Living donor liver transplantation (LDLT) is a treatment option for select patients with unresectable colorectal liver metastasis (uCRLM). We describe our center's experience of patient selection, insurance approval, and outcomes after LDLT after first referral in March 2019. Of the 206 evaluated patients, twenty-three underwent LDLT. We found that patients who were referred earlier in their oncologic course were more likely to be eligible for transplantation. After completion of the Rochester Protocol for LDLT eligibility, recipients had a median delay of care of 10 days (IQR 0-36) related to insurance appeal, with six patients (30%) having a delay longer than 30 days. LDLT recipients had an overall survival proportion of 100% and 91% at 1, and 3 years; and a recurrence-free survival proportion of 100% and 40%, at 1 and 3 years, respectively. All donors underwent right hepatectomy, of which only one donor had a Clavien-Dindo IIIa complication and readmission. There was no donor mortality. We assert that multidisciplinary care and strict patient selection through the Rochester Protocol were paramount to our center's success. In the appropriately selected patient, LDLT for uCRLM may be justified, and patients should be referred to transplant oncology centers for evaluation.

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. Export

Background: Histotripsy is a novel, non-invasive, focused ultrasound therapy that mechanically disrupts targeted tissues through cavitation, offering a precise and non-thermal alternative to conventional locoregional therapies with preservation of vascular and biliary structures. There are limited reports on the early use of histotripsy in primary and secondary liver tumors. Materials and Methods: Patients undergoing histotripsy for the treatment of primary and secondary liver tumors were retrospectively analyzed. The response to histotripsy was evaluated by assessing computed tomography findings in the first 3 months post-procedure period. Results: Twenty-seven patients were included in the study. Nine (33%) received histotripsy with downstaging or bridging intent, whereas 18 (67%) received histotripsy as part of a palliative treatment approach. Among patients with downstaging or bridging intent, seven of eight (87.5%) evaluable patients showed no lesion growth ≤3 months post-procedure. In palliative patients, growth remained controlled during the first 3 months in three of nine (33%) cases, while increasing in the remaining six (67%). Interestingly, tumoral size decreased in tumors not targeted by histotripsy in four patients, including one palliative patient who was not responding to multiple prior treatments. After histotripsy, three patients were successfully downstaged for liver resection and five were eligible for liver transplantation. Conclusion: Histotripsy presents great potential for the treatment of liver tumors, achieving high rates of short-term local disease control while offering vascular and biliary protection advantages, unlike thermal methods. Further work is required to understand a possible response away from the target. Histotripsy, in combination with systemic therapies, could aid in bridging or downstaging patients with advanced disease to achieve surgical resection or transplantation.

Transplant oncology is a rapidly evolving discipline that incorporates oncology, transplant medicine, and surgery. As the field continues to grow, there remains an opportunity to enhance patient selection, detect recurrence after liver transplantation, and optimize treatment after recurrence. Liquid biopsies are an emerging resource to improve patient care. In this review, we evaluate the most recent available data on circulating tumor DNA and how it pertains to primary and metastatic hepatobiliary malignancies. We discuss the opportunities and current limitations to clinical practice, especially in relation to total hepatectomy and liver transplantation. We conclude that as both transplant oncology and our understanding of circulating tumor DNA continue to evolve, rigorous, prospective study is required to integrate this technology into a clinical paradigm.

We report a case of a 55-year-old male with intrahepatic cholangiocarcinoma (iCCA) who underwent living donor liver transplantation (LDLT) after complete radiographic response on second-line pemigatinib. LDLT for iCCA is controversial, but recent reports have cited the potential benefit for patients with unresectable disease, especially those with disease stability after 6 months of systemic therapy. Concomitantly, genomic profiling has identified potentially treatable oncologic targets in iCCA. This patient's tumor genomic profile revealed an FGFR2 rearrangement and was treated with pemigatinib, a competitive inhibitor for fibroblast growth factor receptors 1, 2, and 3. This resulted in a complete radiographic and metabolic response after 2 months of treatment. He was considered eligible for LDLT after 6 months of observation on treatment with a sustained response. He underwent an uncomplicated LDLT (including an uncomplicated donor surgery) and at a 1-year follow-up is without evidence of disease recurrence. We believe this is the first report of LDLT for this indication.