Gemcitabine with Cisplatin Versus Hepatic Arterial Infusion Pump Chemotherapy for Liver-Confined Unresectable Intrahepatic Cholangiocarcinoma

Background: A post-hoc analysis of ABC trials included 34 patients with liver-confined unresectable intrahepatic cholangiocarcinoma (iCCA) who received systemic chemotherapy with gemcitabine and cisplatin (gem-cis). The median overall survival (OS) was 16.7 months and the 3-year OS was 2.8%. The aim of this study was to compare patients treated with systemic gem-cis versus hepatic arterial infusion pump (HAIP) chemotherapy for liver-confined unresectable iCCA. Methods: We retrospectively collected consecutive patients with liver-confined unresectable iCCA who received gem-cis in two centers in the Netherlands to compare with consecutive patients who received HAIP chemotherapy with or without systemic chemotherapy in Memorial Sloan Kettering Cancer Center. Results: In total, 268 patients with liver-confined unresectable iCCA were included; 76 received gem-cis and 192 received HAIP chemotherapy. In the gem-cis group 42 patients (55.3%) had multifocal disease compared with 141 patients (73.4%) in the HAIP group (p = 0.023). Median OS for gem-cis was 11.8 months versus 27.7 months for HAIP chemotherapy (p &lt; 0.001). OS at 3 years was 3.5% (95% confidence interval [CI] 0.0–13.6%) in the gem-cis group versus 34.3% (95% CI 28.1–41.8%) in the HAIP chemotherapy group. After adjusting for male gender, performance status, baseline hepatobiliary disease, and multifocal disease, the hazard ratio (HR) for HAIP chemotherapy was 0.27 (95% CI 0.19–0.39). Conclusions: This study confirmed the results from the ABC trials that survival beyond 3 years is rare for patients with liver-confined unresectable iCCA treated with palliative gem-cis alone. With HAIP chemotherapy, one in three patients was alive at 3 years.</p

Hepatic Arterial Infusion Pump Chemotherapy for Unresectable Intrahepatic Cholangiocarcinoma: A Systematic Review and Meta-Analysis

Background: Patients with unresectable intrahepatic cholangiocarcinoma (iCCA) have poor survival. This systematic review describes the survival outcomes of hepatic arterial infusion pump (HAIP) chemotherapy with floxuridine for patients with unresectable iCCA. Patients and Methods: A literature search was conducted using the electronic databases PubMed, Medline (Ovid), Embase, Web of Science, Google Scholar, and Cochrane to find studies that reported data on the survival of patients with unresectable iCCA treated with HAIP chemotherapy using floxuridine. The quality of the studies was assessed using the Newcastle–Ottawa quality assessment Scale (NOS). Overall survival (OS) was the primary outcome measure, and progression-free survival (PFS), response rates, resection rates, and toxicity were defined as secondary outcome measures. Results: After removing duplicates, 661 publications were assessed, of which nine studies, representing a total of 478 patients, met the inclusion criteria. Three out of nine studies were phase II clinical trials, one study was a prospective dose-escalation study, and the remaining five studies were retrospective cohort studies. After accounting for overlapping cohorts, 154 unique patients were included for pooled analysis. The weighted median OS of patients with unresectable iCCA treated with HAIP chemotherapy with floxuridine was 29.0 months (range 25.0–39 months). The pooled 1-, 2-, 3-, and 5-year OS were 86.4, 55.5, 39.5, and 9.7%, respectively. Conclusion: HAIP chemotherapy with floxuridine for patients with unresectable iCCA was associated with a 3-year OS of 39.5%, which is favorable compared with systemic chemotherapy for which no 3-year survivors were reported in the Advanced Biliary Cancer (ABC) trials

ASO Visual Abstract: Hepatic Arterial Infusion Pump Chemotherapy for Unresectable Intrahepatic Cholangiocarcinoma - A Systematic Review and Meta-analysis

Hepatic arterial infusion pump (HAIP) chemotherapy with floxuridine has been explored as a means to control cancer in the liver. In this systematic review (https://doi.org/10.1245/ s10434-022-11439-x), 478 patients with unresectable intrahepatic cholangiocarcinoma (iCCA) were identified from nine studies; survival outcomes of 154 patients were used in the meta-analysis. HAIP chemotherapy with floxuridine for patients with unresectable iCCA was associated with a pooled 3-year overall survival (OS) of 39.5% (95% confidence interval (CI) 31.5–47.4%) and a weighted median OS of 29.0 months (range 25.0–39 months)

Systemic exposure of floxuridine after hepatic arterial infusion pump chemotherapy with floxuridine in patients with resected colorectal liver metastases

Background: Floxuridine’s high hepatic extraction ratio and short elimination half-life allows maximum liver exposure with minimal systemic side-effects. This study attempts to quantify the systemic exposure of floxuridine. Methods: Patients undergoing continuous hepatic arterial infusion pump (HAIP) floxuridine after resection of colorectal liver metastases (CRLM) in two centres underwent six cycles of floxuridine at start dose 0.12 mg/kg/day. No concomitant systemic chemotherapy was administered. Peripheral venous blood samples were drawn during the first two cycles: pre-dose (only in the second cycle), 30 min, 1 h, 2 h, 7 h, and 15 days after floxuridine infusion. Foxuridine concentration in the residual pump reservoir was measured on day 15 of both cycles. A floxuridine assay with a lower boundary of detection of 0.250 ng/mL was developed. Results: 265 blood samples were collected in the 25 patient included in this study. Floxuridine was mostly measurable at day 7 and day 15 (86 % and 88 % of patients respectively). The median dose corrected concentrations were 0.607 ng/mL [IQR: 0.472–0.747] for cycle 1 day 7, 0.579 ng/mL [IQR: 0.470–0.693] for cycle 1 day 15, 0.646 ng/mL [IQR: 0.463–0.8546] for cycle 2 day 7, and 0.534 ng/mL [IQR: 0.4257–0.7075] for cycle 2 day 15. One patient had remarkably high floxuridine concentrations reaching up to 44 ng/mL during the second cycle, without a clear explanation.The floxuridine concentration in the pump decreased by 14.7 % (range 0.5 %−37.8 %) over a period of 15 days (n = 18). Conclusion: Overall, negligible systemic concentrations of floxuridine were detected. However, remarkably increased levels were detected in one patient. Floxuridine concentration in the pump decreases over time

IRAK-M Expression Limits Dendritic Cell Activation and Proinflammatory Cytokine Production in Response to <i>Helicobacter pylori</i>

<div><p><i>Helicobacter pylori</i> (<i>H. pylori</i>) infects the gastric mucosa and persists for the life of the host. Bacterial persistence may be due to the induction of regulatory T cells (T_regs) whichmay have protective effects against other diseases such as asthma. It has been shown that <i>H. pylori</i> modulates the T cell response through dendritic cell reprogramming but the molecular pathways involved are relatively unknown. The goal of this study was to identify critical elements of dendritic cell (DC) activation and evaluate potential influence on immune activation. Microarray analysis was used to demonstrate limited gene expression changes in <i>H. pylori</i> stimulated bone marrow derived DCs (BMDCs) compared to the BMDCs stimulated with E. coli. IRAK-M, a negative regulator of TLR signaling, was upregulated and we selectedit for investigation of its role in modulating the DC and T cell responses. IRAK-M^−/− and wild type BMDC were compared for their response to <i>H. pylori</i>. Cells lacking IRAK-M produced significantly greater amounts of proinflammatory MIP-2 and reduced amounts of immunomodulatory IL-10 than wild type BMDC. IRAK-M^−/− cells also demonstrated increased MHC II expression upon activation. However, IRAK-M^−/− BMDCs were comparable to wild type BMDCs in inducing T-helper 17 (T_H17) and T_reg responses as demonstrated in vitro using BMDC CD4+ T cells co-culture assays,and in vivo though the adoptive transfer of CD4⁺ FoxP3-GFP T cells into <i>H. pylori</i> infected IRAK-M^−/− mice. These results suggest that <i>H. pylori</i> infection leads to the upregulation of anti-inflammatory molecules like IRAK-M and that IRAK-M has a direct impact on innate functions in DCs such as cytokine and costimulation molecule upregulation but may not affect T cell skewing.</p></div