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.

Transplantation in the Pandemic Era: Perspectives on the Utilization of COVID-19 Positive Organs.

BACKGROUND: At early stages of the pandemic, most organ procurements organizations considered COVID-19 infected donors to be ineligible for organ donation. The aim of this survey is to describe the current practices of the utilization of COVID-19 positive organs donors among American Society of Transplant Surgeons (ASTS) members. METHODS: An anonymous 40-question redcap survey was emailed to ASTS members from June to August 2022. RESULTS: One hundred forty-nine surveys from 10 countries were included for analysis. The majority of the responders were men (66.7%) from North America (95%) and identified as transplant surgeons (68.5%). Most work at academic institutions (76.5%). Almost all responders (94%) were willing to accept an organ from a donor with a history of COVID-19 who tested negative at the time of donation, however, there was no consensus on the length of time after the disease was resolved. Approximately 70% indicated they accept organs from asymptomatic donors with active disease. Only 32 responders indicated they would accept an organ from an individual with a history of "severe" COVID-19 infection and less than one third of the responders would accept an organ from a donor who died from COVID-19 infection. Interestingly, 80% indicated they have protocols at their institution to guide the acceptance of such organs. DISCUSSION: Despite new evidence that the transmission of COVID-19 in non-lung organs is extremely rare, the results of this survey suggest significant heterogeneity in practice and perceptions of the use of COVID-19 positive organs across international centers. We suggest that the implementation of a standardized protocol is of paramount importance to continue safe transplant activity.

Harmonizing Definitions and Perspectives in Extreme Liver Surgery: A Delphi Experts Consensus.

OBJECTIVE: To propose to our community a common language about extreme liver surgery. BACKGROUND: The lack of a clear definition of extreme liver surgery prevents convincing comparisons of results among centers. METHODS: We used a two-round Delphi methodology to quantify consensus among liver surgery experts. For inclusion in the final recommendations, we established a consensus when the positive responses (agree and totally agree) exceeded 70%. The study steering group summarized and reported the recommendations. In general, a five-point Likert scale with a neutral central value was used, and in a few cases multiple choices. Results are displayed as numbers and percentages. RESULTS: A two-round Delphi study was completed by 38 expert surgeons in complex hepatobiliary surgery. The surgeon´s median age was 58 years old (52-63) and the median years of experience was 25 years (20-31). For the proposed definitions of total vascular occlusion, hepatic flow occlusion and inferior vein occlusion, the degree of agreement was 97%, 81% and 84%, respectively. In situ approach (64%) was the preferred, followed by ante situ (22%) and ex situ (14%). Autologous or cadaveric graft for hepatic artery or hepatic vein repair were the most recommended (89%). The use of veno-venous bypass or portocaval shunt revealed the divergence depending on the case. Overall, 75% of the experts agreed with the proposed definition for extreme liver surgery. CONCLUSION: Obtaining a consensus on the definition of extreme liver surgery is essential to guarantee the correct management of patients with highly complex hepatobiliary oncological disease. The management of candidates for extreme liver surgery involves comprehensive care ranging from adequate patient selection to the appropriate surgical strategy.

Overview of Current Hepatocellular Carcinoma Staging Systems: Is There an Optimal System?

Multiple hepatocellular carcinoma (HCC) staging systems have been proposed and used clinically over time. These may consider clinical, pathological, radiological, or treatment response factors, depending on the model. Given the heterogeneity of HCC treatment in its different stages and the validation of the systems in different populations, they are not universal. Likewise, the improvement in diagnostic tools, as well as novel therapeutic alternatives, have made these models more complex. Despite this, some have been modified over time in line with advances in the field, and although there is no universally accepted one, each has its usefulness, strengths, and weaknesses.