Macroscopic Characterization of Hepatocellular Carcinoma: An Underexploited Source of Prognostic Factors.

The macroscopic appearance of a tumor such as hepatocellular carcinoma (HCC) may be defined as its phenotype which is de facto dictated by its genotype. Therefore, macroscopic characteristics of HCC are unlikely random but rather reflect genomic traits of cancer, presumably acting as a valuable source of information that can be retrieved and exploited to infer prognosis. This review aims to provide a comprehensive overview of the available data on the prognostic value of macroscopic characterization in HCC. A total of 57 studies meeting eligible criteria were identified, including patients undergoing liver resection (LR; 47 studies, 83%) or liver transplant (LT; 9 studies, 16%). The following macroscopic variables were investigated: tumor size (n = 42 studies), number of nodules (n = 28), vascular invasion (n = 24), bile duct invasion (n = 6), growth pattern (n = 15), resection margin (n = 11), tumor location (n = 6), capsule (n = 2) and satellite (n = 1). Although the selected studies provided insightful data with notable prognostic performances, a lack of standardization and substantial gaps were noted in the report and the analysis of gross findings. This topic remains incompletely covered. While the available studies underscored the value of macroscopic variables in HCC prognostication, important lacks were also observed. Macroscopic characterization of HCC is likely an underexploited source of prognostic factors that must be actively explored by future multidisciplinary research.

Impact of preoperative statin medication on long-term outcomes after pancreatoduodenectomy for ductal adenocarcinoma: an international multicentric cross-sectional study.

PURPOSE: Statin treatment has been shown in certain population studies and meta-analyses to improve survival of patients with pancreatic ductal adenocarcinoma (PDAC). This study assessed if patients with statin treatment had better overall survival (OS) and disease-free survival (DFS) after upfront pancreatoduodenectomy for PDAC. METHODS: Consecutive PDAC patients were retrospectively collected from three centers in Europe and USA (study period: 2000-2017). Adult patients who underwent upfront pancreatoduodenectomy and survived the first 90 postoperative days were included. Patients with metastasis at diagnosis or with macroscopic incomplete resection were excluded. Patients were considered under statin if started at least one month before pancreatoduodenectomy. Survival rates were calculated using Kaplan-Meier method and compared with log-rank test. RESULTS: A total of 496 patients were included. Median age was 67 years (IQR 59-75), 48% (n = 236) were women, and 141 patients (28%) received statin treatment already preoperatively. Patients with and without statin treatment were comparable in terms of demographics and pre-/intraoperative characteristics, except for age and pre-existing diabetes. Median OS and DFS were similar in patients with and without statin treatment (OS: 29, 95% CI 22-36 vs. 27 months, 95% CI 22-32, p = 0.370, DFS: 18, 95% CI 14-22 vs. 16 months, 95% CI 14-18, p = 0.430). On multivariable Cox regression, lymph node involvement (HR 1.9, 95% CI 1.6-2.2, p < 0.001), tumor differentiation (HR 1.3, 95% CI 1.1-1.6, p = 0.003), and postoperative chemotherapy (HR 0.5, 95% CI 0.4-0.7, p < 0.001) were predictors of OS, whereas statin treatment was not a prognostic factor (HR 0.9, 95% CI 0.7-1.2, p = 0.376). CONCLUSION: In this international cohort of PDAC patients, statin treatment did not influence survival after upfront pancreatoduodenectomy. Nodal involvement, tumor differentiation, and postoperative chemotherapy were independent predictors of OS.

Functional, biological, and radiological evaluation of the pancreaticojejunal anastomosis 1 year after pancreatoduodenectomy: a prospective study.

PURPOSE: This prospective study aimed to analyze the functional, biological, and radiological aspects of the pancreatic anastomosis 1 year after pancreatoduodenectomy (PD). METHODS: From 2016 to 2019, patients with PD indication were screened. Questionnaires about pancreas insufficiency, fecal elastase tests, and magnetic resonance imaging (MRI) were performed before and 1 year after PD. RESULTS: Twenty patients were prospectively included. The only difference between pre- and postoperative questionnaires was constipation (less frequent 1 year after PD). Median pre- and postoperative fecal elastase levels were 96 µg/g (IQR 15-196, normal value > 200) and 15 µg/g (IQR 15-26, p = 0.042). There were no significant differences in terms of main pancreatic duct (MPD) size (4, IQR 3-5 vs. 4 mm, IQR 3-5, p = 0.892), border regularity, stenosis, visibility, image improvement, and secondary pancreatic duct dilation before and after secretin injection. All patients but one (2 refused and 2 were lost to follow-up, 15/16, 94%) had a patent pancreaticojejunal anastomosis on 1-year MRI. CONCLUSION: Although median 1-year fecal elastase was significantly lower than preoperatively, suggesting that exocrine secretion was altered, the anatomical outcome as assessed by MRI was excellent showing high patency rate (15/16, 94%) at 1 year. This emphasizes the difference between anatomy and function.

[Novelties on the management of alveolar echinococcosis]. / Nouveautés dans la prise en charge de l'échinococcose alvéolaire.

Alveolar echinococcosis is an endemic parasitosis in Switzerland. This pathology mainly infects the liver and develops similarly as a malignant tumor with its ability to spread into the hepatic parenchyma and its capacity of developing distant lesions via hematogenous dissemination. Treatment is based on complete surgical resection coupled with albendazole treatment. Recently, ex vivo liver resections with auto-transplantation have been shown to be feasible in case of end-stage alveolar echinococcosis. Moreover, new biomarkers such as programmed death-ligand 1 (PD-L1), a protein with immunomodulation property, have shown their potential impact on the treatment and follow-up of patients with alveolar echinococcosis.

L'échinococcose alvéolaire est une parasitose endémique en Suisse. Cette pathologie touche principalement le foie et se développe telle une tumeur maligne, par sa propension à envahir le parenchyme hépatique et par sa capacité à développer des lésions à distance par voie hématogène. Le traitement repose sur une exérèse chirurgicale complète couplée à un traitement d'albendazole. Récemment, des techniques de résection hépatique ex vivo avec auto-transplantation ont montré leur faisabilité en cas d'échinococcose alvéolaire avancée. De plus, de nouveaux marqueurs, comme le programmed death-ligand 1 (PD-L1), protéine jouant un rôle dans l'immunomodulation, ont montré leur potentiel impact pour le traitement et le suivi des patients atteints d'échinococcose alvéolaire.

Carcinogenic effect of arsenic in digestive cancers: a systematic review.

BACKGROUND: The carcinogenic effect of arsenic (As) has been documented in lung, bladder and skin cancers but remains unclear for digestive cancers, although metabolic pathways of As and recent data suggest that it may be an important determinant in these malignancies as well. OBJECTIVE: This study aimed to systematically review the available literature investigating the potential association between As and digestive cancers. METHODS: An extensive search was conducted in Medline Ovid SP, Cochrane, PubMed, Embase.com, Cochrane Library Wiley, Web of Science and Google Scholar. Studies providing original data in humans, with As measurement and analysis of association with digestive cancers including esogastric cancers (esophagus and stomach), hepato-pancreatico-biliary (HPB) cancers (including biliary tract, liver and pancreas) and colorectal cancers were eligible. RESULTS: A total of 35 studies were identified, 17 ecological, 13 case-control and 5 cohort studies. Associations between As and digestive cancers were reported for both risks of incidence and cancer-related mortality. Overall, 43% (3/7) and 48% (10/21) studies highlighted an association between As and the incidence or the mortality of digestive cancers, respectively. CONCLUSIONS: A substantial proportion of studies exploring the potential link between As and digestive cancers suggested an association, particularly in HPB malignancies. These findings emphasize the need to further investigate this topic with dedicated and high-quality studies, as it may have an important impact, including for prevention strategies.

Programmed death-ligand1 is a determinant of recurrence in alveolar echinococcosis.

OBJECTIVES: Alveolar echinococcosis (AE) recurrence is one of the major stakes in patients undergoing surgery, the main curative treatment. Preliminary data demonstrated an effect of programmed death-ligand1 (PD-L1) inhibitors on AE proliferation in animals. The current study aimed to analyze the prognostic value of PD-L1 expression in tissue samples of patients with AE undergoing surgery. METHODS: A cross-sectional study of patients operated for AE between 2002 and 2017 was performed. Patients with recurrence were matched 1: 2 with patients without recurrence. The matching criteria were PNM staging (P = hepatic localization of the parasite, N = extra-hepatic involvement of neighboring organs, and M = absence or presence of metastasis), resection status, preoperative albendazole treatment, and lesion size. PD-L1 immunohistochemistry staining was performed in surgical liver specimens. The expression of PD-L1 was assessed in immune cells. Disease-free survival was calculated using the Kaplan-Meier method. RESULTS: Among 68 consecutive patients, eight patients with recurrence were matched to 16 patients without recurrence. PD-L1 was overexpressed in patients with recurrence (recurrence: PD-L1 <1%: one, PD-L1 ≥1%: seven; no recurrence: PD-L1 <1%: nine, PD-L1 ≥1%: seven, P = 0.040). Moreover, patients with lower PD-L1 expression (<1%) showed better median disease-free survival (120 months, 95% confidence interval 104-135 vs 74, 95% confidence interval 44-104, P = 0.050). CONCLUSION: These findings highlight the proof of concept of PD-L1 in AE, but further data on its prognostic importance and the role of immune checkpoint blockade as a promising therapeutical strategy are needed.

Assessment of the Predictive Value of Preoperative Serum Albumin and Postoperative Albumin Drop (ΔAlb) for Complications after Pancreas Surgery: A Single-Center Cross-Sectional Study.

BACKGROUND: Serum albumin has been shown to be predictive of complications after various gastrointestinal operations. The present study aimed to assess whether preoperative serum albumin and serum albumin drop on postoperative day 1 are associated with postoperative complications after pancreatic surgery. METHODS: A single-center cross-sectional study was performed. All patients who underwent pancreatectomy between January 2010 and June 2019 and had preoperative serum albumin value and serum albumin value on postoperative day 1 were included. ΔAlb was defined as the difference between preoperative serum albumin and serum albumin on postoperative day 1. Binary logistic regressions were performed to determine independent predictors of postoperative complications. RESULTS: A total of 185 patients were included. Pancreatoduodenectomies were performed in 133 cases, left pancreatectomies in 36, and other pancreas operations in 16. The preoperative serum albumin value was found to be an independent predictor of complications (OR 0.9, 95%CI 0.9-1.0, p = 0.041), whereas ΔAlb was not significantly associated with postoperative complications (OR 1.0, 95%CI 0.9-1.1, p = 0.787). The threshold of 44.5 g/L for preoperative albumin level was found to have the highest combined sensitivity and specificity based on the maximum Youden index. Patients with preoperative albumin < 44.5 g/L had a higher incidence of postoperative complications and higher median comprehensive complication index than patients with preoperative albumin ≥ 44.5 g/L. CONCLUSIONS: This study highlighted that preoperative serum albumin is an independent predictor of postoperative complications after pancreas surgery.

Arsenic may be a carcinogenic determinant of a subset of gallbladder cancer: A pilot study.

Gallbladder cancer (GBC) is one of the deadliest malignancy and treatment options are deplorably limited. Better strategies of prevention are urgently needed but knowledge on risk factors remains scarce. Recent data suggested that arsenic (As) may be involved in GBC carcinogenesis but the question remains debated. To date, there are no data on As measurement in GBC samples. This pilot study aimed to measure As concentrations in tissue samples from patients with GBC compared to non-cancerous gallbladder (NCGB). Included patients underwent cholecystectomy at Hospital Clinico Universidad de Chile, Santiago in Chile, a country with high As exposure, between 2001 and 2020. Tissue samples were preserved in formalin-fixed, paraffin-embedded blocks. Selected samples were retrieved, processed and submitted to inductively coupled plasma mass spectrometry (ICP-MS) to determine As concentrations. A total of 77 patients were included, including 35 GBC and 42 NCGB. The two groups were comparable, except for age (68 vs. 49 years, p < 0.001). Measured in 11 GBC and 38 NCGB, total As was detected in 5 GBC (14%) compared to 0 NCGB samples (p < 0.001). GBC group also showed higher median values of As compared to NCGB (p < 0.001). This pilot study provided a proof-of-concept to measure As concentrations in gallbladder samples and showed higher level of As in GBC samples compared to NCGB, paving the way for future studies aiming to investigate the impact of As on GBC, which may contribute to the prevention of this deadly disease.

A Retrospective Study of the Role of Perioperative Serum Albumin and the Albumin-Bilirubin Grade in Predicting Post-Liver Transplant Length of Stay.

INTRODUCTION: Serum albumin's association with liver transplant outcomes has been investigated with mixed findings. This study aimed to evaluate perioperative albumin level, independently and as part of the albumin-bilirubin (ALBI) grade, as a predictor of post-liver transplant hospital and intensive care unit (ICU) length of stay (LOS). METHODS: Adult liver-only transplant recipients at our institution from September 2011 to May 2019 were included in this retrospective study. Repeat transplants were excluded. Demographic, laboratory, and hospital course data were extracted from an institutional data warehouse. Negative binomial regression was used to assess the association of LOS with ALBI grade, age, BMI, ASA score, Elixhauser comorbidity index, MELD-Na, warm ischemia time, units of platelets and cryoprecipitate transfused, and preoperative serum albumin. RESULTS: Six hundred and sixty-three liver transplant recipients met inclusion criteria. The median preoperative serum albumin was 3.1 [2.6-3.6] g/dL. The median postoperative ICU and hospital LOS were 3.8 [2.4-6.8] and 12 [8-20] days, respectively. Preoperative serum albumin predicted hospital but not ICU LOS (ratio .9 [95% confidence interval (CI) .84-.99], P = .03, hospital LOS vs ratio .92 [95% CI 0.84-1.02], P = .10, ICU LOS). For patients with MELD-Na ≤ 20, ALBI grade-3 predicted longer hospital and ICU LOS (ratio 1.40 [95% CI 1.18-1.66], P < .001, hospital LOS vs ratio 1.62 [95% CI 1.32-1.99], P < .001, ICU LOS). These associations were not significant for patients with MELD-Na > 20. CONCLUSIONS: Serum albumin predicted post-liver transplant hospital LOS. ALBI grade-3 predicted increased hospital and ICU LOS in low MELD-Na recipients.

Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma.

BACKGROUND & AIMS: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. METHODS: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. RESULTS: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. CONCLUSION: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.

Arsenic-contaminated drinking water and cholangiocarcinoma.

INTRODUCTION: Cholangiocarcinoma (CCA) is an aggressive tumor occurring in bile ducts and associated with dismal outcomes. It can be classified according to anatomical location as intrahepatic cholangiocarcinoma (ICC) or extrahepatic cholangiocarcinoma (ECC). Although some risk factors have been identified, our understanding of these tumors remains limited. Arsenic (As) is a prevalent toxicant with established associations with bladder, skin and lung cancers while pilot data on its potential carcinogenic role on digestive tumors are emerging. This ecological study aimed to investigate the association between exposure to As-contaminated drinking water and CCA. METHODS: Analyses were conducted for the US, Taiwan and India due to the quality of publicly available datasets including small area-level information. Statistics included coefficient correlations analyses as well as univariate and multivariate linear regressions. RESULTS: In the US, no correlation was observed between As and CCA. In Taiwan, correlations were identified for ICC in men (Spearman = 0.55, P = 0.01) and women (Spearman = 0.67, P < 0.01), as well as for ECC in men (Spearman = 0.62, P < 0.01). In India, counties with As level of at least 50 µg/L showed higher incidences of ECC in men ( R2 = 0.26, P = 0.01) and women ( R2 = 0.31, P < 0.01). CONCLUSION: These findings highlighted a potential carcinogenic impact of As in drinking water on bile duct cancers, paving the way for future studies aiming to replicate this association with individual data as well as its clinical and ecological implications.

International assessment and validation of the prognostic role of lymph node ratio in patients with resected pancreatic head ductal adenocarcinoma.

Background: Lymph node ratio (LNR; positive/harvested lymph nodes) was identified as overall survival predictor in several cancers, including pancreatic adenocarcinoma. It remains unclear if LNR is predictive of overall survival in pancreatic adenocarcinoma patients staged pN2. This study assessed the prognostic overall survival role of LNR in pancreatic adenocarcinoma patients in relation with lymph node involvement. Methods: A retrospective international study in six different centers (Europe and United States) was performed. Pancreatic adenocarcinoma patients who underwent pancreatoduodenectomy from 2000 to 2017 were included. Patients with neoadjuvant treatment, metastases, R2 resections, or missing data regarding nodal status were excluded. Survival curves were calculated using Kaplan-Meier method and compared using log-rank test. Multivariable Cox regressions were performed to find independent overall survival predictors adjusted for potential confounders. Results: A total of 1,327 patients were included. Lymph node involvement (pN+) was found in 1,026 patients (77%), 561 pN1 (55%) and 465 pN2 (45%). Median LNR in pN+ patients was 0.214 [interquartile range (IQR): 0.105-0.364]. On multivariable analysis, LNR was the strongest overall survival predictor in the entire cohort [hazard ratio (HR) =5.5; 95% confidence interval (CI): 3.1-9.9; P<0.001] and pN+ patients (HR =3.8; 95% CI: 2.2-6.6; P<0.001). Median overall survival was better in patients with LNR <0.225 compared to patients with LNR ≥0.225 in the entire cohort and pN+ patients. Similar results were found in pN2 patients (worse overall survival when LNR ≥0.225). Conclusions: LNR appeared as an important prognostic factor in patients undergoing surgery for pancreatic adenocarcinoma and permitted to stratify overall survival in pN2 patients. LNR should be routinely used in complement to tumor-node-metastasis (TNM) stage to better predict patient prognosis.

An algorithm based on the postoperative decrease of albumin (ΔAlb) to anticipate complications after liver surgery.

BACKGROUND: Perioperative decrease of albumin (ΔAlb) appeared as a promising predictor of complications after digestive surgery, but its role after liver surgery remains unclear. This study aimed to analyze whether and how ΔAlb can be used to predict complications after liver surgery. METHODS: A bicentric retrospective analysis of patients undergoing liver surgery (2010-2016) was performed, following TRIPOD guidelines. The preoperative and postoperative difference of albumin was calculated on POD 0 and defined as ΔAlb. Patients with any missing variable were excluded. The primary endpoint was overall complications according to the Clavien classification. A multiparametric algorithm based on ΔAlb was generated to optimize prediction performance. RESULTS: A total of 110 patients were analyzed. At least one complication occurred in 66 (60%) patients. Patients with and without complication showed a ΔAlb of 15.8 vs. 9.5 g/L (p<0.001). Area under ROC curve (AUC) of ΔAlb was 0.75 (p<0.01.). The ΔAlb-based algorithm showed an AUC of 0.84 (p<0.01), significantly improving performance (p=0.03). Multivariable analysis identified ΔAlb as independent predictor of complications (HR, 1.12; 95% CI, 1.01-1.07; p = 0.002). CONCLUSIONS: ΔAlb appeared as a promising predictor independently associated with the risk of complication after liver surgery. The study presents a novel decision-tree based on ΔAlb to anticipate complications.

Is liquid biopsy the future commutator of decision-making in liver transplantation for hepatocellular carcinoma?

Liver transplant (LT) is the most favorable treatment option for patients with early stage hepatocellular carcinoma (HCC). Numerous attempts have been pursued to establish eligibility criteria and select HCC patients for LT, leading to various systems that essentially integrate clinico-morphological variables. Lacking of sufficient granularity to recapitulate the biological complexity of the disease, all these alternatives display substantial limitations and are thus undeniably imperfect. Liquid biopsy, defined as the molecular analysis of circulating analytes released by a cancer into the bloodstream, was revealed as an incomparable tool in the management of cancers, including HCC. It appears as an ideal candidate to refine selection criteria of LT in HCC. The present comprehensive review analyzed the available literature on this topic. Data in the field, however, remain scarce with only 17 studies. Although rare, these studies provided important and encouraging findings highlighting notable prognostic values and supporting the contribution of liquid biopsy in this specific clinical scenario. These results underpinned the critical and urgent need to intensify and accelerate research on liquid biopsy, in order to determine whether and how liquid biopsy may be integrated in the decision-making of LT in HCC.

Early enteral vs. oral nutrition after Whipple procedure: Study protocol for a multicentric randomized controlled trial (NUTRIWHI trial).

Background: Malnutrition has been shown to be a risk factor for postoperative complications after pancreatoduodenectomy (PD). In addition, patients needing a PD, such as patients with pancreatic cancer or chronic pancreatitis, often are malnourished. The best route of postoperative nutrition after PD remains unknown. The aim of this randomized controlled trial is to evaluate if early postoperative enteral nutrition can decrease complications after PD compared to oral nutrition. Methods: This multicenter, open-label, randomized controlled trial will include 128 patients undergoing PD with a nutritional risk screening ≥3. Patients will be randomized 1:1 using variable block randomization stratified by center to receive either early enteral nutrition (intervention group) or oral nutrition (control group) after PD. Patients in the intervention group will receive enteral nutrition since the first night of the operation (250 ml/12 h), and enteral nutrition will be increased daily if tolerated until 1000 ml/12 h. The primary outcome will be the Comprehensive Complication Index (CCI) at 90 days after PD. Discussion: This study with its multicentric and randomized design will permit to establish if early postoperative enteral nutrition after PD improves postoperative outcomes compared to oral nutrition in malnourished patients. Clinical trial registration: https://clinicaltrials.gov/(NCT05042882) Registration date: September 2021.