BackgroundUnderstanding physician leadership is critical during pandemics and other health crises when formal organisational leaders may be unable to respond expeditiously. This study examined how physician leaders managed to quickly design a new model for acute-care physicians’ work, adopted across four large hospitals in a public health authority in Canada during the COVID-19 pandemic.MethodsThe research employed a qualitative case study methodology, with inductive analysis of interview transcripts and documents. Shortly after a physician work model redesign, we interviewed key informants: the physician leaders and others who participated in or supported the model’s development. Participants were chosen based on their leadership role and through snowballing. All those who were approached agreed to participate.ResultsA process model describes leadership actions during four phases of work model development (priming, early planning, readying for operations and transition). These actions were: (1) recognising the threat, (2) committing to action, (3) forming and organising, (4) building and relying on relationships, (5) developing supporting processes and (6) designing functions and structure. We offer three additional contributions to knowledge about leadership in a time of crisis: (1) leveraging peer-professional leadership to initiate, formalise and organise change processes, (2) designing a new work model on existing and emerging evidence and (3) building and relying on relationships to unify various actors.ConclusionsThe model of peer-professional leadership can deepen understanding of how to lead professionals. Our findings could assist peer-professional and organisational leaders to encourage quick redesign of professionals’ work in response to new phases of the COVID-19 pandemic or other crises.

Before the first generic version of a drug can be marketed, patent litigation often occurs. The process begins when generic manufacturers notify the FDA of their intent to market a generic copy of a brand-name drug protected by patents, which they allege to be invalid or not infringed (called a Paragraph IV Certification). Assuming the brand-name manufacturer timely responds with litigation, a 30-month stay period is triggered, which bars the FDA from authorizing generic entry until the stay period expires or litigation is resolved in favor of the generic manufacturer. To understand whether 30-month stays delay generic entry, we examined the timing of major legal events leading to generic entry for a cohort of 46 generic drugs, including the timing of Paragraph IV Certification filings, stay period expirations, FDA approvals of generics, and generic product launches. We found Paragraph IV Certifications were filed a median of 5.2 years after the brand drug's FDA approval. There was a median of 3.2 years between the stay period expiration and subsequent generic launch. Because stay periods generally expire well in advance of when generic entry typically occurs, 30-month stays are unlikely to impact the timing of generic entry. To facilitate patent dispute resolution and ensure it does not unduly delay the anticipated launch of generic products, patent litigation should be allowed to start immediately following a brand-name drug's FDA approval.

Survival outcomes for patients with neuroblastoma vary markedly and reliable prognostic markers and risk stratification tools are lacking. We sought to identify and validate a transcriptomic signature capable of predicting risk of mortality in patients with neuroblastoma. The TARGET NBL dataset (n = 243) was used to develop the model and two independent cohorts, E-MTAB-179 (n = 478) and GSE85047 (n = 240) were used as validation sets. EFS was the primary outcome and OS was the secondary outcome of interest for all analysis. We identified a 21-gene signature capable of stratifying neuroblastoma patients into high and low risk groups in the E-MTAB-179 (HR 5.87 [3.83–9.01], p < 0.0001, 5 year AUC 0.827) and GSE85047 (HR 3.74 [2.36–5.92], p < 0.0001, 5 year AUC 0.815) validation cohorts. Moreover, the signature remained independent of known clinicopathological variables, and remained prognostic within clinically important subgroups. Further, the signature was effectively incorporated into a risk model with clinicopathological variables to improve prognostic performance across validation cohorts (Pooled Validation HR 6.93 [4.89–9.83], p < 0.0001, 5 year AUC 0.839). Similar prognostic utility was also demonstrated with OS. The identified signature is a robust independent predictor of EFS and OS outcomes in neuroblastoma patients and can be combined with clinically utilized clinicopathological variables to improve prognostic performance.

No abstract

Introduction: Polyamines (PAs) are cationic metabolites that enhance pro-tumorigenic cellular processes including the stimulation of cell division and proliferation, pro-survival gene expression, DNA and protein synthesis, regulation of apoptosis, oxidative stress and angiogenesis. Spermidine is a particularly important polyamine because it acts as an essential substrate of hypusine biosynthesis. Hypusination is required for the post-transcriptional activation of eukaryotic initiation factor 5A (eIF5A) which is critical to cell growth and protein synthesis. Spermidine production is highly regulated through the rate-limiting enzyme ornithine decarboxylase (ODC). Polyamines and eIF5A have been shown to be critical growth promoters in various pediatric cancers. Thus, targeted inhibition of ODC has therapeutic potential for this unique group of currently incurable pediatric malignancies. The anti-protozoan drug α-difluoromethylornithine (DFMO) is a suicide inhibitor of ODC and its effect may be potentiated by GC7 and Aurothioglucose. Previous mechanism based studies indicate that DFMO effectively reduces polyamine levels in neuroblastoma (NB) and provides rationale for ongoing Phase I and II clinical trials. To our knowledge, the effects of DFMO, GC7 and aurothioglucose have not yet been tested in pediatric leukemias. In this report, we evaluate the effectiveness of these therapeutic agents as a novel treatment of refractory hematological malignancies in the pediatric population. Methods: The recently published TARGET 2018 dataset was analyzed to determine the relationship between ODC expression and patient survival. Demographic data from this study was used to identify patients populations who may benefit from an ODC targeted therapy. Western blot analyses were then used to screen a comprehensive panel of pediatric cancer cell lines for ODC expression. Infant and pediatric leukemia cell lines were selected to represent the various subtypes including AML (TIB202, KASUMI) as well as B ALL (SUP-B15, MV411, RS4-11, CCRF-SB ) and T ALL (CEM/C1, MOLT-3). These cells were derived from children with relapsed disease and have varying degrees of resistance to conventional chemotherapy. Drug combination studies were used to define drug candidates having potential synergistic activity when combined with DFMO. Results: A Kaplan-Meier evaluation determined that high expression of ODC was associated with significantly lower patient survival and this finding was confirmed via cox regression analysis. The demographic analysis determined that females were significantly overrepresented in the high expression group whereas no variation was seen between race and ethnicity groups. Furthermore, a correlation was observed between high expression of eIF5A and younger diagnosis, indicating that ODC targeted therapy may be more effective in infant populations. DFMO-induced cytotoxicity was detected in many of the tumor cells including infant AML (TIB202) at an approximate physiologically achievable IC50 value of 200 uM. This was representative of values previously published for neuroblastoma. In infant AML, a western blot analysis determined that DFMO increased the abundance of cleaved PARP, cleaved caspase 3 and cleaved caspase 7 which serve as mechanistic markers of apoptosis. Probing for caspase 8 and caspase 9 showed no difference between treated cells and control. A combination screen of over 80 biologically active compounds was conducted to identify potential synergistic treatment partners of DFMO where GC7 and aurothioglucose (AuTG) ranked among the most promising. Further experimentation determined that doses of GC7 and AuTG, which were not effective as a singular treatment, were able to enhance the ability of DFMO to kill tumor cells. Discussion: The preclinical studies discussed here offer the first proof-of-concept data on a novel treatment approach for refractory leukemia in children. We provide mechanistic evidence to show the ability of DFMO to effectively kill polyamine-dependent tumor cells at physiologically attainable concentrations. In addition, effective drug combinations have been identified to further enhance their clinical utility. Our findings provide key preclinical information on the utility of these drugs as treatment for refractory hematological malignancies in the pediatric population. Disclosures No relevant conflicts of interest to declare.