External validation of the SORG 90-day and 1-year machine learning algorithms for survival in spinal metastatic disease.

BACKGROUND CONTEXT: Preoperative survival estimation in spinal metastatic disease helps determine the appropriateness of invasive management. The SORG ML 90-day and 1-year machine learning algorithms for survival in spinal metastatic disease were previously developed in a single institutional sample but remain to be externally validated. PURPOSE: The purpose of this study was to externally validate these algorithms in an independent population from another institution. STUDY DESIGN/SETTING: Retrospective study at a large, tertiary care center. PATIENT SAMPLE: Patients 18 years or older who underwent surgery between 2003 and 2016. OUTCOME MEASURES: Ninety-day and 1-year mortality. METHODS: Baseline characteristics of the validation cohort were compared to the developmental cohort for the SORG ML algorithms. Discrimination (c-statistic and receiver operating curve), calibration (calibration slope, intercept, calibration plot, and observed proportions by predicted risk groups), overall performance (Brier score), and decision curve analysis were used to assess the performance of the SORG ML algorithms in the validation cohort. RESULTS: Overall, 176 patients underwent surgery for spinal metastatic disease, of which 44 (22.7%) experienced 90-day mortality and 99 (56.2%) experienced 1-year mortality. The validation cohort differed significantly from the developmental cohort on primary tumor histology, metastatic tumor burden, previous systemic therapy, overall comorbidity burden, and preoperative laboratory characteristics. Despite these differences, the SORG ML algorithms generalized well to the validation cohort on discrimination (c-statistic 0.75-0.81 for 90-day mortality and 0.77-0.78 for 1-year mortality), calibration, Brier score, and decision curve analysis. CONCLUSION AND RELEVANCE: Initial results from external validation of the SORG ML 90-day and 1-year algorithms for survival prediction in spinal metastatic disease suggest potential utility of these digital decision aids in clinical practice. Further studies are needed to validate or refute these algorithms in large patient samples from prospective, international, multi-institutional trials.

Low-dose valproic acid with low-dose gemcitabine augments MHC class I-related chain A/B expression without inducing the release of soluble MHC class I-related chain A/B.

To improve natural killer group 2 member D (NKG2D)-dependent cytotoxicity, the inhibition of cleavage and release of major histocompatibility complex class 1-related chain (MIC) molecules from the tumor surface are required. Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, is able to induce cell-surface MICA/B on tumor cells. In the present study, the ability of VPA and gemcitabine (GEM) to upregulate MICA/B in pancreatic cancer cells was investigated, resulting in the inhibition of cleavage and release of MIC molecules from the tumor surface. Flow cytometry was used to quantify MICA/B expression in six human pancreatic cancer lines. Functional cytotoxic activity of γδT cells against pancreatic cancer cells treated with VPA and GEM was determined using cytotoxicity assays. At low doses of VPA (0.7 mM) and GEM (0.001 µM), which did not induce tumor growth alterations, the agents individually increased cell-surface MICA/B expression in MICA/B-positive cell lines, but not in the MICA/B-negative cell line. Furthermore, the combination of VPA and GEM synergistically induced cell-surface MICA/B expression. In MICA/B-positive cell lines, the increase in MICA/B expression was dependent on VPA concentration. The combination of low-dose VPA and GEM enhanced the susceptibility of the PANC-1 cell line to γδT cell-mediated tumor cell lysis. It was observed that soluble MIC was released from PANC-1 in the culture supernatant following treatment with GEM. However, the combination of low-dose VPA with low-dose GEM increased MICA/B expression without inducing soluble MIC, resulting in enhanced tumor cell lysis. The results of the present study suggest that the combined administration of low-dose VPA with low-dose GEM has the potential to enhance the therapeutic effects of immunotherapy in pancreatic cancer. Furthermore, it is proposed that the combination acts, in part, by upregulating MICA/B and prevents soluble MIC from being released.

Low-dose gemcitabine induces major histocompatibility complex class I-related chain A/B expression and enhances an antitumor innate immune response in pancreatic cancer.

We investigated the effect of gemcitabine (GEM), a key drug for pancreatic cancer treatment, on the expression of cell surface MICA/B in pancreatic cancer cells and resulting cytotoxicity of γδ T cells. We assessed the effect of GEM on the upregulation of cell surface MICA/B expression by flow cytometry, utilizing six pancreatic cancer cell lines. MICA and CD16 expressions from resected pancreatic cancer patient specimens, which received neoadjuvant chemotherapy (NAC) with GEM, were analyzed by immunohistochemistry. GEM could increase MICA/B expression on cell surface in pancreatic cancer cell lines (in 2 of 6 cell lines). This effect was most effectively at concentration not affecting cell growth of GEM (0.001 µM), because MICA/B negative population was appeared at concentration at cytostatic and cytotoxic effect to cell growth (0.1 and 10 µM). The cytotoxic activity of γδ T cells against PANC-1 was detected and functions through interactions between NKG2D and MICA/B. However, the enhancement of NKG2D-dependent cytotoxicity with increased MICA/B expression, by GEM treatment, was not observed. In addition, soluble MIC molecules were released from pancreatic cancer cell lines in culture supernatant with GEM treatment. Immunohistochemical staining demonstrated that MICA expression in tumor cells and CD16 positive cells surrounding tumors were significantly higher in the NAC group compared to that of the control group. There was a significant correlation between NAC and MICA expression, as well as NAC and CD16 positive cell expression. The present results indicate that low-dose GEM-induced MICA/B expression enhances innate immune function rather than cytotoxicity in pancreatic cancer. In addition, our result suggests that the inhibition of cleavage and release of MIC molecules from the tumor surface could potentially improve NKG2D-dependent cytotoxicity.