Suchergebnisse

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) may occur after reconstructive or aesthetic breast surgery. Worldwide, approximately 1.7 million breast implant surgeries are performed each year. To date, over 500 cases of BIA-ALCL have been reported around the world, with 16 women having died. This review highlights the most important facts surrounding BIA-ALCL. There is no consensus regarding the true incidence rate of BIA-ALCL as it varies between countries, is probably significantly under-reported and is difficult to estimate due to the true number of breast prostheses used largely being unknown. BIA-ALCL develops in the breast mostly as a seroma surrounding the implant, but contained within the fibrous capsule, or more rarely as a solid mass that can become invasive infiltrating the chest wall and muscle, in some instances spreading to adjacent lymph nodes, in these cases having a far worse prognosis. The causation of BIA-ALCL remains to be established, but it has been proposed that chronic infection and/or implant toxins may be involved. What is clear is that complete capsulectomy is required for treatment of BIA-ALCL, which for early-stage disease leads to cure, whereas chemotherapy is needed for advanced-stage disease, whereby improved results have been reported with the use of brentuximab. A worldwide database for BIA-ALCL and implants should be supported by local governments.

Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status. ; This research is supported with funding from Children with Cancer UK (CWCUK; 16-209) awarded to S.D.T. and L.C.L., R.M.T. was supported by the CWCUK grant and L.C.L. was in receipt of a Cancer Research UK Cambridge Centre Paediatric Programme PhD studentship. N.P., L.J., O.M., I.G.F.A., L.K. and S.D.T. are supported by a European Union Horizon 2020 Marie Skłodowska–Curie Innovative Training Networks (ITN-ETN) Grant, Grant No.: 675712. N.A.P. was supported by ERASMUS+. We are grateful to AstraZeneca for providing us with AZD1208 and Inflection Biosciences for providing us with PIMi. We thank Isaia Barbieri for critical suggestions on the manuscript, BBSCR NIHR Cell phenotyping hub for flow cytometry expertise, the Bauer Core Facility at Harvard University for sequencing, and Liew Jun Mun and Stephen P. Ducray for technical assistance. Funding for the COG/ALSF Childhood Cancer Repository was provided by Alex's Lemonade Stand Foundation ; Sí