The Effect of a Liver Transplant Program on the Outcomes of Resectable Hepatocellular Carcinoma: A Nationwide Multicenter Analysis.

OBJECTIVE: To evaluate the effect of a liver transplantation (LT) program on the outcomes of resectable hepatocellular carcinoma (HCC). BACKGROUND: Surgical treatment of HCC includes both hepatic resection (HR) and LT. However, the presence of cirrhosis and the possibility of recurrence make the management of this disease complex and probably different according to the presence of a LT program. METHODS: Patients undergoing HR for HCC between January 2005 and December 2019 were identified from a national database of HCC. The main study outcomes were major surgical complications according to the Comprehensive Complication Index, posthepatectomy liver failure (PHLF), 90-day mortality, overall survival, and disease-free survival. Secondary outcomes were salvage liver transplantation (SLT) and postrecurrence survival. RESULTS: A total of 3202 patients were included from 25 hospitals over the study period. Three of 25 (12%) had an LT program. The presence of an LT program within a center was associated with a reduced probability of PHLF (odds ratio=0.38) but not with overall survival and disease-free survival. There was an increased probability of SLT when HR was performed in a transplant hospital (odds ratio=12.05). Among transplant-eligible patients, those who underwent LT had a significantly longer postrecurrence survival. CONCLUSIONS: This study showed that the presence of a LT program was associated with decreased PHLF rates and an increased probability to receive SLT in case of recurrence.

Survival benefit of second line therapies for recurrent hepatocellular carcinoma: repeated hepatectomy, thermoablation and second-line transplant referral in a real life national scenario.

BACKGROUND: Despite second-line transplant(SLT) for recurrent hepatocellular carcinoma(rHCC) leads to the longest survival after recurrence(SAR), its real applicability has never been reported. The aim was to compare the SAR of SLT versus repeated hepatectomy and thermoablation(CUR group). METHODS: Patients were enrolled from the Italian register HE.RC.O.LE.S. between 2008 and 2021. Two groups were created: CUR versus SLT. A propensity score matching (PSM) was run to balance the groups. RESULTS: 743 patients were enrolled, CUR = 611 and SLT = 132. Median age at recurrence was 71(IQR 6575) years old and 60(IQR 53-64, p < 0.001) for CUR and SLT respectively. After PSM, median SAR for CUR was 43 months(95%CI = 37 - 93) and not reached for SLT(p < 0.001). SLT patients gained a survival benefit of 9.4 months if compared with CUR. MilanCriteria(MC)-In patients were 82.7% of the CUR group. SLT(HR 0.386, 95%CI = 0.23 - 0.63, p < 0.001) and the MELD score(HR 1.169, 95%CI = 1.07 - 1.27, p < 0.001) were the only predictors of mortality. In case of MC-Out, the only predictor of mortality was the number of nodules at recurrence(HR 1.45, 95%CI= 1.09 - 1.93, p = 0.011). CONCLUSION: It emerged an important transplant under referral in favour of repeated hepatectomy or thermoablation. In patients with MC-Out relapse, the benefit of SLT over CUR was not observed.

Lipidomics of Bioactive Lipids in Alzheimer's and Parkinson's Diseases: Where Are We?

Lipids are not only constituents of cellular membranes, but they are also key signaling mediators, thus acting as "bioactive lipids". Among the prominent roles exerted by bioactive lipids are immune regulation, inflammation, and maintenance of homeostasis. Accumulated evidence indicates the existence of a bidirectional relationship between the immune and nervous systems, and lipids can interact particularly with the aggregation and propagation of many pathogenic proteins that are well-renowned hallmarks of several neurodegenerative disorders, including Alzheimer's (AD) and Parkinson's (PD) diseases. In this review, we summarize the current knowledge about the presence and quantification of the main classes of endogenous bioactive lipids, namely glycerophospholipids/sphingolipids, classical eicosanoids, pro-resolving lipid mediators, and endocannabinoids, in AD and PD patients, as well as their most-used animal models, by means of lipidomic analyses, advocating for these lipid mediators as powerful biomarkers of pathology, diagnosis, and progression, as well as predictors of response or activity to different current therapies for these neurodegenerative diseases.

The largest western experience on salvage hepatectomy for recurrent hepatocellular carcinoma: propensity score-matched analysis on behalf of He.RC.O.Le.Study Group.

BACKGROUND: We aimed to evaluate, in a large Western cohort, perioperative and long-term oncological outcomes of salvage hepatectomy (SH) for recurrent hepatocellular carcinoma (rHCC) after primary hepatectomy (PH) or locoregional treatments. METHODS: Data were collected from the Hepatocarcinoma Recurrence on the Liver Study Group (He.RC.O.Le.S.) Italian Registry. After 1:1 propensity score-matched analysis (PSM), two groups were compared: the PH group (patients submitted to resection for a first HCC) and the SH group (patients resected for intrahepatic rHCC after previous HCC-related treatments). RESULTS: 2689 patients were enrolled. PH included 2339 patients, SH 350. After PSM, 263 patients were selected in each group with major resected nodule median size, intraoperative blood loss and minimally invasive approach significantly lower in the SH group. Long-term outcomes were compared, with no difference in OS and DFS. Univariate and multivariate analyses revealed only microvascular invasion as an independent prognostic factor for OS. CONCLUSION: SH proved to be equivalent to PH in terms of safety, feasibility and long-term outcomes, consistent with data gathered from East Asia. In the awaiting of reliable treatment-allocating algorithms for rHCC, SH appears to be a suitable alternative in patients fit for surgery, regardless of the previous therapeutic modality implemented.

Pharmacological interventions for acute pancreatitis.

BACKGROUND: In people with acute pancreatitis, it is unclear what the role should be for medical treatment as an addition to supportive care such as fluid and electrolyte balance and organ support in people with organ failure. OBJECTIVES: To assess the effects of different pharmacological interventions in people with acute pancreatitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2016, Issue 9), MEDLINE, Embase, Science Citation Index Expanded, and trial registers to October 2016 to identify randomised controlled trials (RCTs). We also searched the references of included trials to identify further trials. SELECTION CRITERIA: We considered only RCTs performed in people with acute pancreatitis, irrespective of aetiology, severity, presence of infection, language, blinding, or publication status for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two review authors independently identified trials and extracted data. We did not perform a network meta-analysis as planned because of the lack of information on potential effect modifiers and differences of type of participants included in the different comparisons, when information was available. We calculated the odds ratio (OR) with 95% confidence intervals (CIs) for the binary outcomes and rate ratios with 95% CIs for count outcomes using a fixed-effect model and random-effects model. MAIN RESULTS: We included 84 RCTs with 8234 participants in this review. Six trials (N = 658) did not report any of the outcomes of interest for this review. The remaining 78 trials excluded 210 participants after randomisation. Thus, a total of 7366 participants in 78 trials contributed to one or more outcomes for this review. The treatments assessed in these 78 trials included antibiotics, antioxidants, aprotinin, atropine, calcitonin, cimetidine, EDTA (ethylenediaminetetraacetic acid), gabexate, glucagon, iniprol, lexipafant, NSAIDs (non-steroidal anti-inflammatory drugs), octreotide, oxyphenonium, probiotics, activated protein C, somatostatin, somatostatin plus omeprazole, somatostatin plus ulinastatin, thymosin, ulinastatin, and inactive control. Apart from the comparison of antibiotics versus control, which included a large proportion of participants with necrotising pancreatitis, the remaining comparisons had only a small proportion of patients with this condition. Most trials included either only participants with severe acute pancreatitis or included a mixture of participants with mild acute pancreatitis and severe acute pancreatitis (75 trials). Overall, the risk of bias in trials was unclear or high for all but one of the trials. SOURCE OF FUNDING: seven trials were not funded or funded by agencies without vested interest in results. Pharmaceutical companies partially or fully funded 21 trials. The source of funding was not available from the remaining trials.Since we considered short-term mortality as the most important outcome, we presented only these results in detail in the abstract. Sixty-seven studies including 6638 participants reported short-term mortality. There was no evidence of any differences in short-term mortality in any of the comparisons (very low-quality evidence). With regards to other primary outcomes, serious adverse events (number) were lower than control in participants taking lexipafant (rate ratio 0.67, 95% CI 0.46 to 0.96; N = 290; 1 study; very low-quality evidence), octreotide (rate ratio 0.74, 95% CI 0.60 to 0.89; N = 770; 5 studies; very low-quality evidence), somatostatin plus omeprazole (rate ratio 0.36, 95% CI 0.19 to 0.70; N = 140; 1 study; low-quality evidence), and somatostatin plus ulinastatin (rate ratio 0.30, 95% CI 0.15 to 0.60; N = 122; 1 study; low-quality evidence). The proportion of people with organ failure was lower in octreotide than control (OR 0.51, 95% CI 0.27 to 0.97; N = 430; 3 studies; very low-quality evidence). The proportion of people with sepsis was lower in lexipafant than control (OR 0.26, 95% CI 0.08 to 0.83; N = 290; 1 study; very low-quality evidence). There was no evidence of differences in any of the remaining comparisons in these outcomes or for any of the remaining primary outcomes (the proportion of participants experiencing at least one serious adverse event and the occurrence of infected pancreatic necrosis). None of the trials reported heath-related quality of life. AUTHORS' CONCLUSIONS: Very low-quality evidence suggests that none of the pharmacological treatments studied decrease short-term mortality in people with acute pancreatitis. However, the confidence intervals were wide and consistent with an increase or decrease in short-term mortality due to the interventions. We did not find consistent clinical benefits with any intervention. Because of the limitations in the prognostic scoring systems and because damage to organs may occur in acute pancreatitis before they are clinically manifest, future trials should consider including pancreatitis of all severity but power the study to measure the differences in the subgroup of people with severe acute pancreatitis. It may be difficult to power the studies based on mortality. Future trials in participants with acute pancreatitis should consider other outcomes such as complications or health-related quality of life as primary outcomes. Such trials should include health-related quality of life, costs, and return to work as outcomes and should follow patients for at least three months (preferably for at least one year).

Laparoscopic left lateral hepatectomy for colorectal metastasis is the standard of care.

PURPOSE: Over the last decade, laparoscopic liver surgery has significantly evolved. The aim of this study was to analyse the outcomes of Laparoscopic Left Lateral Hepatectomy (LLLH) for colorectal cancer (CRC) metastases in a tertiary referral hepato-pancreato-biliary centre. METHODS: A consecutive series of patients undergoing LLLH between January 2009 and April 2013 were analysed using prospectively collected data in a tertiary referral HPB centre. In particular, the study focused on patients who had LLLH for colorectal liver metastasis (CRLM). The following features were analysed: operative time, intraoperative blood loss, number and size of tumours, resection margins, complication rates, follow up period and recurrence rates. RESULTS: A total of 17 patients were finally included. There were no bile leaks or collections and no postoperative bleeding. The median hospital stay was 4 days (range 2-10). The median size of the metastatic lesions was 28.1 mm (range 8-56). The resection was R0 in all except 2 patients (11%) where the margin was less than 1 mm. The mean resection margin was 14.6 mm (range 1-50). Eight patients (47%) did not develop any recurrence till latest follow up. Seven patients (41%) developed recurrence in the liver or lungs. The median time to recurrence was 11 months (range 2-12). There was only one death in the follow up period (22-77 months). Sixteen patients (94%) were alive at the latest follow up. CONCLUSION: LLLH for CRLM is safe and can be performed with low complication rates, adequate resection margins, short hospital stay, and oncologic outcomes similar to those of open surgery.

Network approach in liquidomics landscape.

Tissue-based biopsy is the present main tool to explore the molecular landscape of cancer, but it also has many limits to be frequently executed, being too invasive with the risk of side effects. These limits and the ability of cancer to constantly evolve its genomic profile, have recently led to the need of a less invasive and more accurate alternative, such as liquid biopsy. By searching Circulating Tumor Cells and residues of their nucleic acids or other tumor products in body fluids, especially in blood, but also in urine, stools and saliva, liquid biopsy is becoming the future of clinical oncology. Despite the current lack of a standardization for its workflows, that makes it hard to be reproduced, liquid biopsy has already obtained promising results for cancer screening, diagnosis, prognosis, and risk of recurrence.Through a more accessible molecular profiling of tumors, it could become easier to identify biomarkers predictive of response to treatment, such as EGFR mutations in non-small cell lung cancer and KRAS mutations in colorectal cancer, or Microsatellite Instability and Mismatch Repair as predictive markers of pembrolizumab response.By monitoring circulating tumor DNA in longitudinal repeated sampling of blood we could also predict Minimal Residual Disease and the risk of recurrence in already radically resected patients.In this review we will discuss about the current knowledge of limitations and strengths of the different forms of liquid biopsies for its inclusion in normal cancer management, with a brief nod to their newest biomarkers and its future implications.

Machine Learning Predictive Model to Guide Treatment Allocation for Recurrent Hepatocellular Carcinoma After Surgery.

Importance: Clear indications on how to select retreatments for recurrent hepatocellular carcinoma (HCC) are still lacking. Objective: To create a machine learning predictive model of survival after HCC recurrence to allocate patients to their best potential treatment. Design, Setting, and Participants: Real-life data were obtained from an Italian registry of hepatocellular carcinoma between January 2008 and December 2019 after a median (IQR) follow-up of 27 (12-51) months. External validation was made on data derived by another Italian cohort and a Japanese cohort. Patients who experienced a recurrent HCC after a first surgical approach were included. Patients were profiled, and factors predicting survival after recurrence under different treatments that acted also as treatment effect modifiers were assessed. The model was then fitted individually to identify the best potential treatment. Analysis took place between January and April 2021. Exposures: Patients were enrolled if treated by reoperative hepatectomy or thermoablation, chemoembolization, or sorafenib. Main Outcomes and Measures: Survival after recurrence was the end point. Results: A total of 701 patients with recurrent HCC were enrolled (mean [SD] age, 71 [9] years; 151 [21.5%] female). Of those, 293 patients (41.8%) received reoperative hepatectomy or thermoablation, 188 (26.8%) received sorafenib, and 220 (31.4%) received chemoembolization. Treatment, age, cirrhosis, number, size, and lobar localization of the recurrent nodules, extrahepatic spread, and time to recurrence were all treatment effect modifiers and survival after recurrence predictors. The area under the receiver operating characteristic curve of the predictive model was 78.5% (95% CI, 71.7%-85.3%) at 5 years after recurrence. According to the model, 611 patients (87.2%) would have benefited from reoperative hepatectomy or thermoablation, 37 (5.2%) from sorafenib, and 53 (7.6%) from chemoembolization in terms of potential survival after recurrence. Compared with patients for which the best potential treatment was reoperative hepatectomy or thermoablation, sorafenib and chemoembolization would be the best potential treatment for older patients (median [IQR] age, 78.5 [75.2-83.4] years, 77.02 [73.89-80.46] years, and 71.59 [64.76-76.06] years for sorafenib, chemoembolization, and reoperative hepatectomy or thermoablation, respectively), with a lower median (IQR) number of multiple recurrent nodules (1.00 [1.00-2.00] for sorafenib, 1.00 [1.00-2.00] for chemoembolization, and 2.00 [1.00-3.00] for reoperative hepatectomy or thermoablation). Extrahepatic recurrence was observed in 43.2% (n = 16) for sorafenib as the best potential treatment vs 14.6% (n = 89) for reoperative hepatectomy or thermoablation as the best potential treatment and 0% for chemoembolization as the best potential treatment. Those profiles were used to constitute a patient-tailored algorithm for the best potential treatment allocation. Conclusions and Relevance: The herein presented algorithm should help in allocating patients with recurrent HCC to the best potential treatment according to their specific characteristics in a treatment hierarchy fashion.

Performance of Comprehensive Complication Index and Clavien-Dindo Complication Scoring System in Liver Surgery for Hepatocellular Carcinoma.

BACKGROUND: We aimed to assess the ability of comprehensive complication index (CCI) and Clavien-Dindo complication (CDC) scale to predict excessive length of hospital stay (e-LOS) in patients undergoing liver resection for hepatocellular carcinoma. METHODS: Patients were identified from an Italian multi-institutional database and randomly selected to be included in either a derivation or validation set. Multivariate logistic regression models and ROC curve analysis including either CCI or CDC as predictors of e-LOS were fitted to compare predictive performance. E-LOS was defined as a LOS longer than the 75th percentile among patients with at least one complication. RESULTS: A total of 2669 patients were analyzed (1345 for derivation and 1324 for validation). The odds ratio (OR) was 5.590 (95%CI 4.201; 7.438) for CCI and 5.507 (4.152; 7.304) for CDC. The AUC was 0.964 for CCI and 0.893 for CDC in the derivation set and 0.962 vs. 0.890 in the validation set, respectively. In patients with at least two complications, the OR was 2.793 (1.896; 4.115) for CCI and 2.439 (1.666; 3.570) for CDC with an AUC of 0.850 and 0.673, respectively in the derivation cohort. The AUC was 0.806 for CCI and 0.658 for CDC in the validation set. CONCLUSIONS: When reporting postoperative morbidity in liver surgery, CCI is a preferable scale.

Ultrasound liver map technique for laparoscopic liver resections: perioperative outcomes are not impaired by technical complexity.

Intraoperative liver ultrasound has a crucial role to guide open liver surgery. A 4-step ultrasound liver map technique for laparoscopic liver resection (LLR) has been standardized in our center. The aim of this study was to evaluate outcomes of our technique according to the hepatectomy technical complexity. A difficulty scale (DS) ranging from 1 to 10 was applied to each LLR. A cumulative sum control-chart analysis identified 3 periods of gradually increasing DS. Perioperative outcomes of the 3 periods were compared. 300 LLRs performed between 2006 and 2018 were analyzed. Median DS was 3 for first 100 cases (P1), 5 for cases 101-200 (P2) and 6 for cases 201-300 (P3). A significantly greater percentage of postero-superior segments resections (P1 11%, P2 36%, P3 46%, p < 0.001) were performed in P3. P3 LLRs had a significantly longer transection time (p < 0.001) and wider cut surface area (p < 0.001), but median blood losses were similar among the 3 periods (P1 100 cc, P2 100 cc, P3 140 cc). There were no differences among periods in overall morbidity (P1 12%, P2 17%, P3 17%), major morbidity (P1 1%, P2 2%, P3 3%) and length of hospital stay (5 days in all the three groups). Despite the increasing surgical complexity of LLR, ultrasound liver map technique allows good perioperative outcomes.

[The relationship between the State and workers' unions and its impacts in the union-based health coverage regime in Argentina: an historical and political analysis]. / Relaciones entre el Estado y los sindicatos y sus consecuencias en torno al régimen de obras sociales en Argentina: un análisis histórico-político.

This paper aims at developing a political and historical reconstruction of the period spanning from the late nineteenth century to the present. In particular, this work investigates the relationship between the Argentine State and workers' unions and the impacts of that relationship in the establishment, consolidation and potential decline of the health coverage system administrated by unions, in Argentina called obras sociales. This work will also support the hypothesis that the financing obtained by union leaders through this health coverage system has been an efficient instrument for sustaining a centralized union model and has in some cases guaranteed the continued governance of both union leaders and different national governments.

CEUS Retrograde Cystography Is Helpful in Percutaneous Drainage of Complex Posttransplant Lymphocele.

After monolateral dual kidney transplantation, a 69 years old male patient developed symptomatic lymphocele with mild hydroureteronephrosis, impaired renal function, and right inferior limb oedema. A percutaneous ultrasound-guided drainage of the fluid collection was planned, but the complex mutual relations between the collection and the renal hilus did not allow to identify a suitable route for a safe drainage insertion during conventional ultrasound examination. A retrograde cystography using echographic contrast agent was, therefore, performed, and it clarified the position of both ureters and the renal vessels, permitting an harmless ultrasound-guided percutaneous lymphocele drainage. In conclusion contrast-enhanced ultrasound retrograde cystography may be helpful in percutaneous drainage of complex posttransplant lymphocele.

Laparoscopic right posterior sectionectomy for hepatocellular carcinoma using a modified liver-hanging maneuver.

BACKGROUND: Posterosuperior liver segments are the most difficult locations for laparoscopy to access. This location is considered by most surgeons to be a poor indication for a laparoscopic liver resection due to the limited visualization and the difficulty of controlling bleeding. The liver-hanging maneuver (LHM) is a technique taking aim at reducing intraoperative blood loss through an open approach. METHODS: We report our early experience on adopting a modified liver-hanging technique to perform a totally laparoscopic right posterior sectionectomy to remove a 5-cm hepatocellular carcinoma located in Couinaud's segments 6 and 7. RESULTS: The procedure was completed laparoscopically with acceptable time of surgery and blood loss. A 3.5-cm tumor-free resection margin was achieved. The patient was discharged on postoperative Day 10 without complications. No evidence of recurrence was seen at the 12-month follow-up. CONCLUSIONS: Total laparoscopic posterior sectionectomy using a modified LHM is a possible operative procedure greatly facilitating surgical manipulation. This maneuver was successfully used to mobilize the liver, to guide the hepatic transection, and to prevent bleeding. The potential advantages of this procedure should be evaluated in a comparative study on a large number of patients.

Relaciones entre el Estado y los sindicatos y sus consecuencias en torno al régimen de obras sociales en Argentina: un análisis histórico-político / The relationship between the State and workers’ unions and its impacts in the union-based health coverage regime in Argentina: an historical and political analysis

El presente trabajo se propone realizar una reconstrucción histórico-política, cuyo período transita desde fines del siglo XIX hasta la actualidad, que indague sobre la relación entre el Estado argentino y los sindicatos y sus repercusiones en torno a la constitución, consolidación y potencial ocaso del sistema de prestación de atención médica a los trabajadores administrado por los sindicatos, denominado en Argentina como obras sociales. Asimismo, sostendrá la hipótesis de que el financiamiento obtenido por parte de las cúpulas sindicales a través de las obras sociales ha sido un instrumento eficaz para sostener un modelo sindical centralizado que garantizó, en ciertos casos, gobernabilidad no solo a las cúpulas sino también a los diferentes gobiernos nacionales.

This paper aims at developing a political and historical reconstruction of the period spanning from the late nineteenth century to the present. In particular, this work investigates the relationship between the Argentine State and workers’ unions and the impacts of that relationship in the establishment, consolidation and potential decline of the health coverage system administrated by unions, in Argentina called obras sociales. This work will also support the hypothesis that the financing obtained by union leaders through this health coverage system has been an efficient instrument for sustaining a centralized union model and has in some cases guaranteed the continued governance of both union leaders and different national governments.

Relaciones entre el Estado y los sindicatos y sus consecuencias en torno al régimen de obras sociales en Argentina: un análisis histórico-político / The relationship between the State and workersÆ unions and its impacts in the union-based health coverage regime in Argentina: an historical and political analysis

El presente trabajo se propone realizar una reconstrucción histórico-política, cuyo período transita desde fines del siglo XIX hasta la actualidad, que indague sobre la relación entre el Estado argentino y los sindicatos y sus repercusiones en torno a la constitución, consolidación y potencial ocaso del sistema de prestación de atención médica a los trabajadores administrado por los sindicatos, denominado en Argentina como obras sociales. Asimismo, sostendrá la hipótesis de que el financiamiento obtenido por parte de las cúpulas sindicales a través de las obras sociales ha sido un instrumento eficaz para sostener un modelo sindical centralizado que garantizó, en ciertos casos, gobernabilidad no solo a las cúpulas sino también a los diferentes gobiernos nacionales.(AU)

This paper aims at developing a political and historical reconstruction of the period spanning from the late nineteenth century to the present. In particular, this work investigates the relationship between the Argentine State and workersÆ unions and the impacts of that relationship in the establishment, consolidation and potential decline of the health coverage system administrated by unions, in Argentina called obras sociales. This work will also support the hypothesis that the financing obtained by union leaders through this health coverage system has been an efficient instrument for sustaining a centralized union model and has in some cases guaranteed the continued governance of both union leaders and different national governments.(AU)

Relaciones entre el Estado y los sindicatos y sus consecuencias en torno al régimen de obras sociales en Argentina: un análisis histórico-político. / [The relationship between the State and workers unions and its impacts in the union-based health coverage regime in Argentina: an historical and political analysis].

This paper aims at developing a political and historical reconstruction of the period spanning from the late nineteenth century to the present. In particular, this work investigates the relationship between the Argentine State and workers unions and the impacts of that relationship in the establishment, consolidation and potential decline of the health coverage system administrated by unions, in Argentina called obras sociales. This work will also support the hypothesis that the financing obtained by union leaders through this health coverage system has been an efficient instrument for sustaining a centralized union model and has in some cases guaranteed the continued governance of both union leaders and different national governments.