 450,000 beds. Most residents are older adults, some with dementia, and other residents are people of any age with physical or learning disabilities. Using pulse oximetry in care homes can help the monitoring and care of residents with COVID-19 and other conditions. Objectives To explore the views of care home staff, and the NHS staff they interact with, with regard to using pulse oximetry with residents, as well as the NHS support provided for using pulse oximetry. Design We carried out a rapid mixed-methods evaluation of care homes in England, comprising (1) scoping interviews with NHS leaders, care association directors and care home managers, engaging with relevant literature and co-designing the evaluation with a User Involvement Group; (2) an online survey of care homes; (3) interviews with care home managers and staff, and with NHS staff who support care homes, at six purposively selected sites; and (4) synthesis, reporting and dissemination. The study team undertook online meetings and a workshop to thematically synthesise findings, guided by a theoretical framework. Results We obtained 232 survey responses from 15,362 care homes. Although this was a low (1.5%) response rate, it was expected given exceptional pressures on care home managers and staff at the time of the survey. We conducted 31 interviews at six case study sites. Pulse oximeters were used in many responding care homes before the pandemic and use of pulse oximeters widened during the pandemic. Pulse oximeters are reported by care home managers and staff to provide reassurance to residents and their families, as well as to staff. Using pulse oximeters was usually not challenging for staff and did not add to staff workload or stress levels. Additional support provided through the NHS COVID Oximetry @home programme was welcomed at the care homes receiving it; however, over half of survey respondents were unaware of the programme. In some cases, support from the NHS, including training, was sought but was not always available. Limitations The survey response rate was low (1.5%) and so findings must be treated with caution. Fewer than the intended number of interviews were completed because of participant unavailability. Throughout the COVID-19 pandemic, care homes may have been asked to complete numerous other surveys etc., which may have contributed to these limitations. Owing to anonymity, the research team was unable to determine the range of survey respondents across location, financial budget or quality of care. Conclusions Using pulse oximeters in care homes is considered by managers and staff to have been beneficial to care home residents. Ongoing training opportunities for care home staff in use of pulse oximeters would be beneficial. Escalation processes to and responses from NHS services could be more consistent, alongside promoting the NHS COVID Oximetry @home programme to care homes. Future research Further research should include the experiences of care home residents and their families, as well as finding out more from an NHS perspective about interactions with care home staff. Research to investigate the cost-effectiveness of pulse oximetry in care homes, and of the NHS COVID Oximetry @home programme of support, would be desirable. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full in Health and Social Care Delivery Research; Vol. 10, No. 35. See the NIHR Journals Library website for further project information.

79 Impact of COVID-19 wave 3 paediatric inpatient unit closures on transfers to tertiary care paediatric hospital

Abstract Background During Wave 3 of the COVID-19 pandemic, 15 community hospital paediatric inpatient units (comprising 167 beds) in Toronto were directed to close by the Greater Toronto Area (GTA) Hospital Incident Management System (IMS) Command Centre to increase adult inpatient bed capacity. All paediatric patients from closed inpatient units were redirected to a single tertiary care paediatric hospital, which increased capacity to accommodate these additional patients through activation of surge plans, while community hospitals redeployed resources to fill much needed gaps in adult care. Objectives The objective was to describe patient characteristics of all transfers during the closure to explore the impact of community paediatric inpatient unit closures on transfers to the tertiary hospital. Design/Methods A chart review of all transferred patients was conducted during the mandated closure and subsequent reopening. Transfers excluded ICU-level transfers as these were not impacted by IMS mandated closures. All transfers were categorized as requiring tertiary care (i.e. would typically be transferred) or not requiring tertiary care (i.e. only transferred due to the closure). Variables collected included sending hospital, admitting diagnosis, patient age, hospital disposition, and length of stay. Data was collected until the last paediatric unit reopened. Quality improvement project approval was granted by the institution. Results A total of 858 patients were transferred to the tertiary hospital during the 67 day closure; of those, 530 were transferred solely to increase adult bed capacity (i.e. were categorized as patients requiring non-tertiary care). The majority of patients were admitted to general paediatrics (52%), and 39% went to a surgical inpatient unit. Most patients (68%) admitted had a length of stay between 24 and 72 hours. A third of patients admitted were under 2 years old, and a third were over 12 years old. The top three diagnoses for admission were infections, gastrointestinal issues, and general surgery. Two-thirds (60%) of transfers from closed sites came from three sites. Conclusion More than half of the transfers occurred solely due to the mandated closures, and transfers returned to a stable volume once all sites re-opened. The GTA hospital system was able to respond to the mandated closure effectively through clear high-level communication, escalation processes and structures as well as responsive, real-time problem solving. Closures increased potential adult inpatient capacity by 6740 bed days and demonstrated an unprecedented system-wide approach to the provision of integrated paediatric care across the region.

Development and Evaluation of Strategies to Support Rural Secondments for Junior Physiotherapists

AbstractPurposeRural workforce shortages are a national issue. One strategy is the use of secondments from larger healthcare sites to staff rural sites on a rotational basis. The purpose of this evaluation is to explore the impact of the development, implementation of an educational, training and supervision package for junior Physiotherapists undertaking rural secondments in Northern NSW.Design/methodology/approachPre post evaluation of a training, education and supervision package to support junior Physiotherapists undertaking rural secondments across Northern NSW. A baseline survey of Physiotherapists who had undertaken a secondment in the previous 12 months defined current practice and limitations. From this a targeted education, training and supervision package was developed. Post implementation surveying for a period of 12 months was undertaken to evaluate the packages implementation.FindingsStatistically significant improvements in staff reporting they felt supported and were aware of escalation processes for patients under their care were reported. Additionally improvements were seen in staff reported access to and completing competencies relevant to their secondment.Research implicationsThese findings provide guidance in regards to junior Physiotherapists working on rural secondments and the importance of structured education, training and support mechanisms.Practical implicationsThe findings from this work support the development and implementation of structured education, training and supervision plans prior to undertaking rural secondments.Originality/valueThese findings provide evidence and support the need for structured and target training, education and supervision for staff undertaking rural secondments to ensure staff are confident to work in a rural setting.LimitationsLarger response rates for post implementation survey results may result in different outcomes being reported in comparison to pre implementation results.

Exploring the Escalation Process of Academic Bullying: A Qualitative Study

Higher education in India is known to have a high incidence of workplace bullying, but less is known about the mechanisms of escalation. The present study pinpoints the elements of escalation and their characteristics within academic bullying. The thematic analysis of the data collected through semi￾structured in-depth interviews of twenty faculty members in private-unaided colleges across India, identified six common elements of escalation: trigger, resources assessment, reactance, rejection, helplessness and withdrawal. This study will help employers to establish more effective anti-bullying policies. Additionally, this study is one of the few attempts to address academic bullying in the Indian context.

Geometry optimization of an electrochemical reactor for bleaching kaolin

AbstractHigh-whiteness kaolinite mining reserves are scarce. In some locations, it is necessary to remove material to access them (adding to the cost). Therefore, processes have been developed to eliminate contaminants, such as iron, and provide alternatives to the used contaminated materials that, after being treated, meet quality criteria. In our previous research, we developed an electrochemical process for kaolin whitening at the laboratory level and bench scale, demonstrating the reaction mechanisms that occur during the removal of iron from kaolin. However, the geometry used at the laboratory level does not present the most suitable position for the electrodes. Therefore, in the present study, we focused on the geometry and the function of the electrodes. This is necessary during the escalation process to reach the pilot-scale level. The study was carried out using computer-aided engineering in the COMSOL Multiphysics computer program and by analysing the distribution of the electric potential and the electric current of the geometries considered while performing the scaling. The results indicated that the change in the anode position from perpendicular to parallel to the discs improved the distribution of electric current density on the cathode surface and so increased the elimination of iron through electrochemical deposition. Similarly, to reduce the amount of material used in the construction of the reactor, the anode-size effect was analysed, revealing that relatively small anodes improved the distribution of electric current density over the entire surface of the electrode and not only at the edges.

Unmasking Militants: Organizational Trends in Armed Groups, 1970–2012

Abstract Despite the prevalence of armed groups in world politics, a prominent measurement challenge obscures understanding about many of these militant actors, especially when their activities fall below the threshold of civil war. This note addresses this gap by introducing a new dataset on the organizational characteristics of 1,202 armed groups that operated in 124 countries between 1970 and 2012. It outlines the dataset's construction and uses principal component analysis to explore organizational trends across armed groups. The results show armed groups tend to organize around three archetypes, each with different ideological goals, recruitment tactics, and areas of operation. Armed group campaigns are far more numerous than previously realized and can evolve in intensity over time. Unpacking these trends creates substantial opportunities for developing and testing new group-level theories about the causes of militant formation, escalation processes, and consequences of organizational decisions.

574 The Successful Resurrection of NELA in a District General Hospital

Abstract Aim The NELA requirements of data collection is known to be mandatory. Our DGH had three years of noncompliance. We present an executed plan in the collection of retrospective and prospective process to achieve national standard. Method A new structural setup with anaesthetic and surgical teams was formalised. A recruitment of 13 foundation doctors was made and each were induced to NELA with a teaching session. Allocation of 15–20 hospital numbers with a primary deadline of seven days to achieve full entry was expected. A formal NELA certificate and recognition for taking part from the divisional director was issued. A prospective strategy was initiated with patient ownership from the joint anaesthetic and surgical team involved. A NELA login with local access was setup, plus paper format readily available for rare access situations. A two-email reminder system with further escalation process was introduced if entry was incomplete. The escalation being contact from the clinical lead / divisional director. This information was highlighted at a local meeting plus a familiarity of the NELA database was ensured. Results A large proportion of the retrospective data has been collected over a short time period due to a clear incentivised scheme. Prospectively there has not been any escalation emails needed since the new setup. Conclusion Areas of problems were identified with a wide range of solutions being put forward. A multi collaborative approach was needed plus positive cooperation from the clinical lead, clinical director, and the divisional director to ensure the successful new era.

WE5.4 The Successful Resurrection of NELA in a District General Hospital

Abstract Introduction The NELA requirements of data collection is known to be mandatory. Our DGH had three years of non compliance. We present an executed plan in the collection of retrospective and prospective process to achieve national standard. Method A new structural setup with anaesthetic and surgical teams was formalised. A recruitment of 13 foundation doctors was made and each were induced to NELA with a teaching session. Allocation of 15–20 hospital numbers with a primary deadline of seven days to achieve full entry was expected. A formal NELA certificate and recognition for taking part from the divisional director was issued. A prospective strategy was initiated with patient ownership from the joint anaesthetic and surgical team involved. A NELA login with local access was setup, plus paper format readily available for rare access situations. A two email reminder system with further escalation process was introduced if entry was incomplete. The escalation being contact from the clinical lead / divisional director. This information was highlighted at a local meeting plus a familiarity of the NELA database was ensured. Results A large proportion of the retrospective data has been collected over a short time period due to a clear incentivised scheme. Prospectively there has not been any escalation emails needed since the new setup. Conclusion Areas of problems were identified with a wide range of solutions being put forward. A multi collaborative approach was needed plus positive cooperation from the clinical lead, clinical director and the divisional director to ensure the successful new era.

Strategic Analysis of Dollar Auction

Shubik invented the dollar auction in 1971, which is a straightforward but practical auction model for elucidating the motivations and process of conflict escalation. Later on, several researchers used this paradigm to conduct the study on a variety of subjects. Waniek, for example, investigated the relationship between spitefulness and dollar auction in-depth and presented the optimal decision under different scenarios. In this paper, I simplified his results and merged them into simpler forms. Some proposals that may be advantageous to our economic environment are provided based on the performance.

Acute clinical deterioration and consumer escalation: The understanding and perceptions of hospital staff.

IntroductionConsumer escalation systems allow patients and families to escalate concerns about acute clinical deterioration. Hospital staff can impact upon the success of this process. As part of evaluation processes within a Local Health Network, where a consumer escalation system was introduced in accordance with National requirements, we sought to explore clinicians’ understanding and perceptions of consumer escalation.MethodsVoluntary and anonymous staff surveys pre, and post, system introduction. Quantitative data was analysed using descriptive statistics, chi-square independence, and non-parametric independent samples median tests. Qualitative data was evaluated using content analysis and cross-referenced with quantitative responses.ResultsRespondent’s (pre: 215; post: 89) area of work varied significantly between survey periods. Most agreed that patients/families have a sound knowledge of a patient’s typical health status (pre: 192/215 (89.3%); post 82/88 (93.2%)) and that patients/families should be encouraged to escalate concerns of deterioration to ward staff (pre: 209/212 (98.6%); post: 85/89 (95.5%)). Respondent perceptions of patient/family ability to recognise clinical deterioration varied. Staff agreement towards local response expectations decreased as the degree of clinical requirement increased. Staff concerns of increased workloads (pre: 90/214 (42.1%); post 12/72 (16.7%), p<0.001) and conflict generation (pre: 71/213 (33.3%); post: 7/71 (9.9%), p = 0.001) decreased significantly following system introduction. However, clinician perceptions of positive system effects also decreased (patient-staff rapport pre: 163/213 (76.5%); post: 38/72 (52.8%), p = 0.001; patient centred care pre: 188/214 (87.9%); post: 53/72 (73.6%), p = 0.012; patient safety pre: 173/214 (80.8%); post: 49/72 (68.1%), p = 0.077). Only 53% of respondents (pre: 112/213 (52.6%); post: 48/88 (54.5%)) perceived that patient/family have sufficient confidence to escalate concerns.ConclusionConsumer escalation systems require staff support. Staff perceptions may indicate, and act as, barriers to the operation of consumer escalation processes. Further exploration in identifying and managing staff barriers is crucial to the success of consumer escalation.

Abstract CT253: A Phase 1/2 trial to evaluate the safety and antitumor activity of tipifarnib and alpelisib for patients with HRAS-overexpressing and/or PIK3CA-mutated/amplified recurrent/metastatic head and neck squamous cell carcinoma (The KURRENT trial)

Abstract Background: Understanding connections between key cellular pathways is particularly important when selecting combinatorial cancer therapies. HRAS preferentially activates PI3K 5-fold more efficiently than KRAS, while KRAS is a more efficient activator of RAF (Yan et al. 1998). Further, mutant HRAS is insufficient for oncogenic transformation if it is unable to recruit PI3K in preclinical models (Gupta et al. 2007). Conversely, mutant PI3K requires RAS to drive tumor growth (Zhao and Vogt 2008). HRAS mutation/overexpression and PIK3CA mutations/amplifications account for up to 50% of head and neck squamous cell carcinoma (HNSCC). Recognition of these interdependencies was the basis for the evaluation of HNSCC PDX models (HRAS-mutant, HRAS wildtype-overexpressed, PIK3CA-amplified, and PIK3CA-mutant) which demonstrated additive and synergistic growth effects that confirmed the codependency of these pathways, thus providing robust rationale for investigating combined pathway inhibition in the clinic. The KURRENT trial is enrolling patients with HRAS and/or PIK3CA-dependent tumors who will receive combination treatment with tipifarnib (a potent and selective inhibitor of farnesyltransferase, a critical enzyme for HRAS activity) and alpelisib (an inhibitor of PI3K with inhibitory activity predominantly against the PI3Kα isoform). Methods: The KURRENT trial (KO-TIP-013, NCT04809233) is an ongoing multicenter, open-label, 2-cohort, phase 1/2 trial designed to evaluate the safety of the combination of tipifarnib and alpelisib, determine the recommended combination dose(s) regimen, and evaluate preliminary anti-tumor activity in patients with recurrent/metastatic (R/M) HNSCC whose tumors are dependent upon HRAS and/or PIK3CA signaling. Dependency is defined as an overexpression of the HRAS protein, and/or a PIK3CA mutation and/or amplification. The trial will enroll 40 HNSCC patients (oral cavity, oropharynx, larynx or hypopharynx, sinonasal, nasopharyngeal, or unknown primary subsites regardless of human papillomavirus status); 20 each into two biomarker defined cohorts (Cohort 1: PIK3CA; Cohort 2: HRAS). Participants must have documented treatment failure from at least one prior therapy in the R/M setting and have measurable disease by RECIST v1.1. At the starting dose level, participants will receive tipifarnib at 300 mg twice daily on days 1-7 and 15-21 and alpelisib 200 mg each morning continuously during a 28-day cycle. The trial will use an adaptive dose escalation design (based on a Bayesian logistic regression model) to characterize safety, tolerability, and clinical activity of the combination to identify the Optimal Biologically Active Dose (OBAD) while maintaining a dose limiting toxicity (DLT) rate &amp;lt;33%. No formal interim analysis is planned as the model-based dose escalation process requires decisions based on real-time evaluation of aggregate toxicity and efficacy data. All observed/available data among each cohort will be evaluated before choosing the combination dose for a subsequent cohort. The trial opened for enrollment in October 2021. Citation Format: Glenn J. Hanna, Cesar Perez Batista, Alan L. Ho, Maura L. Gillison, Douglas Adkins, Ashley Dayoub, Bridget Martell, Mollie Leoni, Stephen Dale, Kun Nie, Alex Dmitrienko. A Phase 1/2 trial to evaluate the safety and antitumor activity of tipifarnib and alpelisib for patients with HRAS-overexpressing and/or PIK3CA-mutated/amplified recurrent/metastatic head and neck squamous cell carcinoma (The KURRENT trial) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT253.

Recognizing Early Deterioration in Elderly Care Home Setting - a Snapshot

AimsOur aim is to measure the baseline physical and mental health early deterioration recognition of carers in the care home setting in Harrogate, North Yorkshire. This is part of a larger undergoing quality improvement project that looks at improving elderly care in care homes in the region by implementing a training package.MethodsThe approach was to contact local authorities, in this case, the NHS clinical commissioning group North Yorkshire to identify a struggling care home. We then engaged the care home and designated a leader to coordinate the project. We collected common themes by using focus groups with both carers and our professionals which led to the creation of a 16-item questionnaire covering deterioration literacy. Finally, we electronically and anonymously surveyed the carers (December 2021) and analysed the data via Google Forms.ResultsWe had 22 responses out of 30 possible. As an overview, 100% felt confident in recognizing deterioration, however, 31.8% don't feel confident in managing deterioration. 90.9% need tools to aid recognition, from which 45.5% find tools confusing. Only 50% feel confident to appropriately escalate the incident, from which 36.4% did not know when or to whom to escalate and 13.6% were not sure if escalation was needed but will refer to secondary care regardless. 27.3% think their escalation process needs improvement. When it comes to deterioration themes, 4.6% don't feel confident in identifying confusion, 13.6% feel their knowledge on confusion could be improved and 9.1% don't know how to identify, manage, or escalate confusion. 22.7% don't feel confident in identifying mobility decline and 9.1% don't know how to manage this accordingly. 9.1% feel like their knowledge of skin changes needs improvement. 22.7% feel that their confidence in identifying toilet habits could be improved and 4.5% don't know how to manage or escalate these changes. In terms of carers’ mental health, 50% and 13.6% have mild and moderate anxiety, respectively.ConclusionDeterioration recognition in the elderly is currently a hot topic. Recent studies highlight the need to improve deterioration management to minimize inappropriate referrals and admissions and unnecessary infection exposure of a vulnerable elderly individual. Our results show that besides improving the theoretical knowledge we also must think about a clear escalation process, an easy-to-read deterioration tool, and managing carers' anxiety as part of the training package.

Raising Concerns and Trainee Well-being: What Are the Issues?

AimsRaising concerns is an important part of being a doctor and part of the GMC ‘Good Medical Practice’ guidelines, however as a trainee it often comes with specific challenges. Historically trainees are often left feeling that their concerns are not taken seriously and there is no resolution to problems raised. Here we present the findings of a scoping exercise undertaken as part of a Quality Improvement project exploring these issues within a large mental health Trust.MethodsTrainees across all training grades from Foundation doctors to higher trainees were invited to engage in virtual focus groups specific to their training programme. Contributions were analysed anonymously using a thematic analysis approach by two independent coders. Quantitative data were also gathered using an online survey to capture trainees who had been unable to attend a focus group.ResultsKey results included: •A total of 6 focus groups were attended by more than 35 trainees, with high turnout particularly within Foundation trainees and CT1 doctors.•Three key themes were identified from the qualitative data: difficulties with the process of raising concerns, fear of the consequences and challenging the culture of the organisation.•It was noted that senior trainees felt more comfortable with the process of raising concerns compared with junior colleagues but were more apathetic about the impact of doing so.•12 trainees completed the online survey. Of these, 6 (50%) reported having had patient safety concerns and 7 (58%) had had concerns about their training.•The most common reported barriers to raising concerns were the impact on working relationships (67%), lack of support (50%) and fear of repercussions on their training (50%). 42% of respondents were unsure of how to raise concerns.•Trainee suggestions for change included improved information for trainees and trainers about the process for raising concerns, sharing of feedback about concerns raised more widely and regular opportunity to meet with key stakeholders.ConclusionThe majority of trainees had experienced concerns about either patient safety or training issues. It will be necessary to address the multiple barriers highlighted to enable trainees to feel more confident and able to raise concerns. Increasing awareness of escalation processes, improving the processes themselves and fostering a supportive environment which encourages and supports trainees to raise concerns will be important given the implications for patient safety and trainee well-being.

A phase 1/2 trial to evaluate the safety and antitumor activity of tipifarnib and alpelisib for patients with PIK3CA-mutated/amplified and/or HRAS-overexpressing recurrent/metastatic head and neck squamous cell carcinoma.

TPS6104 Background: Understanding connections between key cellular pathways is particularly important when selecting combinatorial cancer therapies. HRAS preferentially activates PI3K 5-fold more efficiently than KRAS, while KRAS is a more efficient activator of RAF (Yan et al. 1998). Further, mutant HRAS is insufficient for oncogenic transformation if it is unable to recruit PI3K in preclinical models (Gupta et al. 2007). Conversely, mutant PI3K requires RAS to drive tumor growth (Zhao and Vogt 2008). HRAS mutation/overexpression and PIK3CA mutations/amplifications account for up to 50% of head and neck squamous cell carcinoma (HNSCC). Recognition of these interdependencies was the basis for the evaluation of HNSCC PDX models which demonstrated additive or synergistic anti-tumor effects that confirmed the codependency of these pathways, thus providing robust rationale for investigating combined pathway inhibition in the clinic. The KURRENT trial is enrolling patients with HRAS and/or PIK3CA-dependent tumors who will receive combination treatment with tipifarnib (a potent and selective inhibitor of farnesyltransferase, a critical enzyme for HRAS activity) and alpelisib, a PI3K inhibitor. Methods: The KURRENT trial (KO-TIP-013, NCT04809233) is an ongoing multicenter, open-label, 2-cohort, phase 1/2 trial designed to evaluate the safety of the combination of tipifarnib and alpelisib, determine the recommended combination dose(s) regimen, and evaluate preliminary anti-tumor activity in patients with recurrent/metastatic (R/M) HNSCC whose tumors are dependent upon HRAS and/or PIK3CA signaling. The trial will enroll 40 HNSCC patients; 20 each into two biomarker defined cohorts (Cohort 1; PIK3CA; Cohort 2; HRAS). Participants must have documented treatment failure from at least one prior therapy in the R/M setting and have measurable disease by RECIST v1.1. At the starting dose level, participants will receive tipifarnib at 300 mg twice daily on days 1-7 and 15-21 and alpelisib 200 mg each morning continuously during a 28-day cycle. The trial will use an adaptive dose escalation design (based on a Bayesian logistic regression model) to characterize safety, tolerability, and clinical activity of the combination to identify the Optimal Biologically Active Dose (OBAD) while maintaining a dose limiting toxicity (DLT) rate &lt; 33%. No formal interim analysis is planned as the model-based dose escalation process requires decisions based on real-time evaluation of aggregate toxicity and efficacy data. All observed/available data among each cohort will be evaluated before choosing the combination dose for a subsequent cohort. Enrollment into the PIK3CA cohort began in October 2021. Clinical trial information: NCT04809233.

Autologous CD7-targeted CAR T-cell therapy for refractory or relapsed T-cell acute lymphoblastic leukemia/lymphoma.

7035 Background: Refractory or relapsed (r/r) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) has a poor prognosis. Our previous report showed that donor-derived CD7 CAR-T cell therapy could induce remission of r/r T-ALL, but graft-versus-host disease (GVHD) occurred in some patients (Pan et al. J Clin Oncol 2021;39:3340-3351). We recently conducted a phase I trial to evaluate autologous CD7 CAR-T therapy in r/r T-ALL/LBL, which may avoid GVHD while showing the efficacy; here we report the early result with the approval of the Data and Safety Monitoring Committee and Institutional Review Board (IRB). Methods: The patients who had CD7+ r/r T-ALL/LBL and no leukemia cells in peripheral blood were eligible for this phase I trial (NCT04840875). The CD7 CAR construct included an endoplasmic reticulum anchor domain fused to a CD7 binding domain to prevent CD7 expression on cell surface, which contributed to minimize CAR T cell fratricide. CAR T product was checked to ensure lack of tumor contamination before infusion. The trial followed a “3+3” dose escalation process. Adverse events and efficacy were primary and secondary endpoints. Results: A total of 5 patients (Pt1-5), with a median age of 3.8 years (range, 1.9-13), were enrolled between Sept 2021 and Jan 2022. At enrollment, Pt1 had mediastinal mass and blasts in pleural fluid; Pt4 was in central nervous system (CNS)-3 status; Pt2, 3 and 5 had marrow disease with a median burden of 1.35% (range, 0.07%-7.31%). Pt1, 2 and 3 received 5×105 (±20%) cells/kg; Pt5 received 1×106 (±20%) cells/kg; Pt4 received cells below the target dose. Three patients had cytokine release syndrome (CRS), including one grade 3; the median onset was on day 5 (range, 1-9) with the median duration of 4 days (range, 3-14). No patient had neurotoxicity, GVHD or infection. Grade 3-4 hematological toxicity occurred in all five patients, which recovered to grade 2 within 30 days. On one month post-infusion, four patients achieved complete remission, and one patient (Pt4) still had leukemia cells in the cerebrospinal fluid. With the median follow-up time of 62 days (range, 35-136), one patient (Pt1) underwent stem cell transplantation (SCT) on 2.9 months post-infusion, and had a CD7- relapse on 1.4 months post-SCT; the other three responders remained in MRD- CR. In the four patients who received target dose, the median peak CAR T cell count in peripheral blood was 4.27×102/uL (range, 2.49-5.61) by flow cytometry, and all five patients had detectable CAR transgene by PCR on their last visits. There was a decrease of CD7-positive normal T cells and an increase of CD7-negative counterparts in all responders. Conclusions: Autologous CD7 CAR T cell therapy was safe and effective in the induction of remission in r/r T-ALL/LBL patients, without signs of GVHD. Longer follow-up time of more cases will be used to further evaluate this therapy. Clinical trial information: NCT04840875.

Pulmonary Pharmacokinetics of Polymer Lung Surfactants Following Pharyngeal Administration in Mice

We have recently discovered that pulmonary administration of nanoparticles (micelles) formed by amphiphilic poly(styrene-block-ethylene glycol) (PS-PEG) block copolymers has the potential to treat a lung disorder involving lung surfactant (LS) dysfunction (called acute respiratory distress syndrome (ARDS)), as PS-PEG nanoparticles are capable of reducing the surface tension of alveolar fluid, while they are resistant to deactivation caused by plasma proteins/inflammation products unlike natural LS. Herein, we report studies of the clearance pathways and kinetics of PS-PEG nanoparticles from the lung, which are essential for designing further preclinical IND-enabling studies. Using fluorescently labeled PS-PEG nanoparticles, we found that, following pharyngeal aspiration in mice, the retention of these nanoparticles in the lungs extends over 2 weeks, while their transport into other (secondary) organs is relatively insignificant. An analysis based on a multicompartmental pharmacokinetic model suggests a biphasic mechanism involving a fast mucociliary escalator process through the conducting airways and much slower alveolar clearance processes by the action of macrophages and also via direct translocation into the circulation. An excessive dose of PS-PEG nanoparticles led to prolonged retention in the lungs due to saturation of the alveolar clearance capacity.

A consideration of escalation and special measures in NHS Wales

This article examines the escalation process for NHS bodies in Wales and explores the effectiveness of this mechanism as a means of improving performance. Two case studies of health boards that have been subject to special measures are included. The central role of Welsh government in the decision-making process, the length of time a number of organisations have been in ‘escalation’ and the opaqueness of the decision-making criteria used to de-escalate health boards are highlighted. The author discusses potential issues regarding accountability within NHS Wales and whether the eventual establishment of an NHS Executive will address this. The article will also look at how the size and complexity of Welsh health boards may negatively affect their manageability and, if so, whether these matters need to be considered by NHS England as it shifts towards integrated care systems.