Pan-lysyl oxidase inhibition disrupts fibroinflammatory tumor stroma, rendering cholangiocarcinoma susceptible to chemotherapy.

BACKGROUND: Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1-4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA. METHODS: Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays. RESULTS: All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy. CONCLUSIONS: CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA.

Progression-Free Survival for Liver Transplant vs Alternative Therapy in Unresectable Colorectal Liver Metastasis.

This cohort study compares survival outcomes between patients with unresectable colorectal liver metastasis who received chemotherapy-based multimodal therapy and patients who underwent liver transplant.

Opioid Dependence After Lung Cancer Resection: Institutional Analysis of State Prescription Drug Database.

BACKGROUND: The national opioid epidemic is a public health crisis. Thoracic surgery has also been associated with high incidence of new persistent opioid use. Our purpose was to describe the incidence and predictors of opioid use after lung cancer resection. METHODS: Retrospective review of lung cancer resections from 2015 to 2018 was performed using the Ohio Automated Rx Reporting System. Opioid dosing was recorded as milligram morphine equivalents (MME). Patients were stratified by preoperative opioid use. Chronic preoperative opioid users (opioid dependent) filled > 120 days supply of opioid pain medication in the 12 months prior to surgery; intermittent opioid users filled < 120 days. Chronic postoperative opioid users continued monthly use after 180 days postoperatively. RESULTS: 137 patients underwent resection. 16.1% (n = 22) were opioid dependent preoperatively, 29.2% (n = 40) were intermittent opioid users, and 54.7% (n = 75) were opioid naïve. Opioid dependent patients had higher daily inpatient opioid use compared to intermittent users and opioid naïve (43[30.0-118.1] MME vs 17.9[3.5-48.8] MME vs 8.8[2.1-25.0] MME, p < 0.001). Twenty-six percent (n = 35) of all patients were opioid users beyond 180 days postoperatively. Variables associated with opioid use > 180 days were: chronic preoperative opioid use (OR 23.8, p < 0.01), daily inpatient opioid requirement (1.02, p < 0.01), and neoadjuvant chemotherapy (28.2, p < 0.01). CONCLUSIONS: A quarter of patients are opioid dependent after lung cancer resection. This is due to both preexisting and new persistent opioid use. Improved strategies are needed to prevent chronic pain and opioid dependence after lung cancer resection.