The Neoangiogenic Transcriptomic Signature Impacts Hepatocellular Carcinoma Prognosis and Can Be Triggered by Transarterial Chemoembolization Treatment.

Background/Objectives: We evaluated the relationship between the neoangiogenic transcriptomic signature (nTS) and clinical symptoms, treatment outcomes, and survival in hepatocellular carcinoma (HCC) patients. Methods: This study prospectively followed 328 patients in the derivation and 256 in the validation cohort (with a median follow-up of 31 and 22 months, respectively). The nTS was associated with disease presentation, treatments administered, and overall survival rates. Additionally, this study investigated how multiple treatments influenced changes in nTS status and alterations in microRNA expression. Results: The nTS was identified in 27.4% of patients, linked to aggressive features like multifocality and elevated alpha-fetoprotein (AFP), a pattern consistent with that of the validation cohort. Most patients in both cohorts received treatment for HCC. nTS+ patients had limited access to, and benefited less from, liver transplantation or radiofrequency ablation (RFA) compared to nTS- patients. By the end, 78.9% had died, with nTS- patients showing better median survival and response to treatments than their nTS+ counterparts, who had lower survival across all treatment types. Among those who received transarterial chemoembolization (TACE), 31.2% (21/80 patients after the initial treatment and another four following a second TACE) transitioned from an nTS- to an nTS+ status. This shift was associated with lower survival and alterations in microRNA expressions related to oncogenic pathways. Conclusions: The nTS markedly influences treatment eligibility and survival in patients with HCC. Notably, the nTS can develop after repeated TACE procedures, significantly impacting patient survival and altering oncogenic microRNA expression patterns. These findings highlight the critical role of the nTS in guiding treatment decisions and prognostication in HCC management.

Is robotic liver resection feasible in patients with lesions in close proximity to major vessels? A propensity score matching analysis.

INTRODUCTION: Robotic surgery is widely diffused in the surgical field and is becoming increasingly prevalent, however several aspects need more detailed assessment. One of them concerns the role of robotic liver surgery for lesions in contact with major vascular (CMV) pedicles. The aim of our study is to evaluate and compare intra and post operative outcomes in patients undergoing robotic liver resections between lesions in contact or free from major vessels. METHODS: A multicentric retrospective study was performed including 1030 patients who underwent robotic liver resection. Patients were divided into two groups according to vascular contact. Intra and post-operative outcomes were compared between the groups before and after Propensity Score Matching. RESULTS: After propensity score matching 889 patients were included in the study. Among these lesions, 595 were not in contact with major vessels (NCMV) and 294 were in contact with major vessels (CMV). Use of Pringle Manoeuvre was more associated with CMV resections (49.8 % vs 31.2 %, p = 0,0001). No differences in terms of operative time, conversion rate, morbidity and type of complications were observed after PSM. CONCLUSION: The presents study shows how robotic surgery is a valid and safe technique also for resection of tumors close to vascular pedicles.

Open, laparoscopic liver resection and percutaneous thermal ablation in elderly patients with hepatocellular carcinoma: outcomes and therapeutic strategy.

BACKGROUND: Liver resection and percutaneous thermal ablation (PTA) are considered curative option for hepatocellular carcinoma (HCC). This study aims to compare short- and long-term outcomes between open liver resection (OLR), laparoscopic liver resection (LLR), and PTA in elderly patients with single HCC and to define a liver map for therapeutic strategy according to HCC location and size. METHODS: A multicenter retrospective study was conducted in 10 European Hospital Center, including 239 consecutive liver resection (OLR and LLR) and PTA in elderly patients ≥ 70 years old with single HCC ≤ 30 mm. Perioperative data and long-term oncological outcomes were collected and compared between groups before and after propensity score matching. RESULTS: A total of 239 patients were enrolled, distributed as follows: 61 in the ORL group, 88 in the LLR group, and 90 in the PTA group. The hospital stay was longer in OLR and LLR groups compared to the PTA group (6, 5 and 3 days, respectively, p < 0.05). Morbidity was lower in the PTA group compared to the OLR group (11 vs. 26%, respectively, p < 0.05). Overall survival (OS) at 5 years was significantly higher in the OLR and LLR groups compared to the PTA group (82, 81, and 34%, respectively, p < 0.001). Disease-free survival (DFS) at 5 years was also significantly higher in the ORL and LLR groups compared to the PTA group (66, 50 and 20%, respectively, p < 0.001). These results were also confirmed after a propensity score matching analysis between surgery group (OLR and LLR) and the PTA group. PTA was the most used treatment for subcapsular and deep HCC not in contact with vascular structures compared to OLR and LLR. CONCLUSION: PTA in elderly patients ensures a shorter hospital stay and lower morbidity but worst survival compared to liver resection.

The role of resection in hepatocellular carcinoma BCLC stage B: A multi-institutional patient-level meta-analysis and systematic review.

PURPOSE: The Barcelona Clinic Liver Cancer (BCLC) staging schema is widely used for hepatocellular carcinoma (HCC) treatment. In the updated recommendations, HCC BCLC stage B can become candidates for transplantation. In contrast, hepatectomy is currently not recommended. METHODS: This systematic review includes a multi-institutional meta-analysis of patient-level data. Survival, postoperative mortality, morbidity and patient selection criteria for liver resection and transplantation in BCLC stage B are explored. All clinical studies reporting HCC patients with BCLC stage B undergoing liver resection or transplantation were included. RESULTS: A total of 31 studies with 3163 patients were included. Patient level data was available for 580 patients from 9 studies (423 after resection and 157 after transplantation). The overall survival following resection was 50 months and recurrence-free survival was 15 months. Overall survival after transplantation was not reached and recurrence-free survival was 45 months. The major complication rate after resection was 0.11 (95%-CI, 0.0-0.17) with the 90-day mortality rate of 0.03 (95%-CI, 0.03-0.08). Child-Pugh A (93%), minor resection (60%), alpha protein level less than 400 (64%) were common in resected patients. Resected patients were mostly outside the Milan criteria (99%) with mean tumour number of 2.9. Studies reporting liver transplantation in BCLC stage B were scarce. CONCLUSION: Liver resection can be performed safely in selected patients with HCC BCLC stage B, particularly if patients present with preserved liver function. No conclusion can done on liver transplantation due to scarcity of reported studies.

Combining gemcitabine and MSC delivering soluble TRAIL to target pancreatic adenocarcinoma and its stroma.

Pancreatic ductal adenocarcinoma (PDAC) still has a poor response to therapies, partly due to their cancer-associated fibroblasts (CAFs). Here, we investigate the synergistic impact of a combinatory approach between a known chemotherapy agent, such as gemcitabine (GEM), and gene-modified human mesenchymal stromal/stem cells (MSCs) secreting the pro-apoptotic soluble (s)TRAIL (sTRAIL MSCs) on both PDAC cells and CAFs. The combo significantly impacts on PDAC survival in 2D and 3D models. In orthotopic xenograft models, GEM and sTRAIL MSCs induce tumor architecture shredding with a reduction of CK7- and CK8/18-positive cancer cells and the abrogation of spleen metastases. A cytotoxic effect on primary human CAFs is also observed along with an alteration of their transcriptome and a reduction of the related desmoplasia. Collectively, we demonstrate a promising therapeutic profile of combining GEM and sTRAIL MSCs to target both tumoral and stromal compartments in PDAC.

Full Robotic Whole Graft Liver Transplantation: A Step Into The Future.

OBJECTIVE: To report the first European series of full robotic whole liver transplantation (RLT) with technical details and future perspectives. SUMMARY BACKGROUND DATA: Few cases of liver transplantation with a minimally invasive approach using partial grafts have been reported so far, and no cases of robotic whole liver transplantation have been reported in the scientific literature. METHODS: The adopted technique was full robotic liver hepatectomy, followed by robotic implantation after graft introduction through a small midline incision. Patients presenting with Hepatocellular Carcinoma (HCC) in liver cirrhosis with a small caudate lobe, low degree of portal hypertension, no porto-mesenteric thrombosis, as well as low MELD patients have been considered ideal candidates. RESULTS: Six patients underwent RLT between February and March 2024 at Lisbon and Modena University Liver Transplant Centers. Warm ischemia time during RLT ranged between 55 and 90 min, with a total surgery duration between 440 and 710 min. The median total operative time was 595 (±111,3) minutes. Only one recipient had prolonged hyperbilirubinemia, which was safely treated. The median in-hospital stay was 7.5 days, (±4.8 days). CONCLUSIONS: RLT is a promising technique to further reduce the impact of liver transplantation thanks to smaller incision, gentle tissue manipulation, high magnification and precision for vascular and biliary anastomosis, and reduced postoperative pain. This is the first step toward the demonstration of the feasibility of minimally invasive surgery in liver transplantation, although further selection and technical refinements are needed to improve reproducibility.

Long-term outcomes after hypothermic oxygenated machine perfusion and transplantation of 1,202 donor livers in a real-world setting (HOPE-REAL study).

BACKGROUND & AIMS: Despite strong evidence for improved preservation of donor livers by machine perfusion, longer post-transplant follow-up data are urgently needed in an unselected patient population. We aimed to assess long-term outcomes after transplantation of hypothermic oxygenated machine perfusion (HOPE)-treated donor livers based on real-world data (i.e., IDEAL-D stage 4). METHODS: In this international, multicentre, observational cohort study, we collected data from adult recipients of HOPE-treated livers transplanted between January 2012 and December 2021. Analyses were stratified by donation after brain death (DBD) and donation after circulatory death (DCD), sub-divided by their respective risk categories. The primary outcome was death-censored graft survival. Secondary outcomes included the incidence of primary non-function (PNF) and ischaemic cholangiopathy (IC). RESULTS: We report on 1,202 liver transplantations (64% DBD) performed at 22 European centres. For DBD, a total number of 99 benchmark (8%), 176 standard (15%), and 493 extended-criteria (41%) cases were included. For DCD, 117 transplants were classified as low risk (10%), 186 as high risk (16%), and 131 as futile (11%), with significant risk profile variations among centres. Actuarial 1-, 3-, and 5-year death-censored graft survival rates for DBD and DCD livers were 95%, 92%, and 91%, vs. 92%, 87%, and 81%, respectively (log-rank p = 0.003). Within DBD and DCD strata, death-censored graft survival was similar among risk groups (log-rank p = 0.26, p = 0.99). Graft loss due to PNF or IC was 2.3% and 0.4% (DBD), and 5% and 4.1% (DCD). CONCLUSIONS: This study shows excellent 5-year survival after transplantation of HOPE-treated DBD and DCD livers with low rates of graft loss due to PNF or IC, irrespective of their individual risk profile. HOPE treatment has now reached IDEAL-D stage 4, which further supports its implementation in routine clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05520320. IMPACT AND IMPLICATIONS: This study demonstrates the excellent long-term performance of hypothermic oxygenated machine perfusion (HOPE) treatment of donation after circulatory and donation after brain death liver grafts irrespective of their individual risk profile in a real-world setting, outside the evaluation of randomised-controlled trials. While previous studies have established safety, feasibility, and efficacy against the current standard, according to the IDEAL-D evaluation framework, HOPE treatment has now reached the final IDEAL-D stage 4, which further supports its implementation in routine clinical practice.

Robotic Major Hepatectomy in Elderly Patient.

BACKGROUND: the role of minimally invasive liver surgery has been progressively developed, with the practice increasing in safety and feasibility also with respect to major liver resections. The aim of this study was to analyze the feasibility and safety of major liver resection in elderly patients. METHODS: data from a multicentric retrospective database including 1070 consecutive robotic liver resections in nine European hospital centers were analyzed. Among these, 131 were major liver resections. Patients were also divided in two groups (<65 years old and ≥65 years old) and perioperative data were compared between the two groups. RESULTS: a total of 131 patients were included in the study. Operative time was 332 ± 125 min. Postoperative overall complications occurred in 27.1% of patients. Severe complications (Clavien Dindo ≥ 3) were 9.9%. Hospital stay was 6.6 ± 5.3 days. Patients were divided into two groups based on their age: 75 patients < 65 years old and 56 patients ≥ 65 years old. Prolonged pain, lung infection, intensive care stay, and 90-day readmission were worse in the elderly group. The two groups were matched for ASA and Charlson comorbidity score and, after statistical adjustment, postoperative data were similar between two groups. CONCLUSIONS: robotic major liver resection in elderly patients was associated with satisfying short-term outcomes.

Full robotic versus open ALPPS: a bi-institutional comparison of perioperative outcomes.

BACKGROUND: In primarily unresectable liver tumors, ALPPS (Associating Liver Partition and Portal Vein Ligation for Staged hepatectomy) may offer curative two-stage hepatectomy trough a fast and extensive hypertrophy. However, concerns have been raised about the invasiveness of the procedure. Full robotic ALPPS has the potential to reduce the postoperative morbidity trough a less invasive access. The aim of this study was to compare the perioperative outcomes of open and full robotic ALPPS. METHODS: The bicentric study included open ALPPS cases from the University Hospital Zurich, Switzerland and robotic ALPPS cases from the University of Modena and Reggio Emilia, Italy from 01/2015 to 07/2022. Main outcomes were intraoperative parameters and overall complications. RESULTS: Open and full robotic ALPPS were performed in 36 and 7 cases. Robotic ALPPS was associated with less blood loss after both stages (418 ± 237 ml vs. 319 ± 197 ml; P = 0.04 and 631 ± 354 ml vs. 258 ± 53 ml; P = 0.01) as well as a higher rate of interstage discharge (86% vs. 37%; P = 0.02). OT was longer with robotic ALPPS after both stages (371 ± 70 min vs. 449 ± 81 min; P = 0.01 and 282 ± 87 min vs. 373 ± 90 min; P = 0.02). After ALPPS stage 2, there was no difference for overall complications (86% vs. 86%; P = 1.00) and major complications (43% vs. 39%; P = 0.86). The total length of hospital stay was similar (23 ± 17 days vs. 26 ± 13; P = 0.56). CONCLUSION: Robotic ALPPS was safely implemented and showed potential for improved perioperative outcomes compared to open ALPPS in an experienced robotic center. The robotic approach might bring the perioperative risk profile of ALPPS closer to interventional techniques of portal vein embolization/liver venous deprivation.

Immunosuppression in liver transplant oncology: position paper of the Italian Board of Experts in Liver Transplantation (I-BELT).

Liver transplant oncology (TO) represents an area of increasing clinical and scientific interest including a heterogeneous group of clinical-pathological settings. Immunosuppressive management after LT is a key factor relevantly impacting result. However, disease-related guidance is still lacking, and many open questions remain in the field. Based on such a substantial lack of solid evidences, the Italian Board of Experts in Liver Transplantation (I-BELT) (a working group including representatives of all national transplant centers), unprecedently promoted a methodologically sound consensus conference on the topic, based on the GRADE approach. The group final recommendations are herein presented and commented. The 18 PICOs and Statements and their levels of evidence and grades of recommendation are reported and grouped into seven areas: (1) risk stratification by histopathological and bio-molecular parameters and role of mTORi post-LT; (2) steroids and HCC recurrence; (3) management of immunosuppression when HCC recurs after LT; (4) mTORi monotherapy; (5) machine perfusion and HCC recurrence after LT; (6) physiopathology of tumor-infiltrating lymphocytes and immunosuppression, the role of inflammation; (7) immunotherapy in liver transplanted patients. The interest in mammalian targets of rapamycin inhibitors (mTORi), for steroid avoidance and the need for a reduction to CNI exposure emerged from the consensus process. A selected list of unmet needs prompting further investigations have also been developed. The so far heterogeneous and granular approach to immunosuppression in oncologic patients deserves greater efforts for a more standardized therapeutic response to the different clinical scenarios. This consensus process makes a first unprecedented step in this direction, to be developed on a larger scale.

Current role and perspectives of living donor liver transplantation for hepatocellular carcinoma: systematic review of the past 20 years.

Hepatocellular carcinoma (HCC) poses a significant global health challenge, and liver transplantation (LT) remains the best curative option. Living donor liver transplantation (LDLT) emerged as a potential solution to organ scarcity, reducing waitlist times. This comprehensive review explores LDLT practices, focusing on patient selection criteria and oncologic outcomes. A systematic review following PRISMA guidelines included 50 studies (2004-2023) with 8062 patients. Data encompassed baseline characteristics, HCC features, and oncologic outcomes. Further analysis categorized results by geography and publication year. Heterogeneity in patient demographics, tumor burden, and transplant characteristics was observed. Recent LDLT series demonstrated a shift towards refined selection criteria, increased neoadjuvant treatment, and improved oncologic outcomes. Geographic disparities revealed unique challenges in Eastern and Western practices. LDLT proves effective for HCC, addressing donor shortages. Evolving practices highlight the importance of refining inclusion criteria and optimizing tumor management. While geographic differences exist, LDLT, when judiciously applied, offers promising outcomes.

Vena cava replacement and major hepatectomy for liver tumors: international multicenter retrospective cohort study.

INTRODUCTION: Involvement of the inferior vena cava (IVC) and hepatic veins has been considered a relative contraindication to hepatic resection for primary and metastatic liver tumors. However, patients affected by tumors extending to the IVC have limited therapeutic options and suffer worsening of quality of life due to IVC compression. METHODS: Cases of primary and metastatic liver tumors with vena cava infiltration from 10 international centers were collected (7 European, 1 US, 2 Brazilian, 1 Indian) were collected. Inclusion criteria for the study were major liver resection with concomitant vena cava replacement. Clinical data and short-term outcomes were analyzed. RESULTS: Thirty-six cases were finally included in the study. Median tumor max size was 98 mm (range: 25-250). A biliary reconstruction was necessary in 28% of cases, while a vascular reconstruction other than vena cava in 34% of cases. Median operative time was 462 min (range: 230-750), with 750 median ml of estimated blood loss and a median of one pRBC transfused intraoperatively (range: 0-27). Median ICU stay was 4 days (range: 1-30) with overall in-hospital stay of 15 days (range: 3-46), postoperative CCI score of 20.9 (range: 0-100), 12% incidence of PHLF grade B-C. Five patients died in a 90-days interval from surgery, one due to heart failure, one due to septic shock, and three due to multiorgan failure. With a median follow-up of 17 months (interquartile range: 11-37), the estimated 5 years overall survival was 48% (95% CI: 27-66%), and 5-year cumulative incidence of tumor recurrence was 55% (95% CI: 33-73%). CONCLUSIONS: Major liver resections with vena cava replacement can be performed with satisfactory results in expert HPB centers. This surgical strategy represents a feasible alternative for otherwise unresectable lesions and is associated with favorable prognosis compared to nonoperative management, especially in patients affected by intrahepatic cholangiocarcinoma.

Portal vein thrombosis and liver transplantation: management, matching, and outcomes. A retrospective multicenter cohort study.

BACKGROUND AND AIMS: Besides the increased risk of perioperative morbidity, graft failure, and mortality, the majority of PVT are diagnosed at liver transplantation (LT). Improving preoperative management and patient selection may lead to better short-term and long-term outcomes and reduce the risk of a futile LT. The authors aimed to identify predictors of adverse outcomes after LT in patients with nonmalignant portal vein thrombosis (PVT) and improve donor to recipient matching by analyzing the results of the Italian cohort of LT recipients. METHODS: Adult patients who underwent LT in Italy between January 2000 and February 2020 diagnosed with PVT pre-LT or at time of LT were considered eligible for inclusion. Based on a survey encompassing all 26 surgeons participating in the study, a binary composite outcome was defined. Patients were classified as having the composite event if at least one of these conditions occurred: operative time more than 600 min, estimated blood loss greater than 5000 ml, more than 20 ICU days, 90 days mortality, 90 days retransplant. RESULTS: Seven hundred fourteen patients were screened and 698 met the inclusion criteria. The analysis reports the results of 568 patients that fulfilled the criteria to enter the composite outcome analysis.Overall, 156 patients (27.5%) developed the composite outcome. PVT stage 3/4 at transplant and need for any surgical correction of PVT are independent predictors of the composite outcome occurrence. When stratified by PVT grade, overall survival at 1-year ranges from 89.0% with PVT grade 0/1 to 67.4% in patients with PVT grade 3/4 at LT ( P <0.001). Nevertheless, patients with severe PVT can improve their survival when identified risk factors are not present. CONCLUSIONS: Potential LT candidates affected by PVT have a benefit from LT that should be adequately balanced on liver function and type of inflow reconstruction needed to mitigate the incidence of adverse events. Nonetheless, the absence of specific risk factors may improve the outcomes even in patients with PVT grades 3-4.

Robotic Versus Laparoscopic Liver Resection in Various Settings: An International Multicenter Propensity Score Matched Study of 10.075 Patients.

OBJECTIVE: To compare the perioperative outcomes of robotic liver surgery (RLS) and laparoscopic liver surgery (LLS) in various settings. BACKGROUND: Clear advantages of RLS over LLS have rarely been demonstrated, and the associated costs of robotic surgery are generally higher than those of laparoscopic surgery. Therefore, the exact role of the robotic approach in minimally invasive liver surgery remains to be defined. METHODS: In this international retrospective cohort study, the outcomes of patients who underwent RLS and LLS for all indications between 2009 and 2021 in 34 hepatobiliary referral centers were compared. Subgroup analyses were performed to compare both approaches across several types of procedures: (1) minor resections in the anterolateral (2, 3, 4b, 5, and 6) or (2) posterosuperior segments (1, 4a, 7, 8), and (3) major resections (≥3 contiguous segments). Propensity score matching was used to mitigate the influence of selection bias. The primary outcome was textbook outcome in liver surgery (TOLS), previously defined as the absence of intraoperative incidents ≥grade 2, postoperative bile leak ≥grade B, severe morbidity, readmission, and 90-day or in-hospital mortality with the presence of an R0 resection margin in case of malignancy. The absence of a prolonged length of stay was added to define TOLS+. RESULTS: Among the 10.075 included patients, 1.507 underwent RLS and 8.568 LLS. After propensity score matching, both groups constituted 1.505 patients. RLS was associated with higher rates of TOLS (78.3% vs 71.8%, P < 0.001) and TOLS+ (55% vs 50.4%, P = 0.026), less Pringle usage (39.1% vs 47.1%, P < 0.001), blood loss (100 vs 200 milliliters, P < 0.001), transfusions (4.9% vs 7.9%, P = 0.003), conversions (2.7% vs 8.8%, P < 0.001), overall morbidity (19.3% vs 25.7%, P < 0.001), and microscopically irradical resection margins (10.1% vs. 13.8%, P = 0.015), and shorter operative times (190 vs 210 minutes, P = 0.015). In the subgroups, RLS tended to have higher TOLS rates, compared with LLS, for minor resections in the posterosuperior segments (n = 431 per group, 75.9% vs 71.2%, P = 0.184) and major resections (n = 321 per group, 72.9% vs 67.5%, P = 0.086), although these differences did not reach statistical significance. CONCLUSIONS: While both produce excellent outcomes, RLS might facilitate slightly higher TOLS rates than LLS.

Robotic ALPPS for primary and metastatic liver tumours: short-term outcomes versus open approach.

Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) is one of the strategies available for patients initially unresectable. High risk of peri-operative morbidity and mortality limited its application and diffusion. We aimed to analyse short-term outcomes of robotic ALPPS versus open approach, to assess safety and reproducibility of this technique. A retrospective analysis of prospectively maintained databases at University of Modena and Reggio Emilia on patients that underwent ALPPS between January 2015 and September 2022 was conducted. The main aim of the study was to evaluate safety and feasibility of robotic approach, either full robotic or only first-stage robotic, compared to a control group of patients who underwent open ALPPS in the same Institution. 23 patients were included. Nine patients received a full open ALPPS (O-ALPPS), 7 received a full robotic ALPPS (R-ALPPS), and 7 underwent a robotic approach for stage 1, followed by an open approach for stage 2 (R + O-ALPPS). PHLF grade B-C after stage 1 was 0% in all groups, rising to 58% in the R + O-ALPPS group after stage 2 and remaining 0% in the R-ALPPS group. 86% of R-ALPPS cases were discharged from the hospital between stages 1 and 2, and median total in-hospital stay and ICU stay favoured full robotic approach as well. This contemporary study represents the largest series of robotic ALPPS, showing potential advantages from full robotic ALPPS over open approach, resulting in reduced hospital stay and complications and lower incidence of 90-day mortality.

Nutrient restriction-activated Fra-2 promotes tumor progression via IGF1R in miR-15a downmodulated pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, characterized by an intense desmoplastic reaction that compresses blood vessels and limits nutrient supplies. PDAC aggressiveness largely relies on its extraordinary capability to thrive and progress in a challenging tumor microenvironment. Dysregulation of the onco-suppressor miR-15a has been extensively documented in PDAC. Here, we identified the transcription factor Fos-related antigen-2 (Fra-2) as a miR-15a target mediating the adaptive mechanism of PDAC to nutrient deprivation. We report that the IGF1 signaling pathway was enhanced in nutrient deprived PDAC cells and that Fra-2 and IGF1R were significantly overexpressed in miR-15a downmodulated PDAC patients. Mechanistically, we discovered that miR-15a repressed IGF1R expression via Fra-2 targeting. In miR-15a-low context, IGF1R hyperactivated mTOR, modulated the autophagic flux and sustained PDAC growth in nutrient deprivation. In a genetic mouse model, Mir15aKO PDAC showed Fra-2 and Igf1r upregulation and mTOR activation in response to diet restriction. Consistently, nutrient restriction improved the efficacy of IGF1R inhibition in a Fra-2 dependent manner. Overall, our results point to a crucial role of Fra-2 in the cellular stress response due to nutrient restriction typical of pancreatic cancer and support IGF1R as a promising and vulnerable target in miR-15a downmodulated PDAC.

Minimally Invasive Pancreaticoduodenectomy in Elderly versus Younger Patients: A Meta-Analysis.

(1) Background: With ageing, the number of pancreaticoduodenectomies (PD) for benign or malignant disease is expected to increase in elderly patients. However, whether minimally invasive pancreaticoduodenectomy (MIPD) should be performed in the elderly is not clear yet and it is still debated. (2) Materials and Methods: A systematic review and meta-analysis was conducted including seven published articles comparing the technical and post-operative outcomes of MIPD in elderly versus younger patients up to December 2022. (3) Results: In total, 1378 patients were included in the meta-analysis. In term of overall and Clavien-Dindo I/II complication rates, post-operative pancreatic fistula (POPF) grade > A rates and biliary leakage, abdominal collection, post-operative bleeding and delayed gastric emptying rates, no differences emerged between the two groups. However, this study showed slightly higher intraoperative blood loss [MD 43.41, (95%CI 14.45, 72.38) p = 0.003], Clavien-Dindo ≥ III complication rates [OR 1.87, (95%CI 1.13, 3.11) p = 0.02] and mortality rates [OR 2.61, (95%CI 1.20, 5.68) p = 0.02] in the elderly compared with the younger group. Interestingly, as a minor endpoint, no differences in terms of the mean number of harvested lymphnode and of R0 resection rates were found. (4) Conclusion: MIPD seems to be relatively safe; however, there are slightly higher major morbidity, lung complication and mortality rates in elderly patients, who potentially represent the individuals that may benefit the most from the minimally invasive approach.

Clinical Outcomes of Robotic Resection for Perihilar Cholangiocarcinoma: A First, Multicenter, Trans-Atlantic, Expert-Center, Collaborative Study.

INTRODUCTION: Perihilar cholangiocarcinoma is a difficult cancer to treat with frequent vascular invasion, local recurrence, and poor survival. Due to the need for biliary anastomosis and potential vascular resection, the standard approach is an open operation. Suboptimal outcomes after laparoscopic resection had been sporadically reported by high-volume centers. In this first, Trans-Atlantic, multicenter study, we report our outcomes of robotic resection for perihilar cholangiocarcinoma. This is the largest study of its kind in the Western hemisphere. METHODS: Between 2016 and 2023, we prospectively followed patients undergoing robotic resection for perihilar cholangiocarcinoma at three, high-volume, robotic, liver-surgery centers. RESULTS: Thirty-eight patients underwent perihilar cholangiocarcinoma utilizing the robotic technique; Klatskin type-3 was the most common. The median age was 72 years, and 82% of the patients underwent preoperative biliary drainage. Median operative time was 481 minutes with a median estimated blood loss of 200 mL. The number of harvested lymph nodes was seven, and 11 (28%) patients yielded positive lymph nodes. Three patients required vascular reconstruction; 18% of patients had >1 biliary anastomosis. R0 resection margins were achieved in 82% of patients. Clavien-Dindo Grade ≥3 complications were seen in 16% of patients. The length of stay was 6 days. Five patients had an unplanned readmission within 30 days. One patient died within 30 days. With a median follow-up of 15 months, 68% of patients are alive without disease, 13% recurred, and 19% died. CONCLUSIONS: Application of the robotic platform for perihilar cholangiocarcinoma is safe and feasible with acceptable short-term clinical and oncological outcomes.