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Multidisciplinary management of patients with liver metastases (LM) requires a precision medicine approach, based on adequate profiling of tumor biology and robust biomarkers. Radiomics, defined as the high-throughput identification, analysis, and translational applications of radiological textural features, could fulfill this need. The present review aims to elucidate the contribution of radiomic analyses to the management of patients with LM. We performed a systematic review of the literature through the most relevant databases and web sources. English language original articles published before June 2020 and concerning radiomics of LM extracted from CT, MRI, or PET-CT were considered. Thirty-two papers were identified. Baseline higher entropy and lower homogeneity of LM were associated with better survival and higher chemotherapy response rates. A decrease in entropy and an increase in homogeneity after chemotherapy correlated with radiological tumor response. Entropy and homogeneity were also highly predictive of tumor regression grade. In comparison with RECIST criteria, radiomic features provided an earlier prediction of response to chemotherapy. Lastly, texture analyses could differentiate LM from other liver tumors. The commonest limitations of studies were small sample size, retrospective design, lack of validation datasets, and unavailability of univocal cut-off values of radiomic features. In conclusion, radiomics can potentially contribute to the precision medicine approach to patients with LM, but interdisciplinarity, standardization, and adequate software tools are needed to translate the anticipated potentialities into clinical practice.

Hepatic metastasis is a clinical challenge for colorectal cancer (CRC). Senescent cancer cells accumulate in CRC favoring tumor dissemination. Whether this mechanism progresses also in metastasis is unexplored. Here, we integrated spatial transcriptomics, 3D‐microscopy, and multicellular transcriptomics to study the role of cellular senescence in human colorectal liver metastasis (CRLM). We discovered two distinct senescent metastatic cancer cell (SMCC) subtypes, transcriptionally located at the opposite pole of epithelial (e) to mesenchymal (m) transition. SMCCs differ in chemotherapy susceptibility, biological program, and prognostic roles. Mechanistically, epithelial (e)SMCC initiation relies on nucleolar stress, whereby c‐myc dependent oncogene hyperactivation induces ribosomal RPL11 accumulation and DNA damage response. In a 2D pre‐clinical model, we demonstrated that RPL11 co‐localized with HDM2, a p53‐specific ubiquitin ligase, leading to senescence activation in (e)SMCCs. On the contrary, mesenchymal (m)SMCCs undergo TGFβ paracrine activation of NOX4‐p15 effectors. SMCCs display opposing effects also in the immune regulation of neighboring cells, establishing an immunosuppressive environment or leading to an active immune workflow. Both SMCC signatures are predictive biomarkers whose unbalanced ratio determined the clinical outcome in CRLM and CRC patients. Altogether, we provide a comprehensive new understanding of the role of SMCCs in CRLM and highlight their potential as new therapeutic targets to limit CRLM progression. Two distinct senescent cancer ecosystems located at the opposite pole of epithelial (e) to mesenchymal (m) transition duel in metastasis onset of colorectal cancer, defining the immune landscape and the clinical fate of patients.

Background A ≥ 1-mm margin is standard for resection of colorectal liver metastases (CLM). However, R1 resection is not rare (10–30%), and chemotherapy could mitigate its impact. The possibility of detaching CLM from vessels (R1 vascular margin) has been described. A reappraisal of R1 resection is needed. Methods A 19-question survey regarding R1 resection for CLM was sent to hepatobiliary surgeons worldwide. Seven clinical cases were included. Results In total, 276 surgeons from 52 countries completed the survey. Ninety percent reported a negative impact of R1 resection (74% local recurrence, 31% hepatic recurrence, and 36% survival), but 50% considered it sometimes required for resectability. Ninety-one percent of responders suggested that the impact of R1 resection is modulated by the response to chemotherapy and/or CLM characteristics. Half considered the risk of R1 resection to be an indication for preoperative chemotherapy in patients who otherwise underwent upfront resection, and 40% modified the chemotherapy regimen when the tumor response did not guarantee R0 resection. Nevertheless, 80% scheduled R1 resection for multiple bilobar CLM that responded to chemotherapy. Forty-five percent considered the vascular margin equivalent to R0 resection. However, for lesions in contact with the right hepatic vein, right hepatectomy remained the standard. Detachment from the vein was rarely considered (10%), but 27% considered detachment in the presence of multiple bilobar CLM. Conclusions A negative margin is still standard for CLM, but R1 resection is no longer just a technical error. R1 resection should be part of the modern multidisciplinary, aggressive approach to CLM.

Background The diagnosis and management of bile leaks after hepatectomy are heterogeneous because there is no agreement on the definition of post-hepatectomy biliary fistula. The aim of this study was to validate our definition and management of biliary fistulas after hepatic resection and to compare our results with those proposed by other authors. Methods A prospective series of patients who underwent hepatic resection from 2004 to 2012 were established. Drains were maintained for 7 days, and bilirubin was measured on postoperative days (PODs) 3, 5, and 7. Drains were removed if the bilirubin on POD 7 was less than that on POD 5 and less than 171 µmol/l (10 mg/dl). A statistical analysis of prognostic factors for biliary fistula was performed. Results Among 475 consecutive patients, 39 (8 %) had biliary fistulas. Only 8 (1.7 %) patients required postoperative interventions. In comparison with other studies, we observed a higher rate of bile leaks, but at the same time, we observed a lower rate of interventional procedures. The area under the receiver operating characteristic curve on POD 7 had the highest predictive value (0.81; P  < 0.001). Pringle maneuvers lasting ≥90 min (OR = 3.4; P  < 0.001), extended resections (OR = 6.4; P  = 0.007), blood transfusions (OR = 2.4; P  = 0.035), and resections including segment I (OR = 1.9; P  = 0.033) or segment V (OR = 1.8; P  = 0.024) were independently associated with an increased risk of bile leak. Conclusions The proposed definition of biliary fistula provides effective recognition of those that are clinically relevant with a reduction of the risk of unrecognized collections and minimal postoperative morbidity. Registration Number: NCT02056028 ( http://www.clinicaltrials.gov ).

Tumor-associated macrophages (TAMs) represent one of the main tumor-infiltrating immune cell types and are generally categorized into either of two functionally contrasting subtypes, namely classical activated M1 macrophages and alternatively activated M2 macrophages. TAMs showed different activation states that can be represent by the two extremes of the complex profile of macrophages biology, the M1-like phenotype (pro-inflammatory activity) and the M2-like phenotype (anti-inflammatory activity). Based on the tumor type, and grades, TAMs can acquire different functions and properties; usually, the M1-like phenotype is typical of early tumor stages and is associated to an anti-tumor activity, while M2-like phenotype has a pro-inflammatory activity and is related to a poor patients’ prognosis. The classification of macrophages into M1/M2 groups based on well-defined stimuli does not model the infinitely more complex tissue milieu where macrophages (potentially of different origin) would be exposed to multiple signals in different sequential order. This review aims to summarize the recent mass spectrometry-based (MS-based) metabolomics findings about the modifications of metabolism in TAMs polarization in different tumors. The published data shows that MS-based metabolomics is a promising tool to help better understanding TAMs metabolic phenotypes, although it is still poorly applied for TAMs metabolism. The knowledge of key metabolic alterations in TAMs is an essential step for discovering TAMs polarization novel biomarkers and developing novel therapeutic approaches targeting TAM metabolism to repolarize TAMs towards their anti-tumor phenotype.

Background Liver resection (LR) of colorectal metastases is associated with high recurrence risk. Aggressive local retreatment is advocated, but further recurrences may occur. Poor is known about presentation, treatment, and outcome of iterative recurrences. Methods A series of 323 consecutive patients undergoing first LR in the period 2004–2013 was reviewed. Patients with recurrence were included. Any local treatment (surgery, radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT)) was analyzed. If first recurrence (1st Rec) was treated, further recurrences and treatments were considered. Results Overall, 206 (63.8%) patients had 1st Rec; 105 (51.0%) were treated (72 surgery, 19 RFA, 14 SBRT). Among treated patients, 78.1% had 2nd Rec, 74.4% 3rd Rec, 72.2% 4th Rec. Liver involvement progressively decreased (from 81.6 to 30.8%), and pulmonary one increased (from 23.3 to 53.8%). The proportion of treated patients remained stable (1st Rec = 51%, 2nd Rec = 55%, 3rd Rec = 56.3%, 4th Rec = 69.2%): surgery and RFA decreased (from 35.4 to 23.1%; from 9.2 to 0%) and SBRT increased (from 6.8 to 46.2%). Overall, 105 patients received 205 treatments (133 operations in 80 patients). Surgery had the best local disease control: at 2 years 93.4% versus RFA 56.4% ( p  = 0.0008) and SBRT 74.0% ( p  = 0.051). In comparison with chemotherapy, recurrence treatment improved survival after 1st Rec (3-year survival 62.9 vs. 13.4%, p  < 0.0001), 2nd Rec (61.3 vs. 22.5%, p  < 0.0001), and 3rd Rec (2-year survival 88.9 vs. 30.8%, p  = 0.005). Conclusions Aggressive local treatment of recurrent metastases may improve survival, even in the case of iterative recurrences and extrahepatic lesions. Surgery is the standard, but a multidisciplinary approach should be adopted to enlarge the pool of treatable patients.

Background Selection criteria for hepatectomy for hepatocellular carcinoma (HCC) are object of debate. We presented our criteria for safe hepatectomy for HCC, and we compared the results with those obtainable using the most common scores for HCC. Methods All patients submitted to hepatectomy for HCC based on the same criteria were reviewed from our prospectively maintained database. Such criteria included bilirubin (BIL), cholinesterases (CHE), ascites, esophageal varices, and residual liver volume. Results A total of 336 patients were analyzed. One hundred fifteen patients (33 %) had thoracoabdominal approach, but only 39 (12 %) had major or extended resections. The median tumor number was 1 (range 1–33), while the median tumor size was 3.6 cm (range 1.1–28). Of those, 94 (29 %) had postoperative complications, of which 6 % were graded as major (Dindo III–IV). The 90-days mortality was 2 %. The MELD, APRI, and CPT scores were not found to be statistically significant for complications, while combining BIL and CHE we defined four classes of risk. The association of BIL >1 mg/dl (>17.1 µmol/l) and CHE ≤5,900 U/l was the best to detect complications (OR = 4.45; P  = 0.007). Conclusions This study shows that our selection criteria that count mainly on two commonly available, and inexpensive parameters, BIL and CHE, lead to identify patients potentially at risk of postoperative complications after hepatic resection for HCC. Registration number: NCT02056041 ( http://www.clinicaltrials.gov ).

The impact of the contrast medium on the radiomic textural features (TF) extracted from the CT scan is unclear. We investigated the modification of TFs of colorectal liver metastases (CLM), peritumoral tissue, and liver parenchyma. One hundred and sixty-two patients with 409 CLMs undergoing resection (2017–2020) into a single institution were considered. We analyzed the following volumes of interest (VOIs): The CLM (Tumor-VOI); a 5-mm parenchyma rim around the CLM (Margin-VOI); and a 2-mL sample of parenchyma distant from CLM (Liver-VOI). Forty-five TFs were extracted from each VOI (LIFEx®®). Contrast enhancement affected most TFs of the Tumor-VOI (71%) and Margin-VOI (62%), and part of those of the Liver-VOI (44%, p = 0.010). After contrast administration, entropy increased and energy decreased in the Tumor-VOI (0.93 ± 0.10 vs. 0.85 ± 0.14 in pre-contrast; 0.14 ± 0.03 vs. 0.18 ± 0.04, p < 0.001) and Margin-VOI (0.89 ± 0.11 vs. 0.85 ± 0.12; 0.16 ± 0.04 vs. 0.18 ± 0.04, p < 0.001), while remaining stable in the Liver-VOI. Comparing the VOIs, pre-contrast Tumor and Margin-VOI had similar entropy and energy (0.85/0.18 for both), while Liver-VOI had lower values (0.76/0.21, p < 0.001). In the portal phase, a gradient was observed (entropy: Tumor > Margin > Liver; energy: Tumor < Margin < Liver, p < 0.001). Contrast enhancement affected TFs of CLM, while it did not modify entropy and energy of parenchyma. TFs of the peritumoral tissue had modifications similar to the Tumor-VOI despite its radiological aspect being equal to non-tumoral parenchyma.

(1) Background: The assessment of resection margins during surgery of oral cavity squamous cell cancer (OCSCC) dramatically impacts the prognosis of the patient as well as the need for adjuvant treatment in the future. Currently there is an unmet need to improve OCSCC surgical margins which appear to be involved in around 45% cases. Intraoperative imaging techniques, magnetic resonance imaging (MRI) and intraoral ultrasound (ioUS), have emerged as promising tools in guiding surgical resection, although the number of studies available on this subject is still low. The aim of this diagnostic test accuracy (DTA) review is to investigate the accuracy of intraoperative imaging in the assessment of OCSCC margins. (2) Methods: By using the Cochrane-supported platform Review Manager version 5.4, a systematic search was performed on the online databases MEDLINE-EMBASE-CENTRAL using the keywords “oral cavity cancer, squamous cell carcinoma, tongue cancer, surgical margins, magnetic resonance imaging, intraoperative, intra-oral ultrasound”. (3) Results: Ten papers were identified for full-text analysis. The negative predictive value (cutoff < 5 mm) for ioUS ranged from 0.55 to 0.91, that of MRI ranged from 0.5 to 0.91; accuracy analysis performed on four selected studies showed a sensitivity ranging from 0.07 to 0.75 and specificity ranging from 0.81 to 1. Image guidance allowed for a mean improvement in free margin resection of 35%. (4) Conclusions: IoUS shows comparable accuracy to that of ex vivo MRI for the assessment of close and involved surgical margins, and should be preferred as the more affordable and reproducible technique. Both techniques showed higher diagnostic yield if applied to early OCSCC (T1–T2 stages), and when histology is favorable.