Facilitating Organisational Fluidity with Computational Social Matching

Striving to operate in increasingly dynamic environments, organisations can be seen as fluid and communicative entities where traditional boundaries fade away and collaborations emerge ad hoc. To enhance fluidity, we conceptualise computational social matching as a research area investigating how to digitally support the development of mutually suitable compositions of collaborative ties in organisations. In practice, it refers to the use of data analytics and digital methods to identify features of individuals and the structures of existing social networks and to offer automated recommendations for matching actors. In this chapter, we outline an interdisciplinary theoretical space that provides perspectives on how interaction can be practically enhanced by computational social matching, both on the societal and organisational levels. We derive and describe three strategies for professional social matching: social exploration, network theory-based recommendations, and machine learning-based recommendations.Striving to operate in increasingly dynamic environments, organisations can be seen as fluid and communicative entities where traditional boundaries fade away and collaborations emerge ad hoc. To enhance fluidity, we conceptualise computational social matching as a research area investigating how to digitally support the development of mutually suitable compositions of collaborative ties in organisations. In practice, it refers to the use of data analytics and digital methods to identify features of individuals and the structures of existing social networks and to offer automated recommendations for matching actors. In this chapter, we outline an interdisciplinary theoretical space that provides perspectives on how interaction can be practically enhanced by computational social matching, both on the societal and organisational levels. We derive and describe three strategies for professional social matching: social exploration, network theory-based recommendations, and machine learning-based recommendations.Peer reviewe

Clinical Outcomes in Fibrolamellar Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors

Background: Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer primarily affecting children and young adults. Although considered a subset of hepatocellular carcinoma (HCC), FLC has unique molecular and pathologic characteristics, suggesting that it may require different treatment. Immune checkpoint inhibitors (ICIs) are used in the treatment of HCC, but efficacy and safety in FLC has not been characterized. Methods: We performed a multicenter retrospective analysis of patients with FLC to determine responses to ICI therapy. Response rates were assessed based on RECIST 1.1 criteria, and Kaplan–Meier statistics were used for progression-free survival (PFS) and overall survival (OS). Results: FLC tumors were characterized by low tumor mutational burden (TMB) and absent PD-L1 expression. We identified 19 patients who received ICIs, including 15 who received ICI therapy alone [programmed death receptor 1 (PD-1) inhibitor, +/− cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor]. Objective tumor responses were observed in 3/19 patients (15.8%), including 2/15 patients (13.3%) who received ICIs alone, all partial responses. Median PFS and OS were 5.5 and 26.0 months, respectively. Grade 3–4 immune related adverse events were observed in 4/19 (21.1%) patients. Conclusions: ICI therapy has modest clinical activity in FLC, and novel therapeutic combinations are needed

Rethinking the role of Research Ethics Committees in the light of Regulation (EU) No 536/2014 on clinical trials and the COVID‐19 pandemic

Research Ethics Committees (RECs)—or Institutional Review Boards (IRBs), as they are known in the US—were created about 50 years ago to independently assess the ethical acceptability of research projects involving human subjects, their fundamental role being the protection of the dignity and rights of research participants. In this paper we develop some critical reflections about the current situation of RECs. Our starting point is the definition of the role they should ideally play, a role that should necessarily include a collaborative approach and the focus on the ethics component of the review. This ideal is unfortunately quite far from reality: inadequacies in the functioning of RECs have been discussed for decades, along with reform proposals. Both in the US and in the European Union (EU), reforms that aim at the centralization of the review process were recently approved. Even though these reforms were needed, they nonetheless raise concerns. We focus on two such concerns, related in particular to Regulation (EU) No 536/2014: the risk of narrowing the scope of the ethics review and that of disregarding the local context. We argue that the COVID-19 pandemic paved the way for the transition towards the centralized model and that an analysis of its impact on the research review process could provide some interesting insights into possible shortcomings of this new model. We conclude by identifying three objectives that define the role of a REC, objectives that any reform should preserve

Efficacy and safety of immune checkpoint inhibitor rechallenge in individuals with hepatocellular carcinoma

Background & Aims: We investigated the efficacy and safety of immune checkpoint inhibitor (ICI) rechallenge in patients with hepatocellular carcinoma (HCC) who received ICI-based therapies in a previous systemic line. Methods: In this international, retrospective multicenter study, patients with HCC who received at least two lines of ICI-based therapies (ICI-1, ICI-2) at 14 institutions were eligible. The main outcomes included best overall response and treatment-related adverse events. Results: Of 994 ICI-treated patients screened, a total of 58 patients (male, n = 41; 71%) with a mean age of 65.0±9.0 years were included. Median systemic treatment lines of ICI-1 and ICI-2 were 1 (range, 1-4) and 3 (range, 2-9), respectively. ICI-based therapies used at ICI-1 and ICI-2 included ICI alone (ICI-1, n = 26, 45%; ICI-2, n = 4, 7%), dual ICI regimens (n = 1, 2%; n = 12, 21%), or ICI combined with targeted therapies/anti-VEGF (n = 31, 53%; n = 42, 72%). Most patients discontinued ICI-1 due to progression (n = 52, 90%). Objective response rate was 22% at ICI-1 and 26% at ICI-2. Responses at ICI-2 were also seen in patients who had progressive disease as best overall response at ICI-1 (n = 11/21; 52%). Median time-to-progression at ICI-1 and ICI-2 was 5.4 (95% CI 3.0-7.7) months and 5.2 (95% CI 3.3-7.0) months, respectively. Treatment-related adverse events of grade 3-4 at ICI-1 and ICI-2 were observed in 9 (16%) and 10 (17%) patients, respectively. Conclusions: ICI rechallenge was safe and resulted in a treatment benefit in a meaningful proportion of patients with HCC. These data provide a rationale for investigating ICI-based regimens in patients who progressed on first-line immunotherapy in prospective trials. Impact and implications: Therapeutic sequencing after first-line immune checkpoint inhibitor (ICI)-based therapy for advanced hepatocellular carcinoma (HCC) remains a challenge as no available second-line treatment options have been studied in immunotherapy-pretreated patients. Particularly, the role of ICI rechallenge in patients with HCC is unclear, as data from prospective trials are lacking. We investigated the efficacy and safety of ICI-based regimens in patients with HCC pretreated with immunotherapy in a retrospective, international, multicenter study. Our data provide the rationale for prospective trials investigating the role of ICI-based regimens in patients who have progressed on first-line immunotherapy

PBRM1 mutations might render a subtype of biliary tract cancers sensitive to drugs targeting the DNA damage repair system

Abstract Polybromo-1 (PBRM1) loss of function mutations are present in a fraction of biliary tract cancers (BTCs). PBRM1, a subunit of the PBAF chromatin-remodeling complex, is involved in DNA damage repair. Herein, we aimed to decipher the molecular landscape of PBRM1 mutated (mut) BTCs and to define potential translational aspects. Totally, 1848 BTC samples were analyzed using next-generation DNA-sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). siRNA-mediated knockdown of PBRM1 was performed in the BTC cell line EGI1 to assess the therapeutic vulnerabilities of ATR and PARP inhibitors in vitro. PBRM1 mutations were identified in 8.1% (n = 150) of BTCs and were more prevalent in intrahepatic BTCs (9.9%) compared to gallbladder cancers (6.0%) or extrahepatic BTCs (4.5%). Higher rates of co-mutations in chromatin-remodeling genes (e.g., ARID1A 31% vs. 16%) and DNA damage repair genes (e.g., ATRX 4.4% vs. 0.3%) were detected in PBRM1-mutated (mut) vs. PBRM1-wildtype (wt) BTCs. No difference in real-world overall survival was observed between PBRM1-mut and PBRM1-wt patients (HR 1.043, 95% CI 0.821–1.325, p = 0.731). In vitro, experiments suggested that PARP ± ATR inhibitors induce synthetic lethality in the PBRM1 knockdown BTC model. Our findings served as the scientific rationale for PARP inhibition in a heavily pretreated PBRM1-mut BTC patient, which induced disease control. This study represents the largest and most extensive molecular profiling study of PBRM1-mut BTCs, which in vitro sensitizes to DNA damage repair inhibiting compounds. Our findings might serve as a rationale for future testing of PARP/ATR inhibitors in PBRM1-mut BTCs