Liver hypertrophy induced by partial portal vein occlusion (PVL) is accelerated by adding simultaneous parenchymal transection ("ALPPS procedure"). This preclinical experimental study in pigs tests the hypothesis that simultaneous ligation of portal and hepatic veins of the liver also accelerates regeneration by abrogation of porto-portal collaterals without need for operative transection. A pig model of portal vein occlusion was compared with the novel model of simultaneous portal and hepatic vein occlusion, where major hepatic veins draining the portal vein-deprived lobe were identified with intraoperative ultrasonography and ligated using pledgeted transparenchymal sutures. Kinetic growth was compared, and the portal vein system was then studied after 7 days using epoxy casts of the portal circulation. Portal vein flow and portal pressure were measured, and Ki-67 staining was used to evaluate the proliferative response. Pigs were randomly assigned to portal vein occlusion (n = 8) or simultaneous portal and hepatic vein occlusion (n = 6). Simultaneous portal and hepatic vein occlusion was well tolerated and led to mild cytolysis, with no necrosis in the outflow vein-deprived liver sectors. The portal vein-supplied sector increased by 90 ± 22% (mean ± standard deviation) after simultaneous portal and hepatic vein occlusion compared with 29 ± 18% after PVL (P < .001). Collaterals to the deportalized liver developed after 7 days in both procedures but were markedly reduced in simultaneous portal and hepatic vein occlusion. Ki-67 staining at 7 days was comparable. This study in pigs found that simultaneous portal and hepatic vein occlusion led to rapid hypertrophy without necrosis of the deportalized liver. The findings suggest that the use of simultaneous portal and hepatic vein occlusion accelerates liver hypertrophy for extended liver resections and should be evaluated further.

Major liver resection is often required for complete clearance of colorectal liver metastases (CRLM). Patients with insufficient future liver remnant (FLR) volume/function are at high risk of post-hepatectomy liver failure (PHLF) and require FLR hypertrophy-inducing procedures to enable safe resection. The most recent variant of these procedures is combined portal and hepatic vein embolization (PVE/HVE). The DRAGON 1 trial evaluates the safety and efficacy of PVE/HVE, while assessing recruitment potential for the DRAGON 2 randomized trial. DRAGON 1 is a prospective, single-arm, international, multicenter trial. Patients with upfront unresectable CRLM due to a small FLR were included. The primary outcome was the ability of centers to recruit three patients and perform PVE/HVE and liver resection without 90-day mortality. Secondary outcomes included recruitment capacity, PVE/HVE technical details, FLR volume changes, complications, and resection rates. The study is registered at ClinicalTrials.gov, identifier: NCT04272931. In total, 102 patients were included from 43 centers. Twenty-four centers (24/43 = 56%) recruited three or more patients, and 20 centers (20/43 = 47%) achieved this without 90-day mortality. Of 96 patients undergoing PVE/HVE, no post-embolization mortality occurred, though major complications were reported in two patients. Resection was completed in 86 patients (86/96 = 90%), with seven patients (7/86 = 8%) dying within 90 days. PHLF grade B/C (International Study Group of Liver Surgery criteria) occurred in 19 patients (19/86 = 22%). DRAGON 1 demonstrates that PVE/HVE is safe, with no embolization-related mortality, low morbidity, and high resection rates in upfront unresectable CRLM. The Dutch Cancer Society, National Institute for Health and Care Research UK, Maastricht UMC+, Abbott Laboratories and Guerbet.

Kelch-like 1 (KLHL1) is a neuronal actin-binding protein that modulates voltage-gated CaV2.1 (P/Q-type) and CaV3.2 (α1H T-type) calcium channels; KLHL1 knockdown experiments (KD) cause down-regulation of both channel types and altered synaptic properties in cultured rat hippocampal neurons (Perissinotti et al., 2014). Here, we studied the effect of ablation of KLHL1 on calcium channel function and synaptic properties in cultured hippocampal neurons from KLHL1 knockout (KO) mice. Western blot data showed the P/Q-type channel α1A subunit was less abundant in KO hippocampus compared to wildtype (WT); and PQ-type calcium currents were smaller in KO neurons than WT during early days in vitro, although this decrease was compensated for at late stages by increases in L-type calcium current. In contrast, T-type currents did not change in culture. However, biophysical properties and western blot analysis revealed a differential contribution of T-type channel isoforms in the KO, with CaV3.2 α1H subunit being down-regulated and CaV3.1 α1G up-regulated. Synapsin I levels were reduced in the KO hippocampus; cultured neurons displayed a concomitant reduction in synapsin I puncta and decreased miniature excitatory postsynaptic current (mEPSC) frequency. In summary, genetic ablation of the calcium channel modulator resulted in compensatory mechanisms to maintain calcium current homeostasis in hippocampal KO neurons; however, synaptic alterations resulted in a reduction of excitatory synapse number, causing an imbalance of the excitatory-inhibitory synaptic input ratio favoring inhibition.

Immunotherapy has revolutionized the treatment of several cancers, including melanoma and lung cancer. However, for colorectal cancer, it is ineffective for 95% of patients with microsatellite-stable disease. Recent evidence suggests that the liver’s immune microenvironment plays a pivotal role in limiting the effectiveness of immunotherapy. There is also evidence to show that targeting liver metastases with locoregional therapies, such as surgery or irradiation, could potentiate immunotherapy for these patients. This review presents evidence from preclinical studies regarding the underlying mechanisms and from clinical studies that support this approach. Furthermore, we outline potential directions for future clinical trials. This innovative strategy could potentially establish immunotherapy as an effective treatment for MS-stable colorectal cancer patients, which are currently considered resistant.