Search

Summary We report a case of metastatic pancreatic neuroendocrine carcinoma associated with paraneoplastic Cushing’s syndrome, successively treated with five lines of treatment (platin-etoposide, LV5FU2-dacarbazine, FOLFIRINOX, pembrolizumab, and paclitaxel) and anti-secretory treatment. Circulating-free DNA (cfDNA) was analysed at each morphological evaluation starting from the second-line treatment. cfDNA changes were well correlated with the disease course, and cfDNA may be used as a predictive marker and/or as an early marker of response. In addition, the absolute count of atypical cells was elevated upon disease progression. Learning points cfDNA changes were well correlated with the Cushing’s syndrome course and with the tumour burden changes assessed by laboratory markers and by RECIST criteria. cfDNA analysis was used to determine the pharmacogenetic patterns of the present patient. An elevated number of atypical circulating cells was noticed upon disease progression.

BACKGROUND The treatment of metastatic colorectal cancer (mCRC) relies of chemotherapy. The efficacy of the standard FOLFIRI-therapy could be improved by a modification of the regimen by splitting the dose of irinotecan on day 1 and day 3 in the FOLFIRI3 regimen. AIM To determine safety and efficacy of FOLFIRI3 regimen. METHODS This is a monocentric retrospective study evaluating the efficacy and safety of the FOLFIRI3 regimen given alone or in combination with bevacizumab or aflibercept in patients with previously treated mCRC. RESULTS One hundred and fifty-three consecutive patients were included (18 treated with FOLFIRI3, 99 with FOLFIRI3 plus bevacizumab and 36 with FOLFIRI3 plus aflibercept). The overall response rate (ORR) and disease control rate were 51% and 62%, respectively. Similar ORRs were observed in all 3 cohorts. Median progression-free survival (PFS) and overall survival (OS) were 3.9 mo (95%CI: 3.2-4.9) and 9.4 mo (95%CI: 6.6-12), respectively. Median PFS and OS values were improved in the FOLFIRI3 plus aflibercept group. The most common grade 3-4 adverse events were diarrhoea (21.6%) and neutropenia (11.8%), and these toxicities were more frequent in the FOLFIRI3 plus aflibercept group. According to the multivariate Cox proportional model, previous surgery of metastasis and aflibercept were associated with outcomes. CONCLUSION The modification of the FOLFIRI regimen impacted treatment response of mCRC patients. The addition of an antiangiogenic agent, in particular aflibercept, enhanced the clinical benefit and improved survival.

Introduction: Gastroenteropancreatic neuroendocrine carcinomas (GEPNEC) are characterized by a heterogeneous molecular profile and a poor prognosis. Circulating tumour DNA (ctDNA) analysis may be useful for NEC management. This study aimed at describing ctDNA mutations, to assess their predictive value for response to chemotherapies, and their change according to disease progression. Methods: The CIRCAN-NEC study included patients with GEPNEC or NEC from an unknown primary, scheduled to begin first- or second-line chemotherapy. Blood samples were collected prior to chemotherapy initiation, at first evaluation, and during disease progression. ctDNA was sequenced by next-generation sequencing (NGS). Molecular response was defined as a decrease of at least 30% of the mutant allele fraction. Results: All 24 patients included received platinum-etoposide first-line chemotherapy; 19 received a FOLFIRI-based post-first-line regimen. Twenty-two patients had at least one driver mutation: TP53 (n = 21), RB1 (n = 2), KRAS (n = 4), and BRAF (n = 3). Ten (42%) had an “adenocarcinoma-like” profile. Five of 6 patients with matching ctDNA/tissue NGS harboured at least one concordant mutation (44% concordance at the gene level). The concordance rate between ctDNA mutation/immunohistochemistry profile was 64% (7/11) for TP53/p53+ and 14% (1/7) for RB1/pRb−. In this pilot study including few patients by subgroups, patients with KRAS (HR = 3.60, 95% CI [1.06–12.04]) and BRAF (HR = 4.25, 95% CI [1.11–16.40]) mutations had shorter progression-free survival (PFS) under platinum-etoposide, while the 2 patients with RB1 mutations had shorter PFS under FOLFIRI-based chemotherapy. Twenty-eight periods of treatment were assessed: 10 patients had a molecular response (7/10 had a morphological response), which was associated with longer PFS (HR = 0.37, 95% CI [0.15; 0.91]). Conclusion: This pilot study shows a high sensitivity of ctDNA assessment, which is encouraging for the future management of GEPNEC (tumour molecular diagnosis and evaluation of disease progression).

PurposeLiterature encompassing sustainable leadership and developing leaders sustainably are still in infancy (Lambert, 2011). Nevertheless indications identify leadership as a vital cog in achieving sustainable organisations. Sustainable leadership can allow a fast, resilient response which is competitive and appealing to all stakeholders (Avery and Bergsteiner, 2011a, b). Arguably, organisations’ need to stop considering leadership as a control function (Casserley and Critchley, 2010; Crews, 2010) and instead focus on dialogue and mutual-interdependency between leaders and their followers (Barr and Dowding, 2012). The purpose of this paper is to explore and analyse the concept of sustainable leadership to present a conceptual framework surrounding sustainable leadership.Design/methodology/approachThis conceptual paper will review the existing frameworks of sustainable leadership and present a conceptualisation of the frameworks. This conceptualisation synthesises frameworks and literature surrounding the concept of sustainable leadership which involves work from Casserley and Critchley (2010), Avery and Bergsteiner (2011a, b), Hargreaves and Fink (2006), Davies (2007) and Lambert (2011). Seminal themes from the synthesised frameworks are presented in order to attempt to unify the conceptualisation of sustainable leadership.FindingsWithin leadership literature, stakeholder approaches (Groves and LaRocca, 2011; Avery and Bergsteiner, 2011a); discourses underlining the importance of relationship between leaders and followers (Barr and Dowding, 2012); and discussions about the need to develop reflexive and participative leadership models (Kopp and Martinuzzi, 2013) have become prominent. Sustainable leadership embraces all of these new components. The concept advocates organisations should shift emphasis from a traditional singular focus on finances, to a view that organisations are contributors to wider environmental and social influences (Crews, 2010; Avery and Bergsteiner, 2011a).Originality/valueThis paper explores the theoretical frameworks which surround sustainable leadership and will synthesise and present commonly referenced facets of the concept within the internal and external factors influencing sustainable leadership.