Cimetidine Attenuates Therapeutic Effect of Anti-PD-1 and Anti-PD-L1 and Modulates Tumor Microenvironment in Colon Cancer.

Histamine modulates immunity by binding to histamine receptor 2 (H2R). Cimetidine, an H2R antagonist that inhibits gastric acid secretion and treats gastrointestinal ulcers, interferes with histamine-mediated immunomodulation and may have anticancer activity. This study examined cimetidine's effect on the anticancer effect of anti-PD-L1 in colon cancer. The MTT assay, colony formation assay, and DNA histograms assessed cell viability, clonogenicity, and cell cycle distribution, respectively. Flow cytometry measured H2R and PD-L1 expression and estimated specific immune cell lineages. For the in vivo study, tumor cells were subcutaneously implanted into the right flank of BALB/c mice. Cimetidine had no significant effect on CT26 cell viability, clonogenicity, or cell cycle distribution. It also did not affect H2R and PD-L1 expression levels in CT26 cells. In vivo, anti-PD-1 and anti-PD-L1 suppressed CT26 tumor growth, whereas cimetidine showed mild antitumor activity. In the combined experiment, cimetidine significantly attenuated anti-PD-1 and anti-PD-L1' antitumor effects without major toxicity. In the tumor microenvironment, anti-PD-L1 increased CD3+ T, CD4+ T, and CD8+ T cells and M1 macrophages. Combined treatment with cimetidine reversed this. Cimetidine also reversed anti-PD-1 and anti-PD-L1's decrease in circulating and tumor-associated neutrophils. Cimetidine attenuated anti-PD-L1's antitumor effect and modulated the tumor microenvironment in colon cancer.

Survival Analysis of Allografting and Antiprotrusio Cage in Treating Massive Acetabular Bone Defects.

BACKGROUND: Massive acetabular bone defects reconstructed with allografting and antiprotrusio cage in revision hip arthroplasty is less reported in the literature. We here report a series of 84 antiprotrusio cages and analyze the risk factors associated with failure. METHODS: All instances of use of an antiprotrusio cage for massive acetabular defect (Paprosky type IIc, III, and pelvic discontinuity) between 2002 and 2017 in the authors' institute were reviewed after institutional review board's approval. Survival analyses based on clinical data, bone defect (Paprosky system), type of allograft, size of cage, fixation quality, and position of cage were performed. Failure was defined as cage loosening or breakage, poor hip function, or cage revision for any reason. RESULTS: A total of 84 cages in 77 patients (mean age, 62.9 years), with a mean follow-up period of 6.2 years, had a survival rate of 82.1%. Failure was noted in 15 hips, including mechanical failure in 8 hips, recurrent dislocation in 1 hip, poor hip function in 1 hip, and periprosthetic joint infection in 5 hips. Pelvic discontinuity, reconstruction with morselized allograft alone, and fewer than 4 fixation points to the host bone were associated with higher failure rates (hazard ratios, 4.02, 3.42, and 9.9, respectively). CONCLUSION: We found that an antiprotrusio cage combined with strut allografts, fixed securely to the host bone (>4 fixation points), are beneficial for the management of massive acetabular bone defects. However, pelvic discontinuity remains a challenge that warrants the further study of technical or prosthetic innovations, such as triflange implants, cup cage, and 3D-printed implants.