Robot-assisted cervical esophagectomy with simultaneous transhiatal abdominal procedure for thoracic esophageal carcinoma.

BACKGROUND: Minimally invasive robot-assisted cervical esophagectomy has been sporadically reported as a novel thoracic esophagectomy technique for patients with thoracic esophageal carcinoma. Most reports indicate that the abdominal component of robot-assisted cervical esophagectomy is performed sequentially after the cervical phase. However, if the cervical and abdominal phases are performed simultaneously using a nerve integrity monitoring system with no administration of muscle relaxants, there are two major advantages: a reduced risk of recurrent nerve palsy and a shorter operative time. We herein report our experience performing novel robot-assisted transcervical esophagectomy with a simultaneous transhiatal abdominal approach using a nerve integrity monitoring system. METHODS: Thirty cases of robot-assisted cervical esophagectomy performed from 2023 to April 2024 were reviewed. The operative and short-term surgical outcomes of this procedure were compared with those of robot-assisted cervical esophagectomy using a sequential abdominal approach, and the feasibility and efficacy of the simultaneous procedure were analyzed. RESULTS: All patients successfully underwent robot-assisted cervical esophagectomy with no intraoperative adverse events. There were no differences in the patients' demographic or operative data between the two groups. There was no difference in the mean operation time for the cervical procedure (p = 0.23). However, there was a significant difference in the total time for the whole procedure (sequential group: 453.8 ± 26.8 min, simultaneous group: 291.2 ± 36.1 min; p < 0.01). There were no differences in postoperative surgical complications between the groups. There was also no difference in the total number of surgically harvested mediastinal lymph nodes (p = 0.33). CONCLUSIONS: Robot-assisted transcervical esophagectomy, a new technique for thoracic esophageal cancer, was safe and feasible under intraoperative management using nerve integrity monitoring without muscle relaxants. This procedure facilitates intraoperative monitoring of recurrent laryngeal nerve activity, significantly shortening the total operative time.

Cost-effectiveness of a precision hepatocellular carcinoma surveillance strategy in patients with cirrhosis.

Background: Hepatocellular carcinoma (HCC) surveillance is currently performed using a one-size-fits-all strategy with ultrasound plus AFP (US + AFP). There is increasing interest in risk-stratified and precision surveillance strategies incorporating individual risk and variance in surveillance test performance; however, the cost-effectiveness of these approaches has not been evaluated. Methods: We conducted a cost-effectiveness analysis to evaluate four surveillance strategies (no surveillance, universal US + AFP surveillance, risk-stratified surveillance, and precision surveillance) in a simulated cohort of 50-year-old patients with compensated cirrhosis. The most cost-effective strategy was that with the highest incremental cost-effectiveness ratio (ICER) and below the willingness-to-pay (WTP) threshold of $150,000/QALY gained. Model inputs were based on literature review, and costs were derived from the Medicare fee schedule. Findings: The precision surveillance strategy demonstrated variation in recommended surveillance test based on HCC risk category and patient factors. US + AFP, risk-stratified, and precision surveillance detected more HCC cases per 100,000 population than no surveillance, with a higher proportion of early-stage cases for precision surveillance (67.6%) than risk-stratified (63.8%), universal ultrasound (63.2%), and no surveillance (38.0%). Compared to no surveillance, precision surveillance was most cost-effective, with an ICER of $104,614/QALY gained, whereas US + AFP and risk-stratified surveillance were both dominated. Compared to US + AFP, risk-stratified surveillance was cost saving and dominated US + AFP, whereas precision surveillance was cost-effective, with an ICER of $98,103/QALY gained. Results were sensitive to survival with early-stage HCC, cost of early-stage HCC treatment, and surveillance utilization. Precision surveillance remained the most cost-effective when WTP thresholds exceeded $110,000/QALY gained. Interpretation: A precision surveillance strategy is the most cost-effective method for HCC surveillance. This approach could maximize surveillance benefits in high-risk patients, while minimizing surveillance harms in low-risk individuals. Funding: National Cancer Institute (U01 CA230694, R01 CA222900, R01 CA212008, and U24ca086368) and Cancer Prevention Research Institute of Texas (CPRIT) (RP200554).

Assessing the outcomes of posterior thoracic para-aortic lymph node dissection after induction chemotherapy in patients with esophageal squamous cell carcinoma.

Posterior thoracic para-aortic lymph node (TPAN) metastasis is a distant metastasis of esophageal cancer. Several case reports have shown that radical esophagectomy and lymphadenectomy for posterior TPAN improve the prognosis of patients with cStage IVB esophageal cancer and solitary posterior TPAN metastasis; however, the true value of this procedure is unclear. The primary objective of this study was to evaluate the short- and long-term outcomes of lymphadenectomy for posterior TPAN after induction chemotherapy in esophageal cancer. This study enrolled 15 patients who underwent radical esophagectomy for cStage IVB esophageal cancer with solitary posterior TPAN metastasis after induction chemotherapy between January 2013 and October 2022 at our hospital. The short- and long-term of radical esophagectomy and lymphadenectomy for posterior TPAN were retrospectively evaluated. All patients who underwent radical esophagectomy and lymphadenectomy for posterior TPAN achieved a pR0 in this study. The median operative time and intraoperative blood loss were 385 minutes and 164 ml, respectively. Four patients (26.7%) had postoperative complications of Clavien-Dindo grade II or more. The median postoperative hospital stay was 15 days. The 5-year overall survival and recurrence-free survival rates were 55.6% (95% confidence interval: 23.1-79.0) and 55.0% (95% confidence interval: 25.3-77.2), respectively. We showed that lymphadenectomy for posterior TPAN metastasis was associated with an improved prognosis of some patients with advanced esophageal cancer. This technique may serve as a viable treatment option for patients who respond well to induction chemotherapy.

An atlas of the human liver diurnal transcriptome and its perturbation by hepatitis C virus infection.

Chronic liver disease and cancer are global health challenges. The role of the circadian clock as a regulator of liver physiology and disease is well established in rodents, however, the identity and epigenetic regulation of rhythmically expressed genes in human disease is less well studied. Here we unravel the rhythmic transcriptome and epigenome of human hepatocytes using male human liver chimeric mice. We identify a large number of rhythmically expressed protein coding genes in human hepatocytes of male chimeric mice, which includes key transcription factors, chromatin modifiers, and critical enzymes. We show that hepatitis C virus (HCV) infection, a major cause of liver disease and cancer, perturbs the transcriptome by altering the rhythmicity of the expression of more than 1000 genes, and affects the epigenome, leading to an activation of critical pathways mediating metabolic alterations, fibrosis, and cancer. HCV-perturbed rhythmic pathways remain dysregulated in patients with advanced liver disease. Collectively, these data support a role for virus-induced perturbation of the hepatic rhythmic transcriptome and pathways in cancer development and may provide opportunities for cancer prevention and biomarkers to predict HCC risk.

The Spatial Extracellular Proteomic Tumor Microenvironment Distinguishes Molecular Subtypes of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) mortality rates continue to increase faster than those of other cancer types due to high heterogeneity, which limits diagnosis and treatment. Pathological and molecular subtyping have identified that HCC tumors with poor outcomes are characterized by intratumoral collagenous accumulation. However, the translational and post-translational regulation of tumor collagen, which is critical to the outcome, remains largely unknown. Here, we investigate the spatial extracellular proteome to understand the differences associated with HCC tumors defined by Hoshida transcriptomic subtypes of poor outcome (Subtype 1; S1; n = 12) and better outcome (Subtype 3; S3; n = 24) that show differential stroma-regulated pathways. Collagen-targeted mass spectrometry imaging (MSI) with the same-tissue reference libraries, built from untargeted and targeted LC-MS/MS was used to spatially define the extracellular microenvironment from clinically-characterized, formalin-fixed, paraffin-embedded tissue sections. Collagen α-1(I) chain domains for discoidin-domain receptor and integrin binding showed distinctive spatial distribution within the tumor microenvironment. Hydroxylated proline (HYP)-containing peptides from the triple helical regions of fibrillar collagens distinguished S1 from S3 tumors. Exploratory machine learning on multiple peptides extracted from the tumor regions could distinguish S1 and S3 tumors (with an area under the receiver operating curve of ≥0.98; 95% confidence intervals between 0.976 and 1.00; and accuracies above 94%). An overall finding was that the extracellular microenvironment has a high potential to predict clinically relevant outcomes in HCC.

Total RAMIE with three-field lymph node dissection by a simultaneous two-team approach using a new docking method for esophageal cancer.

BACKGROUND: Thoracic esophageal cancer surgery using robotic approaches for the thoracic and abdominal parts has recently been reported as total robot-assisted minimally invasive esophagectomy (RAMIE). We herein present the first report of a new technique for esophageal cancer: total RAMIE with three-field lymph node dissection (3FLND) by a simultaneous two-team approach using a new docking method. METHODS: We reviewed 20 patients who underwent total RAMIE with 3FLND by a simultaneous two-team approach at the National Cancer Center East Hospital from March 2023 to September 2023. Short-term surgical outcomes and the safety and efficacy of this technique were analyzed. RESULTS: The mean operative time for abdominal surgery with this new docking technique was 135 ± 19.6 min. The total operative time was 488 ± 42.9 min, and the time from the end of abdominal manipulation to the end of surgery was 80.1 ± 15.6 min. The intraoperative blood loss was 116.7 ± 64.4 mL. The incidence of anastomotic leakage, postoperative vocal cord paralysis, and postoperative pneumonia was 10%, 5%, and 10%, respectively. The median postoperative hospital stay was 14 days (range 11-63 days). No in-hospital deaths occurred, and R0 resection was possible in all cases. The average number of lymph nodes dissected was 87.7. CONCLUSION: These results demonstrate that total RAMIE with a simultaneous two-team approach using the new docking method can be safely introduced. The simultaneous cervical and abdominal manipulation with the new docking method allowed total RAMIE without prolonging the operating time, suggesting that it may be a valuable approach for esophageal cancer surgery.

PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer.

Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP-1c activation. In summary, PKD1 mutations exert adaptive functionality on the organ level without increasing transformation risk.

Efficiency of conversion surgery for esophageal squamous cell carcinoma with solitary abdominal para-aortic lymph node metastasis.

PURPOSE: Abdominal para-aortic lymph nodes (PANs) are sites of distant metastasis in esophageal squamous cell cancer (ESCC). The prognosis of patients with Stage IVB ESCC and abdominal PAN metastasis is extremely poor. However, chemotherapy for ESCC has recently been developed, and the effectiveness of combined induction therapy and conversion surgery remains unclear. The primary objective of this study was to evaluate the short- and long-term outcomes of conversion surgery for ESCC and solitary abdominal PAN metastases after induction therapy. METHODS: Thirteen patients who underwent conversion esophagectomy for cStage IVB ESCC with solitary abdominal PAN metastasis after induction therapy between January 2017 and October 2022 at our institution were enrolled. The short- and long-term outcomes of conversion surgery were retrospectively evaluated. RESULTS: Three patients (23.1%) had pathological abdominal PAN metastasis, and six patients (46.2%) without pathological abdominal PAN metastasis showed that chemotherapy eliminated the tumors in the abdominal PAN. Three patients (23.1%) had postoperative complications of Clavien-Dindo grade II or higher. The 3-year overall and recurrence-free survival rates were 83.1% and 51.3%, respectively. CONCLUSIONS: Our findings showed that conversion surgery for ESCC and solitary abdominal PAN metastasis led to a good prognosis when induction therapy was successful.

Emerging Roles of Spatial Transcriptomics in Liver Research.

Spatial transcriptomics, leveraging sequencing- and imaging-based techniques, has emerged as a groundbreaking technology for mapping gene expression within the complex architectures of tissues. This approach provides an in-depth understanding of cellular and molecular dynamics across various states of healthy and diseased livers. Through the integration of sophisticated bioinformatics strategies, it enables detailed exploration of cellular heterogeneity, transitions in cell states, and intricate cell-cell interactions with remarkable precision. In liver research, spatial transcriptomics has been particularly revelatory, identifying distinct zonated functions of hepatocytes that are crucial for understanding the metabolic and detoxification processes of the liver. Moreover, this technology has unveiled new insights into the pathogenesis of liver diseases, such as the role of lipid-associated macrophages in steatosis and endothelial cell signals in liver regeneration and repair. In the domain of liver cancer, spatial transcriptomics has proven instrumental in delineating intratumor heterogeneity, identifying supportive microenvironmental niches and revealing the complex interplay between tumor cells and the immune system as well as susceptibility to immune checkpoint inhibitors. In conclusion, spatial transcriptomics represents a significant advance in hepatology, promising to enhance our understanding and treatment of liver diseases.

Effectiveness of 1-year pemafibrate treatment on steatotic liver disease: the influence of alcohol consumption.

BACKGROUND/AIMS: Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator that improves serum alanine aminotransferase (ALT) in dyslipidemia patients. We previously reported that pemafibrate significantly improves liver function, serum triglyceride (TG) levels and liver stiffness in non-alcoholic fatty liver disease patients, however the influence of alcohol consumption was not considered. Therefore, we explored pemafibrate efficacy in patients with steatotic liver disease (SLD) and alcohol-associated liver disease (ALD). METHODS: We retrospectively evaluated pemafibrate efficacy on liver enzymes and lipids in metabolic dysfunction-associated SLD (MASLD) (n = 93), MASLD plus increased alcohol intake (MetALD; n = 23) and ALD (n = 22) patients who had taken pemafibrate for at least 48 weeks. Liver shear wave velocity (SWV, n = 75) was also evaluated. RESULTS: In MASLD group, ALT, aspartate aminotransferase (AST), γ-glutamyl transpeptidase (γ-GTP) and TG values were significantly decreased from baseline to week 24 and week 48 ( P  < 0.0001). ALT and TG values in MetALD group and ALT and AST values in ALD group were also significantly decreased from baseline to week 24 and week 48. Study participant SWV values decreased from baseline to week 48. We observed no significant difference in changes to ALT, AST, γ-GTP and TG (value at week 24 or week 48 minus value at baseline) among the three groups. CONCLUSION: Pemafibrate improves liver function and liver stiffness thus making it a promising therapeutic agent for SLD, even in patients with excess alcohol consumption (MetALD and ALD groups).

Robot-assisted transcervical esophagectomy with a bilateral cervical approach for thoracic esophagectomy.

BACKGROUND: Thoracic esophageal cancer resection through the neck approach has recently been reported as mediastinoscopic surgery. We present the first report of a new minimally invasive technique for thoracic esophageal cancer: robot-assisted transcervical esophagectomy with a bilateral cervical approach. METHODS: Ten cases of robot-assisted bilateral transcervical esophagectomy performed at the National Cancer Center Hospital East, Japan, from February 2023 to August 2023 were reviewed. The short-term surgical outcomes were presented, and the feasibility and efficacy of this procedure were discussed. RESULTS: The mean operation time for the cervical procedure was 184.2 ± 23.6 min. The total time for the whole procedure was 472.7 ± 28.4 min, and total intraoperative blood loss was 162.2 ± 40.0 ml. Among the 10 cases, one patient developed recurrent nerve paralysis, one patient developed pulmonary complications, and no patients developed postoperative pneumonia. The median postoperative hospital stay was 22 (range: 12-43) days. No patients developed severe postoperative surgical complications, which were graded as Clavien-Dindo ≥ III. The total number of surgically harvested mediastinal lymph nodes was 37.2 ± 11.2. CONCLUSIONS: Robot-assisted bilateral transcervical esophagectomy, a novel procedure for thoracic esophageal cancer, was safe and feasible. Using this procedure, the incidence of recurrent nerve palsy, which is a problem with transcervical esophagectomy and mediastinoscopic esophagectomy, is expected to decrease.

Prognosis of patients with residual pathological disease after neoadjuvant docetaxel, cisplatin, and 5-fluorouracil therapy and surgery for esophageal squamous cell carcinoma: a retrospective cohort study.

Background: Docetaxel, cisplatin, and 5-fluorouracil (DCF) combination chemotherapy has been established as one of the standard neoadjuvant therapies for locally advanced esophageal squamous cell carcinoma (ESCC). However, little is known about prognostic factors in patients with residual pathological disease after neoadjuvant DCF followed by surgery for locally advanced ESCC who are candidates for adjuvant nivolumab. Objectives: This study aimed to investigate prognostic factors in patients with residual pathological disease after neoadjuvant DCF chemotherapy followed by surgery for locally advanced ESCC. Design: This was a retrospective cohort study. Methods: This retrospective cohort study included patients who received neoadjuvant DCF followed by surgery for locally advanced ESCC between June 2014 and January 2020 at the National Cancer Center Hospital East. Results: Among a total of 210 patients, 45 patients (21.4%) achieved a pathological complete response. The 3-year disease-free survival (DFS) rate was significantly lower in patients with residual pathological disease than in those with a pathological complete response [53.5% versus 74.5%; hazard ratio (HR): 2.09, 95% confidence interval (CI): 1.16-3.77, p = 0.01]. In patients with residual pathological disease (n = 165), multivariate analysis revealed that pathological node positivity (HR: 3.59, 95% CI: 1.92-6.71, p < 0.01), supraclavicular lymph node metastasis (HR: 2.15, 95% CI: 1.19-3.90, p = 0.01), and lymphovascular invasion (HR: 1.90, 95% CI: 1.14-3.17, p = 0.02) were significantly associated with poor DFS. Conclusion: In this largest-to-date cohort study, patients with residual pathological disease after neoadjuvant DCF followed by surgery for locally advanced ESCC had a poor prognosis. In these patients, pathological node positivity, including supraclavicular lymph node metastasis, and lymphovascular invasion were considered significant prognostic factors.

A novel device to assess the oxygen saturation and congestion status of the gastric conduit in thoracic esophagectomy.

BACKGROUND: In thoracic esophagectomy, anastomotic leakage is one of the most important surgical complications. Indocyanine green (ICG) is the most widely used method to assess tissue blood flow; however, this technique has been pointed out to have disadvantages such as difficulty in evaluating the degree of congestion, lack of objectivity in evaluating the degree of staining, and bias easily caused by ICG injection, camera distance, and other factors. Evaluating tissue oxygen saturation (StO2) overcomes these disadvantages and can be performed easily and repeatedly. It is also possible to measure objective values including the degree of congestion. We evaluate novel imaging technology to assess tissue oxygen saturation (StO2) in the gastric conduit during thoracic esophagectomy. METHODS: Fifty patients were enrolled, with seven excluded due to intraoperative findings, leaving 43 for analysis. These patients underwent thoracic esophagectomy for esophageal cancer. The device was used intraoperatively to evaluate tissue oxygen saturation (StO2) and total hemoglobin index (T-HbI), which guided the optimal site for gastric tube anastomosis. The efficacies of StO2 and T-HbI in relation to short-term outcomes were analyzed. RESULTS: StO2, indicating blood supply to the gastric tube, remained stable beyond the right gastroepiploic artery (RGEA) end but significantly decreased distally to the demarcation line (p <  0.05). T-HbI, indicative of congestion, significantly decreased past the RGEA (p <  0.05). Three patients experienced anastomotic leakage. These patients exhibited significantly lower StO2 (p <  0.01) and higher T-HbI (p <  0.01) at both the RGEA end and the demarcation line. Furthermore, the anastomotic site, usually within 3 cm of the RGEA's anorectal side, also showed significantly lower StO2 (p <  0.01) and higher T-HbI (p <  0.01) in patients with anastomotic leakage. CONCLUSIONS: The novel device provides real-time, objective evaluations of blood flow and congestion in the gastric tube. It proves useful for safer reconstruction during thoracic esophagectomy, particularly by identifying optimal anastomosis sites and predicting potential anastomotic leakage.

A novel imaging technology to assess tissue oxygen saturation and its correlation with indocyanine green in the gastric conduit during thoracic esophagectomy.

BACKGROUND: Anastomotic leakage in esophagectomy is a serious complication, and assessing blood perfusion in the conduit can help minimize this risk. Indocyanine green is the most widely used method to assess tissue blood flow; however, this technique has disadvantages. Evaluating tissue oxygen saturation in the gastric conduit during thoracic esophagectomy compared with indocyanine green blood perfusion assessment addresses these disadvantages and can be performed easily and repeatedly. METHODS: This was a prospective study of patients with esophageal cancer who underwent thoracic esophagectomy. Intraoperative tissue oxygen saturation and indocyanine green measurements were obtained to determine the anastomotic site and to compare the correlation between the 2 methods. Tissue oxygen saturation and indocyanine green values were obtained at the tip of the gastric conduit, the demarcation line indicating visible perfusion, and the end of the right gastroepiploic artery. RESULTS: Fifty-seven patients were enrolled in this study; 3 developed anastomotic leakage, and all 3 underwent robotic thoracic surgery. The tissue oxygen saturation value decreased gradually toward the tip of the conduit, as did congestion, and was significantly decreased at the tip compared with the value at the demarcation line (P = .001). Mean tissue oxygen saturation differed significantly between the leakage and no-leakage groups at the anastomosis site (P = .04). We found a negative correlation between tissue oxygen saturation and indocyanine green values at the end of the right gastroepiploic artery (r = -0.361; P = .03). CONCLUSION: Tissue oxygen saturation imaging was useful in determining the anastomotic site and addressed the disadvantages associated with indocyanine green.

Serum Zinc-α2-glycoprotein Levels Are Associated with the Hepatorenal Function and Predict the Survival in Cases of Chronic Liver Disease.

Objective Zinc-α2-glycoprotein (ZAG) is secreted by various organs, such as liver, kidney and adipose tissue, is involved in lipolysis, and may contribute to the pathogenesis of chronic liver disease (CLD). We therefore assessed whether or not ZAG is a surrogate marker for the hepatorenal function, body composition and all causes of mortality, as well as complications, including ascites, hepatic encephalopathy (HE) and portosystemic shunts (PSS) in CLD. Methods Serum ZAG levels were measured in 180 CLD patients upon hospital admission. The associations of ZAG levels with the liver functional reserve and clinical parameters were investigated using a multiple regression analysis. Kaplan-Meier analyses were performed to evaluate the associations of the ZAG/creatinine ratio (ZAG/Cr) and prognostic factors with mortality. Results High serum ZAG levels were associated with preserving the liver function and renal insufficiency. A multiple regression analysis showed that the estimated glomerular filtration rate (p<0.0001), albumin-bilirubin (ALBI) score (p=0.0018) and subcutaneous fat area (p=0.0023) had a significant independent correlation with serum ZAG levels. Serum ZAG levels were elevated in the absence of HE (p=0.0023) and PSS (p=0.0003). In all patients and those without hepatocellular carcinoma (HCC), the cumulative mortality rate was significantly decreased in patients with a high ZAG/Cr compared with those with a low ZAG/Cr (p=0.0018 and p=0.0002, respectively). The ZAG/Cr, presence of HCC, ALBI score and psoas muscle index were independent predictors of the prognosis in CLD patients. Conclusion Serum ZAG levels are associated with the hepatorenal function and can be used to predict the survival in CLD patients.

[Management of Postoperative Infectious Complications After Thoracic Esophagectomy].

Although minimally invasive procedures such as thoracoscopic surgery and robot-assisted surgery have become increasingly popular in esophageal cancer in recent years, perioperative management remains a very important topic. However, perioperative management is still an extremely important issue, as esophagectomy is still a highly invasive procedure. Especially in recent years, as the patient population ages, it is expected that we will have more and more opportunities to deal with patients with various pre-existing medical conditions in addition to the original decline in physical function. In this article, we discuss the management of infectious complications in the perioperative management of esophageal surgery, with a particular focus on esophagectomy and reconstruction.

Combination Therapy of Immune Checkpoint Inhibitors with Locoregional Therapy for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is estimated to be the fourth leading cause of cancer-related deaths globally, and its overall prognosis is dismal because most cases are diagnosed at a late stage and are unamenable to curative treatment. The emergence of immune checkpoint inhibitors (ICIs) has dramatically improved the therapeutic efficacy for advanced hepatocellular carcinoma; however, their response rates remain unsatisfactory, partly because >50% of HCC exhibit an ICI-nonresponsive tumor microenvironment characterized by a paucity of cytotoxic T cells (immune-cold), as well as difficulty in their infiltration into tumor sites (immune excluded). To overcome this limitation, combination therapies with locoregional therapies, including ablation, transarterial embolization, and radiotherapy, which are usually used for early stage HCCs, have been actively explored to enhance ICI efficacy by promoting the release of tumor-associated antigens and cytokines, and eventually accelerating the so-called cancer-immunity cycle. Various combination therapies have been investigated in early- to late-phase clinical trials, and some have shown promising results. This comprehensive article provides an overview of the immune landscape for HCC to understand ICI efficacy and its limitations and, subsequently, reviews the status of combinatorial therapies of ICIs with locoregional therapy for HCC.

Proton Beam Therapy versus Radiofrequency Ablation for Patients with Treatment-Naïve Single Hepatocellular Carcinoma: A Propensity Score Analysis.

Introduction: Proton beam therapy (PBT) is known to be an effective locoregional treatment for hepatocellular carcinoma (HCC). However, few comparative studies in treatment-naïve cases have been reported. The aim of this study was to compare the survival outcomes of PBT with those of radiofrequency ablation (RFA) in patients with treatment-naïve solitary HCC. Methods: Ninety-five consecutive patients with treatment-naïve HCC, a single nodule measuring ≤5 cm in diameter, and a Child-Pugh score of ≤8 who were treated with PBT at the University of Tsukuba Hospital between 2001 and 2013 were enrolled in the study. In addition, 836 patients with treatment-naïve HCC treated by RFA at the University of Tokyo Hospital during the same period were analyzed as controls. Recurrence-free survival (RFS) and overall survival (OS) were compared in 83 patient pairs after propensity score matching. Results: The 1-year, 3-year, and 5-year RFS rates were 86.6%, 49.5%, and 35.5%, respectively, in the PBT group and 59.5%, 34.0%, and 20.9% in the RFA group (p = 0.058); the respective OS rates were 97.6%, 77.8%, and 57.1% in the PBT group and 95.1%, 81.7%, and 67.7% in the RFA group (p = 0.16). Regarding adverse effects, no grade 3 or higher adverse events were noted in the PBT; however, two grade 3 adverse events occurred within 30 days of RFA in the RFA group: one hemoperitoneum and one hemothorax. Discussion: After propensity score matching, PBT showed no significant difference in RFS and OS compared to RFA. PBT can be an alternative for patients with solitary treatment-naïve HCC.

Endogenous renal adiponectin drives gluconeogenesis through enhancing pyruvate and fatty acid utilization.

Adiponectin is a secretory protein, primarily produced in adipocytes. However, low but detectable expression of adiponectin can be observed in cell types beyond adipocytes, particularly in kidney tubular cells, but its local renal role is unknown. We assessed the impact of renal adiponectin by utilizing male inducible kidney tubular cell-specific adiponectin overexpression or knockout mice. Kidney-specific adiponectin overexpression induces a doubling of phosphoenolpyruvate carboxylase expression and enhanced pyruvate-mediated glucose production, tricarboxylic acid cycle intermediates and an upregulation of fatty acid oxidation (FAO). Inhibition of FAO reduces the adiponectin-induced enhancement of glucose production, highlighting the role of FAO in the induction of renal gluconeogenesis. In contrast, mice lacking adiponectin in the kidney exhibit enhanced glucose tolerance, lower utilization and greater accumulation of lipid species. Hence, renal adiponectin is an inducer of gluconeogenesis by driving enhanced local FAO and further underlines the important systemic contribution of renal gluconeogenesis.

Master Transcription Factor Reprogramming Unleashes Selective Translation Promoting Castration Resistance and Immune Evasion in Lethal Prostate Cancer.

Signaling rewiring allows tumors to survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer unleashes eukaryotic initiation factor 3B (eIF3B)-dependent translation reprogramming of key mRNAs conferring resistance to androgen deprivation therapy (ADT) and promoting immune evasion. Mechanistically, MITF represses through direct promoter binding eIF3B, which in turn regulates the translation of specific mRNAs. Genome-wide eIF3B enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq) showed specialized binding to a UC-rich motif present in subsets of 5' untranslated regions. Indeed, translation of the androgen receptor and major histocompatibility complex I (MHC-I) through this motif is sensitive to eIF3B amount. Notably, pharmacologic targeting of eIF3B-dependent translation in preclinical models sensitizes prostate cancer to ADT and anti-PD-1 therapy. These findings uncover a hidden connection between transcriptional and translational rewiring promoting therapy-refractory lethal prostate cancer and provide a druggable mechanism that may transcend into effective combined therapeutic strategies. SIGNIFICANCE: Our study shows that specialized eIF3B-dependent translation of specific mRNAs released upon downregulation of the master transcription factor MITF confers castration resistance and immune evasion in lethal prostate cancer. Pharmacologic targeting of this mechanism delays castration resistance and increases immune-checkpoint efficacy. This article is featured in Selected Articles from This Issue, p. 2489.