Prevention of Post-Hepatectomy Liver Failure in Cirrhotic Patients Undergoing Minimally Invasive Liver Surgery for HCC: Has the Round Ligament to Be Preserved?

Post-hepatectomy liver failure (PHLF) represents a major cause of morbidity and mortality after liver resection. The factors related to PHLF are represented not only by the volume and function of the future liver remnant but also by the severity of portal hypertension. The aim of this study was to assess whether the preservation of the round ligament (RL) may mitigate portal hypertension, thus decreasing the risk of PHLF and ascites in cirrhotic patients while undergoing minimally invasive liver surgery (MILS). All the cirrhotic patients who underwent MILS for HCC from 2016 to 2021 in two international tertiary referral centers were retrospectively analyzed, comparing cases with the RL preserved vs. those with the RL divided. Only patients with cirrhosis ≥ Child A6, portal hypertension, and ICG-R15 > 10% were included. Main postoperative outcomes were compared, and the risk factors for postoperative ascites (severe PHLF, grade B/C) were investigated through a logistic regression. After the application of the selection criteria, a total of 130 MILS patients were identified, with 86 patients with the RL preserved and 44 with the RL divided. The RL-preserved group showed lower incidences of severe PHLF (7.0% vs. 20.5%, p = 0.023) and ascites (5.8% vs. 18.2%, p = 0.026) in comparison with the RL-divided group. After uni/multivariate analysis, the risk factors related to postoperative ascites were RL division and platelets < 92 × 103/µL, calculated with ROC analysis. The preservation of the round ligament during MILS may mitigate portal hypertension, preventing PHLF and ascites in cirrhotic patients with borderline liver function.

Intraductal papillary neoplasm of the bile duct: The new frontier of biliary pathology.

Intraductal papillary neoplasms of the bile duct (IPNBs) represent a rare variant of biliary tumors characterized by a papillary growth within the bile duct lumen. Since their first description in 2001, several classifications have been proposed, mainly based on histopathological, radiological and clinical features, although no specific guidelines addressing their management have been developed. Bile duct neoplasms generally develop through a multistep process, involving different precursor pathways, ranging from the initial lesion, detectable only microscopically, i.e. biliary intraepithelial neoplasia, to the distinctive grades of IPNB until the final stage represented by invasive cholangiocarcinoma. Complex and advanced investigations, mainly relying on magnetic resonance imaging (MRI) and cholangioscopy, are required to reach a correct diagnosis and to define an adequate bile duct mapping, which supports proper treatment. The recently introduced subclassifications of types 1 and 2 highlight the histopathological and clinical aspects of IPNB, as well as their natural evolution with a particular focus on prognosis and survival. Aggressive surgical resection, including hepatectomy, pancreaticoduodenectomy or both, represents the treatment of choice, yielding optimal results in terms of survival, although several endoscopic approaches have been described. IPNBs are newly recognized preinvasive neoplasms of the bile duct with high malignant potential. The novel subclassification of types 1 and 2 defines the histological and clinical aspects, prognosis and survival. Diagnosis is mainly based on MRI and cholangioscopy. Surgical resection represents the mainstay of treatment, although endoscopic resection is currently applied to nonsurgically fit patients. New frontiers in genetic research have identified the processes underlying the carcinogenesis of IPNB, to identify targeted therapies.

Neoadjuvant Treatment in Resectable Pancreatic Cancer. Is It Time for Pushing on It?

Pancreatic resection still represents the only curative option for patients affected by pancreatic ductal adenocarcinoma (PDAC). However, the association with modern chemotherapy regimens is a key factor in improving the inauspicious oncological outcome. The benefit of neoadjuvant treatment (NAT) for borderline resectable/locally advanced PDAC has been demonstrated; this evidence raises the question of whether even resectable PDAC should undergo NAT rather than upfront surgery. NAT may avoid futile surgery because of undetected distant metastases or aggressive tumor biology, providing more effective systemic control of the disease, which is hampered when adjuvant chemotherapy is delayed or precluded. However, recent data show controversial results regarding the efficacy and safety of NAT in resectable PDAC compared to upfront surgery. Although several prospective studies and meta-analyses indicate better oncologic outcomes after NAT, there are some biases, such as the methodological approaches used to capture the events of interest, which could make these results hardly reproducible. For instance, per-protocol studies, considering only the postoperative outcomes, tend to overestimate the performance of NAT by excluding patients who will never be suitable for surgery due to the development of chemotoxicity or tumor progression. To draw reliable conclusions, the studies should capture the events of interest of both strategies (NAT/upfront surgery) from the time of allocation to a specific treatment in an intention-to-treat fashion. This critical review highlights the current literature data concerning the use of NAT in resectable PDAC, summarizing the results of high-quality studies and focusing on the methodological issues of the most recent pieces of evidence.

Neoadjuvant therapy in the treatment of hilar cholangiocarcinoma: Review of the literature.

Cholangiocarcinoma (CCA) is a malignant tumor of the biliary system and includes, according to the anatomical classification, intra hepatic CCA (iCCA), hilar CCA (hCCA) and distal CCA (dCCA). Hilar CCA is the most challenging type in terms of diagnosis, treatment and prognosis. Surgery is the only treatment possibly providing long-term survival, but only few patients are considered resectable at the time of diagnosis. In fact, tumor's extension to segmentary or subsegmentary biliary ducts, along with large lymph node involvement or intrahepatic metastases, precludes the surgical approach. To achieve R0 margins is mandatory for the disease-free survival and overall survival. In case of unresectable locally advanced hCCA, radiochemotherapy (RCT) as neoadjuvant treatment demonstrated to be a therapeutic option before either hepatic resection or liver transplantation. Before liver surgery, RCT is believed to enhance the R0 margins rate. For patients meeting the Mayo Clinic criteria, RCT prior to orthotopic liver transplant (OLT) has proved to produce acceptable 5-years survivals. In this review, we analyze the current role of neoadjuvant RCT before resection as well as before OLT.

Treatment of hepatocellular carcinoma: a cost analysis of yttrium-90 transarterial radioembolization versus sorafenib.

AIM: The aim was to evaluate cost-effectiveness of yttrium-90 transarterial radioembolization (TARE) in comparison to sorafenib treatment. PATIENTS & METHODS: A single-center, retrospective, observational study was performed, 166 patients with intermediate-/advanced-stage hepatocellular carcinoma were treated with sorafenib and 19 with TARE. The patients out of the sorafenib group matching the inclusion criteria for TARE, were reassigned to a subgroup SOR3. RESULTS: Mean costs for SOR3 patients amounted to €27,992 per patient, instead for TARE treatment, mean expense per patient was €17,761 (p = 0.028). Overall survival was similar between the two groups, while midterm survival rates (p = 0.012) were significantly higher with TARE treatment. CONCLUSION: TARE causes significantly lower treatment costs than sorafenib with better outcome in midterm survival.

A standardized model of brain death, donor treatment, and lung transplantation for studies on organ preservation and reconditioning.

BACKGROUND: We set a model of brain death, donor management, and lung transplantation for studies on lung preservation and reconditioning before transplantation. METHODS: Ten pigs (39.7 ± 5.9 Kg) were investigated. Five animals underwent brain death and were treated as organ donors; the lungs were then procured and cold stored (Ischemia). Five recipients underwent left lung transplantation and post-reperfusion follow-up (Graft). Cardiorespiratory and metabolic parameters were collected. Lung gene expression of cytokines (tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interferon gamma (IFNγ), high mobility group box-1 (HMGB-1)), chemokines (chemokine CC motif ligand-2 (CCL2-MCP-1), chemokine CXC motif ligand-10 (CXCL-10), interleukin-8 (IL-8)), and endothelial activation markers (endothelin-1 (EDN-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), selectin-E (SELE)) was assessed by real-time polymerase chain reaction (PCR). RESULTS: Tachycardia and hypertension occurred during brain death induction; cardiac output rose, systemic vascular resistance dropped (P < 0.05), and diabetes insipidus occurred. Lung-protective ventilation strategy was applied: 9 h after brain death induction, PaO2 was 192 ± 12 mmHg at positive end-expiratory pressure (PEEP) 8.0 ± 1.8 cmH2O and FiO2 of 40%; wet-to-dry ratio (W/D) was 5.8 ± 0.5, and extravascular lung water (EVLW) was 359 ± 80 mL. Procured lungs were cold-stored for 471 ± 24 min (Ischemia) at the end of which W/D was 6.1 ± 0.9. Left lungs were transplanted and reperfused (warm ischemia 98 ± 14 min). Six hours after controlled reperfusion, PaO2 was 192 ± 23 mmHg (PEEP 8.7 ± 1.5 cmH2O, FiO2 40%), W/D was 5.6 ± 0.4, and EVLW was 366 ± 117 mL. Levels of IL-8 rose at the end of donor management (BD, P < 0.05); CCL2-MCP-1, IL-8, HMGB-1, and SELE were significantly altered after reperfusion (Graft, P < 0.05). CONCLUSIONS: We have set a standardized, reproducible pig model resembling the entire process of organ donation that may be used as a platform to test in vivo and ex vivo strategies of donor lung optimization before transplantation.

Early and late de novo tumors after liver transplantation in adults: the late onset of bladder tumors in men.

BACKGROUND: De novo tumors (DNT) after liver transplantation (LT) represent a growing concern. PATIENTS AND METHODS: We analyzed the incidence of DNT, type, time of onset, risk factors and mortality (as of 2010) in 494 adult patients transplanted in the last 26 years (1983-2009). RESULTS: DNT occurred in 41 (8.3%) of the patients. The Standardized Incidence Ratio (SIR) compared with the Italian population was 1.8. There was a higher incidence in males (SIR 2.0), an expected extremely high rate of Kaposi's sarcoma (SIR 127.95) and unexpected higher rates of tumors of the bladder in males (SIR 3.3). The incidence of DNT was higher within the first two years of LT (SIR 2.7) for Kaposi's sarcoma (SIR 393.3) and after 10 years (SIR 1.7) for bladder tumors (SIR 10.6). Multivariate analysis identified alcoholic cirrhosis (HR = 3.0, 95% CI = 1.2-7.8) and sclerosing cholangitis (HR = 3.5, 95% CI = 1.1-11.3) in the recipient as main risk factors for the occurrence of DNT. CONCLUSIONS: Surveillance protocols for DNT must be specifically oriented to patients transplanted for alcoholic cirrhosis and sclerosing cholangitis. They should focus on early detection of Kaposi's sarcomas, and more remarkably, on late development bladder tumors in men after LT.

ß-adrenergic agonist infusion during extracorporeal lung perfusion: effects on glucose concentration in the perfusion fluid and on lung function.

BACKGROUND: We recently showed in a pig model of ex vivo lung perfusion (EVLP) that lung edema correlates with glucose consumption. We investigated whether salbutamol, a ß-adrenergic receptor agonist known to upregulate fluid transport in the lung, modulates glucose concentration in the perfusate during EVLP. METHODS: Lungs from domestic pigs underwent normothermic EVLP. At the end of controlled reperfusion, lungs were ventilated and perfused for 60 minutes, then randomized to salbutamol (ß-Agonist) infusion or placebo (Control) for 180 minutes. Functional parameters were assessed. RESULTS: In the ß-Agonist group, glucose concentration decreased over time more than corresponding Control values (analysis of variance [ANOVA], p = 0.05). Mean pulmonary artery pressure (mPAP) was 16 ± 1 mm Hg in the ß-Agonist group vs 21 ± 1 mm Hg in the Controls (ANOVA p < 0.05). Baseline mPAP was correlated with the drop of mPAP after the ß-agonist infusion (R(2) = 0.856, p < 0.05). Dynamic compliance dropped from 51 ± 10 to 31 ± 6 ml/cm H(2)O in the ß-Agonist group and from 60 ± 4 to 21 ± 3 ml/cm H(2)O in the Control group (ANOVA, p < 0.05 ß-agonist vs Control). The Δ partial pressure of oxygen/fraction of inspired oxygen was 418 ± 15 and 393 ± 12 mm Hg in the ß-Agonist and Control groups, respectively (t-test p = 0.106). CONCLUSIONS: Glucose concentration in the perfusate was affected by salbutamol. Salbutamol was associated with lower pulmonary pressures and better lung mechanics. These data suggest a possible role for salbutamol as a pharmacologic adjunct during EVLP before transplantation.

Lung stress and strain during mechanical ventilation: any safe threshold?

RATIONALE: Unphysiologic strain (the ratio between tidal volume and functional residual capacity) and stress (the transpulmonary pressure) can cause ventilator-induced lung damage. OBJECTIVES: To identify a strain-stress threshold (if any) above which ventilator-induced lung damage can occur. METHODS: Twenty-nine healthy pigs were mechanically ventilated for 54 hours with a tidal volume producing a strain between 0.45 and 3.30. Ventilator-induced lung damage was defined as net increase in lung weight. MEASUREMENTS AND MAIN RESULTS: Initial lung weight and functional residual capacity were measured with computed tomography. Final lung weight was measured using a balance. After setting tidal volume, data collection included respiratory system mechanics, gas exchange and hemodynamics (every 6 h); cytokine levels in serum (every 12 h) and bronchoalveolar lavage fluid (end of the experiment); and blood laboratory examination (start and end of the experiment). Two clusters of animals could be clearly identified: animals that increased their lung weight (n = 14) and those that did not (n = 15). Tidal volume was 38 ± 9 ml/kg in the former and 22 ± 8 ml/kg in the latter group, corresponding to a strain of 2.16 ± 0.58 and 1.29 ± 0.57 and a stress of 13 ± 5 and 8 ± 3 cm H(2)O, respectively. Lung weight gain was associated with deterioration in respiratory system mechanics, gas exchange, and hemodynamics, pulmonary and systemic inflammation and multiple organ dysfunction. CONCLUSIONS: In healthy pigs, ventilator-induced lung damage develops only when a strain greater than 1.5-2 is reached or overcome. Because of differences in intrinsic lung properties, caution is warranted in translating these findings to humans.