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Deep-located liver tumors involving hepatic veins at the caval confluence or main Glissonean pedicles generally require a major hepatectomy. An intraoperative ultrasound guidance policy opened a possibility to opt for parenchyma-sparing procedures as alternatives to major hepatectomy, called transversal hepatectomies. We ought to standardize the procedure and analyze the surgical outcome, oncological suitability, and salvageability.This is a retrospective cohort study. All consecutive patients undergoing hepatectomies for liver tumors between January 2005 and August 2020 were reviewed. Transversal hepatectomies were classified as follows: upper transversal hepatectomy: resection of the posterosuperior segments along with at least 1 hepatic vein and preservation of the anteroinferior ones; roller coaster hepatectomy: transversal hepatectomy with tumor vessel detachment from at least 2 hepatic veins; and lower transversal hepatectomy: amputation of the distal portion of at least 1 hepatic vein with tumor vessel detachment from first/second-order Glissonean pedicles. Morbidity, mortality, local recurrences, and salvageability in cases of relapse were considered.A total of 61 transversal hepatectomies were performed: 40 (66%) upper transversal hepatectomies, 19 (31%) roller coaster hepatectomies, and 2 (3%) lower transversal hepatectomies. The median preserved liver volume was 67% (range 41-86). Mortality was 0, and major morbidity was 6%. Local recurrence occurred in 7 (11%) patients. Ten out of 34 (29%) patients with liver-only recurrence received redo surgery.Transversal hepatectomies offer a new parenchyma-sparing perspective for the management of complex tumor presentation, which would otherwise demand major tissue removal or even unresectability. Safety, adequate local control, and salvageability are further pillars of this approach herein systematized.

Patients with colorectal liver metastasis (CLM) present with heterogenous clinical outcomes and improved classification is needed to ameliorate the therapeutic output. Macrophages (Mϕ) hold promise as prognostic classifiers and therapeutic targets. Here, stemming from a single-cell analysis of mononuclear phagocytes infiltrating human CLM, we identified two Mϕ markers associated with distinct populations with opposite clinical relevance. The invasive margin of CLM was enriched in pro-inflammatory monocyte-derived Mϕ (MoMϕ) expressing the monocytic marker SERPINB2, and a more differentiated population, tumor-associated Mϕ (TAM), expressing glycoprotein nonmetastatic melanoma protein B (GPNMB). SERPINB2+ MoMϕ had an early inflammatory profile, whereas GPNMB+ TAMs were enriched in pathways of matrix degradation, angiogenesis, and lipid metabolism and were found closer to the tumor margin, as confirmed by spatial transcriptomics on CLM specimens. In a cohort of patients, a high infiltration of SERPINB2+ cells independently associated with longer disease-free survival (DFS; P = 0.033), whereas a high density of GPNMB+ cells correlated with shorter DFS (P = 0.012) and overall survival (P = 0.002). Cell–cell interaction analysis defined opposing roles for MoMϕ and TAMs, suggesting that SERPINB2+ and GPNMB+ cells are discrete populations of Mϕ and may be exploited for further translation to an immune-based stratification tool. This study provides evidence of how multi-omics approaches can identify nonredundant, clinically relevant markers for further translation to immune-based patient stratification tools and therapeutic targets. GPNMB has been shown to set Mϕ in an immunosuppressive mode. Our high dimensional analyses provide further evidence that GPNMB is a negative prognostic indicator and a potential player in the protumor function of Mϕ populations.

The landscape and function of the immune infiltrate of intrahepatic cholangiocarcinoma (iCCA), a rare, yet aggressive tumor of the biliary tract, remains poorly characterized, limiting development of successful immunotherapies. Herein, we aimed to define the molecular characteristics of tumor-infiltrating leukocytes with a special focus on CD4+ regulatory T cells (Tregs).We used high-dimensional single-cell technologies to characterize the T-cell and myeloid compartments of iCCA tissues, comparing these with their tumor-free peritumoral and circulating counterparts. We further used genomics and cellular assays to define the iCCA-specific role of a novel transcription factor, mesenchyme homeobox 1 (MEOX1), in Treg biology.We found poor infiltration of putative tumor-specific CD39+ CD8+ T cells accompanied by abundant infiltration of hyperactivated CD4+ Tregs. Single-cell RNA-sequencing identified an altered network of transcription factors in iCCA-infiltrating compared to peritumoral T cells, suggesting reduced effector functions by tumor-infiltrating CD8+ T cells and enhanced immunosuppression by CD4+ Tregs. Specifically, we found that expression of MEOX1 was highly enriched in tumor-infiltrating Tregs, and demonstrated that MEOX1 overexpression is sufficient to reprogram circulating Tregs to acquire the transcriptional and epigenetic landscape of tumor-infiltrating Tregs. Accordingly, enrichment of the MEOX1-dependent gene program in Tregs was strongly associated with poor prognosis in a large cohort of patients with iCCA.We observed abundant infiltration of hyperactivated CD4+ Tregs in iCCA tumors along with reduced CD8+ T-cell effector functions. Interfering with hyperactivated Tregs should be explored as an approach to enhance antitumor immunity in iCCA.Immune cells have the potential to slow or halt the progression of tumors. However, some tumors, such as intrahepatic cholangiocarcinoma, are associated with very limited immune responses (and infiltration of cancer-targeting immune cells). Herein, we show that a specific population of regulatory T cells (a type of immune cell that actually suppresses the immune response) are hyperactivated in intrahepatic cholangiocarcinoma. Targeting these cells could enable cancer-targeting immune cells to act more effectively and should be looked at as a potential therapeutic approach to this aggressive cancer type.

Despite current evidence, the use of drains in liver surgery is still controversial. We conducted an international survey to investigate the clinical use of drains in the E-AHPBA, A-HPBA and A-PHPBA communities. An open survey of 30 questions was prepared on Google-Form and distributed by email to all members. One hundred and ninety-one HPB surgeons responded to the survey. One hundred and twelve surgeons (58.6%) reported routine use of abdominal drains after liver resections. Eighty-eight (46.1%) responded that removal was driven by low volume and low bilirubin levels in the drains. For minor liver resection, 97 (50.8%) surgeons reported using drains selectively; in contrast, 134 (70.2%) surgeons prefer to use a drain always after major procedures. Among patients with cirrhosis, 87 (45.5%) surgeons reported routine drains placement, while 84 (44.0%) considered drains selectively. A no-drain policy was most prevalent among surgeons from North America (80%) versus Asian-Pacific (70.0%), European and African (60.8%), and South American (61.5%) surgeons. Among minimally invasive surgeons, 74.2% reported drain use only in selected cases versus 35.0% among surgeons who performed open surgery. The practice of draining after liver surgery is still highly variable among centers and surgeons around the world, with a high variability according to the underlying liver condition and planned surgical approach.

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Supplementary Figures 1-4, Tables S1 and S5

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Patients with colorectal liver metastasis (CLM) present with heterogenous clinical outcomes and improved classification is needed to ameliorate the therapeutic output. Macrophages (Mϕ) hold promise as prognostic classifiers and therapeutic targets. Here, stemming from a single-cell analysis of mononuclear phagocytes infiltrating human CLM, we identified two Mϕ markers associated with distinct populations with opposite clinical relevance. The invasive margin of CLM was enriched in pro-inflammatory monocyte-derived Mϕ (MoMϕ) expressing the monocytic marker SERPINB2, and a more differentiated population, tumor-associated Mϕ (TAM), expressing glycoprotein nonmetastatic melanoma protein B (GPNMB). SERPINB2+ MoMϕ had an early inflammatory profile, whereas GPNMB+ TAMs were enriched in pathways of matrix degradation, angiogenesis, and lipid metabolism and were found closer to the tumor margin, as confirmed by spatial transcriptomics on CLM specimens. In a cohort of patients, a high infiltration of SERPINB2+ cells independently associated with longer disease-free survival (DFS; P = 0.033), whereas a high density of GPNMB+ cells correlated with shorter DFS (P = 0.012) and overall survival (P = 0.002). Cell–cell interaction analysis defined opposing roles for MoMϕ and TAMs, suggesting that SERPINB2+ and GPNMB+ cells are discrete populations of Mϕ and may be exploited for further translation to an immune-based stratification tool. This study provides evidence of how multi-omics approaches can identify nonredundant, clinically relevant markers for further translation to immune-based patient stratification tools and therapeutic targets. GPNMB has been shown to set Mϕ in an immunosuppressive mode. Our high dimensional analyses provide further evidence that GPNMB is a negative prognostic indicator and a potential player in the protumor function of Mϕ populations.

Disease progression (PD) at neoadjuvant chemotherapy for patients with colorectal liver metastases (CLMs) is considered a contraindication to hepatic resection. Our aim was to estimate the overall survival (OS) in patients undergoing surgery compared with those treated exclusively with chemotherapy in cases of PD. Patients from a single centre with PD were analyzed and subdivided into two groups: hepatectomy (HEP) versus chemotherapy (CHT). An Inverse Probability Weighting (IPW) was run to balance the baseline differences between the two groups. A Cox regression was carried out on identifying factors predicting mortality. From 2010 to 2020, 105 patients in PD to at least one line of chemotherapy were analyzed. Of these, 27 (25.7%) underwent hepatic resection. After a median follow-up of 30 (IQR 14–46) months, 61.9% were dead. The OS values at 1 and 3 years were 54.4 and 10.6% for CHT, and 95 and 46.8% for HEP (p < 0.001). After IPW, two balanced pseudopopulations were obtained: HEP = 85 and CHT = 103. The OS values at 1 and 3 years were 54.4 and 10.6% for CHT, and 97.8 and 49.3% for HEP (HR 0.256, 95%CI: 0.08–0.78, p = 0.033). After IPW, in the multivariate model, surgery resulted in the only protective variable (HR 0.198, 95%CI: 0.08–0.48, p = 0.0016). Our results show that hepatic resection could offer a chance of a longer OS than the prosecution of chemotherapy only in originally resectable patients.

The liver is the most common metastatic site in colorectal cancer (CRC) patients. Indeed, 25–30% of the cases develop colorectal liver metastasis (CLM), showing an extremely poor 5-year survival rate and resistance to conventional anticancer therapies. Tumor-associated macrophages (TAMs) provide a nurturing microenvironment for CRC metastasis, promoting epithelial-to-mesenchymal transition (EMT) through the TGF-β signaling pathway, thus driving tumor cells to acquire mesenchymal properties that allow them to migrate from the primary tumor and invade the new metastatic site. EMT is known to contribute to the disruption of blood vessel integrity and the generation of circulating tumor cells (CTCs), thus being closely related to high metastatic potential in numerous solid cancers. Despite the fact that it is well-recognized that the crosstalk between tumor cells and the inflammatory microenvironment is crucial in the EMT process, the association between the EMT and the role of TAMs is still poorly understood. In this review, we elaborated on the role that TAMs exert in the induction of EMT during CLM development. Since TAMs are the major source of TGF-β in the liver, we also focused on novel insights into their role in TGF-β-induced EMT.

There is still debate over how reviewing oncological histories and addressing appropriate therapies in multidisciplinary team (MDT) discussions may affect patients’ overall survival (OS). The aim of this study was to describe MDT outcomes for a single cancer center’s patients affected by colorectal liver metastases (CRLMs). From 2010 to 2020, a total of 847 patients with CRLMs were discussed at our weekly MDT meeting. Patients’ characteristics and MDT decisions were analyzed in two groups: patients receiving systemic therapy (ST) versus patients receiving locoregional treatment (LRT). Propensity-score matching (PSM) was run to reduce the risk of selection bias. The median time from MDT indication to treatment was 27 (IQR 13–51) days. The median OS was 30 (95%CI = 27–34) months. After PSM, OS for patients undergoing LRT was 51 (95%CI = 36–64) months compared with 15 (95%CI = 13–20) months for ST patients (p < 0.0001). In this large retrospective study, the MDT discussions were useful in providing the patients with all available locoregional options.

Background: Previous studies on oocyte extract supplementation showed benefits in patients with liver tumours. In this trial, we hypothesized that the oocyte extract supplement impacted the QoL after hepatectomy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Methods: This was a multicentre, double-blind, randomized clinical trial designed to assess the QoL of patients receiving a supplement of oocyte extract or placebo postoperatively. QoL was assessed using the Short Form-36 questionnaire in participants randomly assigned to treatment (Synchrolevels) or placebo. All study personnel and participants were masked to treatment assignment. The endpoint was the change in the QoL score. Results: Between June 2018 and September 2022, 66 of 128 expected patients were considered as per interim analysis, of which 33 were assigned to the treatment and 33 to the placebo group. Baseline and clinicopathological characteristics were similar between the two groups. In the treatment group, the health, mental and psychological status improved for many of the items considered, reaching statistical significance, while in the placebo group, those items either did not change or were impaired in comparison with the corresponding baseline. Conclusions: Supplementation with oocyte extract modifies QoL after liver surgery by enhancing functional recovery. Further in-depth studies are required to confirm this evidence.

We describe a complex case of extended hepatectomy with venous outflow reconstruction for the treatment of advanced mass-forming cholangiocarcinoma (MFCCC) invading the three main hepatic veins (HVs). A 50-year-old woman who received a diagnosis of MFCCC and judged unresectable, was referred to our hospital. After multidisciplinary team evaluation, the patient underwent abdominal computed tomography, gadoxetic acid-enhanced magnetic resonance imaging, and fluorodeoxyglucose positron emission tomography. The radiological examinations showed a large mass located in S4s-8 and S1, in contact with the right hepatic vein (RHV), the inferior right hepatic vein, the anterior wall of the inferior vena cava (IVC), infiltrating the middle and left hepatic veins (MHV, LHV). Several communicating veins between the RHV, MHV and LHV were detected. The case was further investigated, and the surgical strategy planned by means of using three-dimensional simulation software. A total upper transversal hepatectomy with resection of the main HVs and outflow reconstruction was performed. The outflow of the remnant liver was restored performing a vascular anastomosis between the parenchymal stump of the RHV and the IVC. Meticulous review of pre-operative imaging techniques with three-dimensional simulation of hepatectomy together with advanced use of intra-operative ultrasound allowed us to offer the chance of cure to a patient otherwise considered unresectable.

Background Anatomical resection (AR) is a recommended surgical treatment for hepatocellular carcinoma (HCC). However, the conventional procedure (dye injection) for AR is difficult to reproduce. As an alternative, the tumour-feeding portal pedicle compression technique (finger-compression technique) has been proposed as an easy and reversible procedure. Here, we propose a new method combining indocyanine green (ICG) imaging with the finger-compression technique. Methods Eligible patients were prospectively enrolled to undergo ICG compression (ICG-C) anatomical hepatectomy for HCC. Results Fifteen patients underwent AR using the ICG-C technique. Overall, the surgical procedures included six segmentectomies, seven subsegmentectomies, and two right posterior sectionectomies. The median tumour size was 5.8 cm (range 2–7 cm). All procedures had an R0 margin. There were no major complications among patients, and minor morbidity occurred in three patients. Conclusions ICG-C is a safe, feasible and effective technique for patients eligible for AR.

More than 50% of all patients with colorectal cancer (CRC) develop liver metastases (CLM), a clinical condition characterized by poor prognosis and lack of reliable prognostic markers. Vδ1 cells are a subset of tissue-resident gamma delta (γδ) T lymphocytes endowed with a broad array of antitumor functions and showing a natural high tropism for the liver. However, little is known about their impact in the clinical outcomes of CLM.We isolated human γδ T cells from peripheral blood (PB) and peritumoral (PT) tissue of 93 patients undergone surgical procedures to remove CLM. The phenotype of freshly purified γδ T cells was assessed by multiparametric flow cytometry, the transcriptional profiles by single cell RNA-sequencing, the functional annotations by Gene Ontology enrichment analyses and the clonotype by γδ T cell receptor (TCR)-sequencing.The microenvironment of CLM is characterized by a heterogeneous immune infiltrate comprising different subsets of γδ tumor-infiltrating lymphocytes (TILs) able to egress the liver and re-circulate in PB. Vδ1 T cells represent the largest population of γδ TILs within the PT compartment of CLM that is greatly enriched in Vδ1 T effector (TThe enrichment of tissue-resident CD69

Background: Natural killer (NK) cells play a key role in immune surveillance and response to tumors, their function regulated by NK cell receptors and their ligands. The DNAM-1 activating receptor recognizes the CD155 molecule expressed in several tumor cells, such as hepatocellular carcinoma (HCC). This study aims to investigate the role of the DNAM-1/CD155 axis in mediating the NK cell response in patients with HCC. Methods: Soluble CD155 was measured by ELISA. CD155 expression was sought in HCC cells by immunohistochemistry, qPCR, and flow cytometry. DNAM-1 modulation in NK cells was evaluated in transwell experiments and by a siRNA-mediated knockdown. NK cell functions were examined by direct DNAM-1 triggering. Results: sCD155 was increased in sera from HCC patients and correlated with the parameters of an advanced disease. The expression of CD155 in HCC showed a positive trend toward better overall survival. DNAM-1 downmodulation was induced by CD155-expressing HCC cells, in agreement with lower DNAM-1 expressions in tumor-infiltrating NK (NK-TIL) cells. DNAM-1-mediated cytotoxicity was defective both in circulating NK cells and in NK-TIL of HCC patients. Conclusions: We provide evidence of alterations in the DNAM-1/CD155 axis in HCC, suggesting a possible mechanism of tumor resistance to innate immune surveillance.

In the last years, several studies have been focused on elucidate the role of tumor microenvironment (TME) in cancer development and progression. Within TME, cells from adaptive and innate immune system are one of the main abundant components. The dynamic interactions between immune and cancer cells lead to the activation of complex molecular mechanisms that sustain tumor growth. This important cross-talk has been elucidate for several kind of tumors and occurs also in patients with liver cancer, such as hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Liver is well-known to be an important immunological organ with unique microenvironment. Here, in normal conditions, the rich immune-infiltrating cells cooperate with non-parenchymal cells, such as liver sinusoidal endothelial cells and Kupffer cells, favoring self-tolerance against gut antigens. The presence of underling liver immunosuppressive microenvironment highlights the importance to dissect the interaction between HCC and iCCA cells with immune infiltrating cells, in order to understand how this cross-talk promotes tumor growth. Deeper attention is, in fact, focused on immune-based therapy for these tumors, as promising approach to counteract the intrinsic anti-tumor activity of this microenvironment. In this review, we will examine the key pathways underlying TME cell-cell communications, with deeper focus on the role of natural killer cells in primary liver tumors, such as HCC and iCCA, as new opportunities for immune-based therapeutic strategies.

Background Recent evidence suggests that gadolinium ethoxybenzyl diethylenetriamine penta acetic acid–enhanced (Gd-EOB-DTPA) magnetic resonance imaging may be used to evaluate liver function. The aim of this study was to assess whether the signal intensity of Gd-EOB-DTPA magnetic resonance imaging may be used to predict functional liver reserve and posthepatectomy liver failure in patients undergoing hepatectomy for liver tumors. Methods This is an observational retrospective study on 137 preoperative Gd-EOB-DTPA magnetic resonance imaging of patients undergoing hepatectomy between 2015 and 2018. Mean signal intensity of liver (L20) and spleen (S20) were measured on T1-weighted single-breath-hold 3-dimensional fat-saturated gradient echo sequences acquired 20 minutes after Gd-EOB-DTPA administration. The hepatocellular uptake index of liver volume (VL) was calculated with the formula VL([L20/S20] – 1) and was tested with several score systems for liver diseases and to the occurrence of post-hepatectomy liver failure. Results Patients with diseased liver had significantly lower values of hepatic uptake index in comparison with those with normal function. This was found for a Model for End-Stage Liver Disease score ≤9 versus >9 (P = .04), combination of bilirubin and cholinesterases levels score ≤2 versus >2 (P = .02), albumin to bilirubin grades (P = .03), and Humanitas score ≤6 versus >6 (P = .03). Twenty-two patients (16%) developed posthepatectomy liver failure, and 2 (1.4%) died within 90 days. The hepatocellular uptake index was significantly lower in those patients with posthepatectomy liver failure (P Conclusion The hepatocellular uptake index hepatocellular uptake index measured on preoperative Gd-EOB-DTPA magnetic resonance imaging identifies patients with diseased liver and predicts posthepatectomy liver failure. This index could be used to discern those patients at higher risk of complications after hepatectomy.

Background and aims Complete surgical resection with negative margin is one of the pillars in treatment of liver tumours. However, current techniques for intra‐operative assessment of tumour resection margins are time‐consuming and empirical. Mass spectrometry (MS) combined with artificial intelligence (AI) is useful for classifying tissues and provides valuable prognostic information. The aim of this study was to develop a MS‐based system for rapid and objective liver cancer identification and classification. Methods A large dataset derived from 222 patients with hepatocellular carcinoma (HCC, 117 tumours and 105 non‐tumours) and 96 patients with mass‐forming cholangiocarcinoma (MFCCC, 50 tumours and 46 non‐tumours) were analysed by Probe Electrospray Ionization (PESI) MS. AI by means of support vector machine (SVM) and random forest (RF) algorithms was employed. For each classifier, sensitivity, specificity and accuracy were calculated. Results The overall diagnostic accuracy exceeded 94% in both the AI algorithms. For identification of HCC vs non‐tumour tissue, RF was the best, with 98.2% accuracy, 97.4% sensitivity and 99% specificity. For MFCCC vs non‐tumour tissue, both algorithms gave 99.0% accuracy, 98% sensitivity and 100% specificity. Conclusions The herein reported MS‐based system, combined with AI, permits liver cancer identification with high accuracy. Its bench‐top size, minimal sample preparation and short working time are the main advantages. From diagnostics to therapeutics, it has the potential to influence the decision‐making process in real‐time with the ultimate aim of improving cancer patient cure.

Hepatocholangiocarcinoma (HCC-CC) is a rare malignancy containing features of both hepatocellular carcinoma (HCC) and mass-forming cholangiocarcinoma (MFCCC), of which the outcome after hepatectomy remains to be clarified. The aim of this study was to analyze the characteristics and outcomes of patients with transitional HCC-CC and compare them with those of patients with HCC and MFCCC. Our prospectively maintained database was queried, and 14 transitional HCC-CC patients were identified over a total of 406 consecutive hepatic resections. A 1:1:1 match was performed with HCC and MFCCC patients operated in the same period. A total of 42 patients were matched according to tumor stage (T1-2-3, N0, M0), number of tumors, R0 resection, no 90-day mortality, and follow-up. Primary endpoints were disease-free survival (DFS) and overall survival (OS). Disease-free survival rates at 1-, 3-, and 5-year were 71.4%, 57.1%, 35.7% for transitional HCC-CC patients; 85.7%, 40.4%, 10.1% for HCC patients; 85.1%, 34.0%, 22.7% for MFCCC patients (5-year DFS: HCC-CC vs. HCC, p = 0.575; HCC-CC vs. MFCCC, p = 0.766, respectively). Similarly, OS rates at 1-, 3-, and 5-year were 92.9%, 71.4%, 64.3% for transitional HCC-CC patients; 100%, 64.3%, 41.7% for HCC patients; 100%, 54.5%, 43.6% for MFCCC patients (5-year OS: HCC-CC vs. HCC, p = 0.891; HCC-CC vs. MFCCC, p = 0.673, respectively). When accurately matched with respect to tumor burden, transitional HCC-CC patients show similar outcomes to those of HCC and MFCCC patients. Further evaluations of differences in tumor biology are necessary to better characterize the prognosis of transitional HCC-CC patients.

R0 margin is the standard in the surgical treatment of colorectal liver metastases (CLM). Recently R1 surgery, at least that enabling CLM vessel-detachment (R1vasc), seems comparable to R0. As a possible background of that biologic factors could play some role. Among them, KRAS has been investigated in the present study.Patients who underwent curative surgery for CLM between 2008 and 2016 were identified. R0, R1vasc and parenchymal R1 (R1par; tumor exposure once dissected from the parenchyma) resections with known KRAS status were analyzed.Of 1000 resection areas in 340 patients, 654 (65%) R0, 98 (10%) R1vasc and 248 (25%) R1par. In mutated KRAS (mKRAS), local recurrence (LR) was similar between R0 and R1vasc (per-patient 4,8% vs. 2%, p = 0.628; per-area 2,1% vs. 1,9%, p = 0.940), while higher in R1par (per-patient 25,4% and per-area 19,5%; p 0.001 for both). In wild-type KRAS (wtKRAS), R0 had less LR compared to R1vasc (per-patient 7,6% vs 14,6%, p = 0.335; per-area 3,1% vs 13,3%, p = 0.012) and R1par (per-patient 18,3%, p = 0.060; per-area 9,9%, p = 0.013). KRAS did not impact LR in R0 (per-patient 7,6% vs. 4,8%, p = 0.491; per-area 3,1% vs. 2,1%, p = 0.555), while wtKRAS R1par had less LR compared to mKRAS R1par (per-patient 18,3% vs 25,4%, p = 0.404; per-area 9,9% vs 19,5%, p = 0.048). Inversely, LR was increased in wtKRAS R1vasc compared to mKRAS R1vasc (per-patient 14,6% vs 2%, p = 0.043; per-area 13,3% vs 1,9%, p = 0.046).KRAS status does not impact LR risk in R0 resection. Inversely, R1vasc vs R1par LR risk is reduced in mKRAS, and increased in wtKRAS. If confirmed these results are of note.

Kirsten rat sarcoma viral oncogene homolog KRAS proto-oncogene is the most common altered gene in colorectal cancer (CRC). Determining its mutational status, which is associated with worse prognosis and resistance to anti-epidermal growth factor receptor (EGFR) inhibitors, is essential for managing patients with CRC and colon liver metastases (CLM). Emerging studies highlighted the relationship of KRAS-mutated cancers and tumor microenvironment components, mainly with T cells. The aim of this study was to analyze the relationship of CLM immune cell infiltrate with KRAS mutational status. We performed a retrospective study on paraffin-embedded CLM tissue sections from patients surgically resected at the Department of Hepatobiliary and General Surgery of Humanitas Clinical and Cancer Center. We studied the distribution of lymphocytes (CD3+ cells), macrophages (CD163+), and neutrophils (CD66b+) in CLM tumoral and peritumoral area. Percentage of positive cells was correlated with tumor macroscopic characteristic, clinical aspects, and KRAS mutation. We observed a significant increase in CD66b+ cells in the peritumoral area in patients KRAS-mutated compared to KRAS wild-type patients. Percentages of lymphocytes and macrophages did not show significant differences. Further, neutrophils were found to be significantly increased also in the bloodstream of KRAS-mutated patients, indicating increased mobilization of neutrophils and recruitment in the CLM site. In conclusion, this study reveals a new intriguing aspect of the peritumoral microenvironment, which could pave the way for new prognostic and predictive markers for patient stratification.

ImportanceClear indications on how to select retreatments for recurrent hepatocellular carcinoma (HCC) are still lacking.ObjectiveTo create a machine learning predictive model of survival after HCC recurrence to allocate patients to their best potential treatment.Design, Setting, and ParticipantsReal-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.ExposuresPatients were enrolled if treated by reoperative hepatectomy or thermoablation, chemoembolization, or sorafenib.Main Outcomes and MeasuresSurvival after recurrence was the end point.ResultsA 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 RelevanceThe 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.

Benchmark analysis for open liver surgery for cirrhotic patients with hepatocellular carcinoma (HCC) is still undefined.Patients were identified from the Italian national registry HE.RC.O.LE.S. The Achievable Benchmark of Care (ABC) method was employed to identify the benchmarks. The outcomes assessed were the rate of complications, major comorbidities, post-operative ascites (POA), post-hepatectomy liver failure (PHLF), 90-day mortality. Benchmarking was stratified for surgical complexity (CP1, CP2 and CP3).A total of 978 of 2698 patients fulfilled the inclusion criteria. 431 (44.1%) patients were treated with CP1 procedures, 239 (24.4%) with CP2 and 308 (31.5%) with CP3 procedures. Patients submitted to CP1 had a worse underlying liver function, while the tumor burden was more severe in CP3 cases. The ABC for complications (13.1%, 19.2% and 28.1% for CP1, CP2 and CP3 respectively), major complications (7.6%, 11.1%, 12.5%) and 90-day mortality (0%, 3.3%, 3.6%) increased with the surgical difficulty, but not POA (4.4%, 3.3% and 2.6% respectively) and PHLF (0% for all groups).We propose benchmarks for open liver resections in HCC cirrhotic patients, stratified for surgical complexity. The difference between the benchmark values and the results obtained during everyday practice reflects the room for potential growth, with the aim to encourage constant improvement among liver surgeons.

Background and aims: We investigated the clinical impact of the newly defined metabolic-associated fatty liver disease (MAFLD) in patients undergoing hepatectomy for HCC (MAFLD-HCC) comparing the characteristics and outcomes of patients with MAFLD-HCC to viral- and alcoholic-related HCC (HCV-HCC, HBV-HCC, A-HCC). Methods: A retrospective analysis of patients included in the He.RC.O.Le.S. Group registry was performed. The characteristics, short- and long-term outcomes of 1315 patients included were compared according to the study group before and after an exact propensity score match (PSM). Results: Among the whole study population, 264 (20.1%) had MAFLD-HCC, 205 (15.6%) had HBV-HCC, 671 (51.0%) had HCV-HCC and 175 (13.3%) had A-HCC. MAFLD-HCC patients had higher BMI (p < 0.001), Charlson Comorbidities Index (p < 0.001), size of tumour (p < 0.001), and presence of cirrhosis (p < 0.001). After PSM, the 90-day mortality and severe morbidity rates were 5.9% and 7.1% in MAFLD-HCC, 2.3% and 7.1% in HBV-HCC, 3.5% and 11.7% in HCV-HCC, and 1.2% and 8.2% in A-HCC (p = 0.061 and p = 0.447, respectively). The 5-year OS and RFS rates were 54.4% and 37.1% in MAFLD-HCC, 64.9% and 32.2% in HBV-HCC, 53.4% and 24.7% in HCV-HCC and 62.0% and 37.8% in A-HCC (p = 0.345 and p = 0.389, respectively). Cirrhosis, multiple tumours, size and satellitosis seems to be the independent predictors of OS. Conclusion: Hepatectomy for MAFLD-HCC seems to have a higher but acceptable operative risk. However, long-term outcomes seems to be related to clinical and pathological factors rather than aetiological risk factors.

Addressing patients to neoadjuvant systemic chemotherapy followed by surgery rather than surgical resection upfront is controversial in the case of resectable colorectal –liver metastases (CLM). The aim of this study was to develop a machine-learning model to identify the best potential candidates for upfront surgery (UPS) versus neoadjuvant perioperative chemotherapy followed by surgery (NEOS). Patients at first liver resection for CLM were consecutively enrolled and collected into two groups, regardless of whether they had UPS or NEOS. An inverse –probability weighting (IPW) was performed to weight baseline differences; survival analyses; and risk predictions were estimated. A mortality risk model was built by Random-Forest (RF) to assess the best –potential treatment (BPT) for each patient. The characteristics of BPT-upfront and BPT-neoadjuvant candidates were automatically identified after developing a classification –and –regression tree (CART). A total of 448 patients were enrolled between 2008 and 2020: 95 UPS and 353 NEOS. After IPW, two balanced pseudo-populations were obtained: UPS = 432 and NEOS = 440. Neoadjuvant therapy did not significantly affect the risk of mortality (HR 1.44, 95% CI: 0.95–2.17, p = 0.07). A mortality prediction model was fitted by RF. The BPT was NEOS for 364 patients and UPS for 84. At CART, planning R1vasc surgery was the main factor determining the best candidates for NEOS and UPS, followed by primitive tumor localization, number of metastases, sex, and pre-operative CEA. Based on these results, a decision three was developed. The proposed treatment algorithm allows for better allocation according to the patient’s tailored risk of mortality.

We describe a case of complex parenchyma-sparing hepatectomy for multiple bilobar colorectal liver metastases. A 66-years-old male, who previously received a diagnosis of a stenosing adenocarcinoma of the hepatic flexure and synchronous bilobar liver metastases, was referred to our hospital. At the time of the presentation of the disease, a contrast-enhanced CT scan showed 24 liver lesions, with a bilobar distribution and two major cluster of lesions in segment 6 and 7. After neoadjuvant chemotherapy, global partial response, with complete response for most lesions, was detected: seven lesions were visible after re-staging. Surgical strategy was planned by means of three-dimensional reconstruction and simulation software. A unique transection plane comprising partial resection of segments 2, 3, 4, 5 and 8 and complete resection of segments 6 and 7 was performed. Left, middle and right hepatic veins were exposed on the cut surface. Accurate preoperative planning and intraoperative ultrasound for resection guidance allowed us to follow complex transection planes and treat a patient with a high burden of bilobar deeply located disease in a parenchymal-sparing perspective.

After the initial description of COVID-19 in Wuhan, China, Italy was hit first in Europe and the impact has been rapidly enlarging. In early April 2020, at the epidemic peak, there were more than 33,000 patients hospitalized including more than 4,000 in Intensive Care Units (ICU). On May 15, the confirmed cases in Italy approached 224,000 patients (5th highest number worldwide), with more than 31,000 deaths (3rd highest number worldwide). Non-urgent, non-cancer procedures were stopped to reallocate nurses and anesthetists to face the COVID-19 emergency. The timeline of the progressive involvement by COVID-19 patients of 36 hospitals referrals for surgical oncology in Italy was shown in this article. Only emergency, and elective oncological procedures were allowed with obvious limitations in terms of numbers of operable cases. Criteria for prioritizing oncologic patients waiting for surgery were released by each region, mainly issuing main factors for decision making, biological aggressiveness or symptomatic disease, the interval from the latest treatment, and the risk of un-resectability if delayed. However, the lack of facilities mostly influenced the decision or not to proceed. The risk of operating on oncological patients with ongoing SARS-CoV-2 syndrome is real, and a preoperative flowchart for ruling out this occurrence has been promoted. In our center, the day before surgery, chest CT and swab testing have been introduced, and a similar behavior has been recommended prior to patients' discharge. The care of patients addressed for surgical oncology should be featured by dedicated paths to secure proper and prompt disease management.

Systemic and local inflammation plays an important role in many cancers and colorectal liver metastases (CRLM). While the role of local immune response mediated by CD3+ tumour-infiltrating lymphocytes is well-established, new evidence on systemic inflammation and cancer, such as neutrophil-lymphocyte ratio (NLR), is emerging. The aim of this study is to seek an association between the CD3+ lymphocytes and NLR with patients’ prognosis and possibly stratifying it accordingly. From January 2005 to January 2013, 128 consecutive patients affected by CRLM and treated with chemotherapy and surgery were included in the study. Different cutoff levels were calculated with ROC curves for each of the biomarkers, and their relative outcome in terms of overall survival (OS) and recurrence-free survival (RFS) was determined. Associating the two biomarkers, three risk groups were determined: low risk (two protective biomarkers), intermediate risk (one protective biomarker) and high risk (no protective biomarker). After a median follow-up of 45 months, median OS and RFS were 44 and 9 months, respectively. For OS, 29 (22.66%), 59 (46.09%) and 40 (31.25%) patients were in the low, intermediate and high-risk groups, respectively. Adjusted Cox regression analysis showed an increased risk of death in the intermediate group (HR 2.67 p = 0.007 95% CI 1.31–5.42) and high-risk group (HR 2.86 p = 0.005 95% CI 1.37–5.99) compared to the low-risk group (reference). Systemic and local immune response index allows stratification of patients in different OS and RFS risk groups.