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Trastuzumab in combination with platinum-based chemotherapy is the standard first-line regimen in HER2-positive advanced gastric cancer. However, there are very few data concerning efficacy of continuing trastuzumab beyond first-line progression.
This retrospective multicenter study included all consecutive patients with HER2-positive advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma who received a second-line of chemotherapy with or without trastuzumab after progression on platinum-based chemotherapy plus trastuzumab. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method and compared using log-rank test. The prognostic variables with P values ≤ 0.05 in univariate analysis were eligible for the Cox multivariable regression model.
From May 2010 to December 2015, 104 patients were included (median age, 60.8 years; male, 78.8%; ECOG performance status [PS] 0-1, 71.2%). The continuation (n=39) versus discontinuation (n=65) of trastuzumab beyond progression was significantly associated with an improvement of median PFS (4.4 versus 2.3 months; P=0.002) and OS (12.6 versus 6.1 months; P=0.001. In the multivariate analysis including the ECOG PS, number of metastatic sites and measurable disease, the continuation of trastuzumab beyond progression remained significantly associated with longer PFS (HR, 0.56; 95% CI, 0.35-0.89; P=0.01) and OS (HR, 0.47; 95% CI, 0.28-0.79; P=0.004).
This study suggests that continuation of trastuzumab beyond progression has clinical benefit in patients with HER2-positive advanced gastric cancer. These results deserve a prospective randomized validation.
advanced gastric cancer, trastuzumab, HER2, second-line chemotherapy, beyond progression
Trastuzumab beyond progression in patients with HER2-positive advanced gastric adenocarcinoma: a multicenter AGEO study
Juliette Palle,1 David Tougeron,2 Astrid Pozet,3 Emilie Soularue,4 Pascal Artru,5 Florence Leroy,6 Olivier Dubreuil,7 Matthieu Sarabi,8 Nicolas Williet,9 Sylvain Manfredi,10 Jerome Martin-Babau,11 Christine Rebischung,12 Meher Ben Abdelghani,13 Ludovic Evesque,14 Johann Dreanic,15 Vincent Hautefeuille,16 Samy Louafi,17 David Sefrioui,18 Francesco Savinelli,19 May Mabro,20 Benoit Rousseau,21 Cedric Lecaille,22 Olivier Bouche,23 Christophe Louvet,24 Thierry Lecomte,25 Franck Bonnetain,3 Julien Taieb,1,26 and Aziz Zaanan1,26
2017 Nov 24;
Oligodendrocytes produce myelin for rapid transmission and saltatory conduction of action potentials in the vertebrate central nervous system. Activation of the myelination program requires several transcription factors including Sox10, Olig2, and Nkx2.2. Functional interactions among them are poorly understood and important components of the regulatory network are still unknown. Here, we identify Nfat proteins as Sox10 targets and regulators of oligodendroglial differentiation in rodents and humans. Overall levels and nuclear fraction increase during differentiation. Inhibition of Nfat activity impedes oligodendrocyte differentiation in vitro and in vivo. On a molecular level, Nfat proteins cooperate with Sox10 to relieve reciprocal repression of Olig2 and Nkx2.2 as precondition for oligodendroglial differentiation and myelination. As Nfat activity depends on calcium-dependent activation of calcineurin signaling, regulatory network and oligodendroglial differentiation become sensitive to calcium signals. NFAT proteins are also detected in human oligodendrocytes, downregulated in active multiple sclerosis lesions and thus likely relevant in demyelinating disease.
Nfat/calcineurin signaling promotes oligodendrocyte differentiation and myelination by transcription factor network tuning
Matthias Weider,#1 Laura Julia Starost,#2,3 Katharina Groll,#2 Melanie Kuspert,1 Elisabeth Sock,1 Miriam Wedel,1 Franziska Frob,1 Christian Schmitt,1 Tina Baroti,1 Anna C. Hartwig,1 Simone Hillgartner,1 Sandra Piefke,1 Tanja Fadler,1 Marc Ehrlich,2,3 Corinna Ehlert,2 Martin Stehling,3 Stefanie Albrecht,2 Ammar Jabali,2 Hans R. Scholer,3 Jurgen Winkler,4 Tanja Kuhlmann,corresponding author#2 and Michael Wegnercorresponding author#1
There are few quantitative studies on palliative care provision to Indigenous Australians, a population known to experience distinctive barriers to quality healthcare and to have poorer health outcomes than other Australians.
To investigate equity of specialist palliative care service provision through characterising and comparing Indigenous and non-Indigenous patients at entry to care.
Using data (01/01/2010-30/06/2015) from all services participating in the multi-jurisdictional Palliative Care Outcomes Collaboration, Indigenous and non-Indigenous patients entering palliative care were compared on proportions vis-à-vis those expected from national statutory datasets, demographic characteristics, and entry-to-care status across fourteen ‘problem’ domains (e.g., pain, functional impairment) after matching by age, sex, and specific diagnosis.
Of 140,267 patients, 1,465 (1.0%, much lower than expected from statutory data) were Indigenous, 133,987 (95.5%) non-Indigenous, and 4,905 (3.5%) had a missing identifier. The proportion of patients with a missing identifier diminished markedly over the study period, without a corresponding increase in the proportion identified as Indigenous. Indigenous compared with non-Indigenous patients were younger (mean 62.8 versus 73.0 years, p<0.001), a higher proportion were female (51.5% versus 46.3%; p<0.001) or resided outside major cities (44.2% versus 21.5%, p<0.001). Across all domains, Indigenous compared with matched non-Indigenous patients had lower or equal risk of status requiring prompt intervention. Conclusions Indigenous patients (especially those residing outside major cities) are substantially under-represented in care by services participating in the nationwide specialist palliative care Collaboration, likely reflecting widespread access barriers. However, the similarity of status indicators among Indigenous and non-Indigenous patients at entry to care suggests that Indigenous patients who are able to access these services do not disproportionately experience clinically important impediments to care initiation.
Indigenous compared with non-Indigenous Australian patients at entry to specialist palliative care: Cross-sectional findings from a multi-jurisdictional dataset
John A. Woods, Formal analysis, Methodology, Writing - original draft,#1,* Jade C. Newton, Formal analysis, Methodology, Writing - original draft,#2,3 Sandra C. Thompson, Conceptualization, Supervision, Writing - review & editing,1 Eva Malacova, Supervision, Writing - review & editing,4,5,¤ Hanh T. Ngo, Methodology, Writing - review & editing,6,7 Judith M. Katzenellenbogen, Methodology, Writing - review & editing,5,8 Kevin Murray, Methodology, Writing - review & editing,5 Shaouli Shahid, Supervision, Writing - review & editing,9 and Claire E. Johnson, Conceptualization, Supervision, Writing - review & editing2,10,11 Rosemary Frey, Editor