These authors contributed equally to this work Background: The reverse shoulder arthroplasty (RSA) may be a promising alternative for proximal humerus tumours because of good postoperative shoulder function. However, the conventional reverse shoulder prosthesis can not meet individual needs and RSA has been associated with a relatively high complication rate. Therefore, implant design and surgical reconstruction technique warrant further study. Methods: Between September 2015 and May 2018, 7 patients were treated via RSA after enbloc resection of the proximal humerus tumours. A 3D-printed guiding baseplate was used to assist the implant of the 3D-printed glenoid prosthesis; a personalized humerus prosthesis was used to reconstruct the proximal humerus. The functional outcomes were assessed by range of motion (ROM) of the shoulder joint, Musculoskeletal Tumour Society (MSTS) functional score, and Toronto Extremity Salvage Score (TESS). We also analyzed tumour recurrence, metastases, and complications associated with the reconstruction procedure. Results: All patients were observed for 14 to 36 months, with an average of 23.6 months. At the final follow-up, the mean MSTS score was 85.7% (range, 73.3-93.3%), and the mean TESS score was 90.0% (range, 84.1-95.9%). No instability, infection, scapular notching, loosening or fracture were observed in this series. One patient with GCT suffered from pulmonary metastasis, while one with osteosarcoma died because of pulmonary metastasis. Conclusion: The 3D-printed guiding baseplate facilitated the accurate implantation of the glenoid prosthesis. The RSA based on a 3D-printed glenoid prosthesis and a personalized custom-made humerus prosthesis significantly improved the shoulder function and decreased the complication rate. Further studies of a larger scale with longer follow-up are required to validate this technology.
Purpose: Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma (ICC). However, little is known about the intertumor heterogeneity (ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making. Experimental Design: We obtained 66 tumor samples from 16 patients with multifocal ICC and characterized the tumor and immune heterogeneity using whole-exome sequencing, bulk and single-cell RNA sequencing, methylation microarray, and multiplex immunostaining. Patients were divided into high- or low-ITH groups according to the median ITH index. Two independent cohorts were used to validate findings. Responses to anti-PD-1 therapy were assessed. Results: Multifocal ICC presented considerable intertumor genomic, transcriptional, and epigenomic heterogeneity within a patient in high ITH group. The immune profile among multiple tumors within a patient was relatively less heterogeneous in high- or low-ITH group, and consistent responses of multiple tumors to anti-PD-1 immunotherapy were observed. Unsupervised clustering of immune markers identified one low and one high immune subtype, with higher immune cell infiltration, closer tumor–immune cell interactions, and upregulated IFN-signature expression in high-immune subtype. Determining expression levels of CD8B and ICOS facilitated this immune classification and prediction of patient prognosis. Finally, promoter DNA methylation contributed to different immune profiles of two subtypes by regulating immune-gene expression. Conclusions: There is comprehensive heterogeneity in the genome, transcriptome, and epigenome of multifocal ICC. On the basis of the less heterogeneous immune profile of ICC, we suggest an immune classification that stratifies patients' prognosis and may support personalized immunotherapy.
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