Venous thromboembolism (VTE) after open hepatectomy compared to minimally invasive liver resection: a systematic review and meta-analysis.

BACKGROUND: Even though the risk of postoperative venous thromboembolism (VTE) after liver resection is well recognized, the association between surgical approach and VTE risk is unknown. This study aims to compare VTE rates following open liver resection (OLR) and minimally invasive liver resection (MILR). METHODS: MEDLINE, Web Of Sciences and EMBASE databases were interrogated to identify eligible studies published between February 2016 and August 2022. Studies were considered suitable if they reported a comparison between OLR and MILR (including laparoscopic liver resection [LLR] or robotic liver resection [RLR]). RESULTS: Fourteen studies including 11 356 patients met the inclusion criteria. 5622 patients underwent OLR and 5734 patients underwent MILR. The VTE rate was higher among patients who underwent OLR compared to MILR (2.8% vs 1.4%, OR (95% CI) = 1.84, p=<00001). Similarly, the subgroup analysis showed a higher rate of deep venous thrombosis (DVT) (1.4% vs 0.7%, OR (95% CI) = 1.98, p = 0.02) and pulmonary embolism (PE) (1.3% vs 0.7%, OR (95% CI) = 1.88, p = 0.002) in patients who underwent OLR compared to MILR. DISCUSSION: Patients who undergo open hepatectomy have a higher incidence of postoperative VTE when compared to those undergoing minimally invasive liver resection. This finding was consistent for both DVT and PE.

Genetically driven CD39 expression shapes human tumor-infiltrating CD8+ T-cell functions.

In our study, we investigated the role of CD39 on tumor-infiltrating CD8+ T lymphocytes (CD8+ TILs) in colorectal, head and neck and pancreatic cancers. Partially confirming recent observations correlating the CD39 expression with T-cell exhaustion, we demonstrated a divergent functional activity in CD39+ CD8+ TILs. On the one hand, CD39+ CD8+ TILs (as compared to their CD39- counterparts) produced significantly lower IFN-γ and IL-2 amounts, expressed higher PD-1, and inversely correlated with perforin and granzyme B expression. On the other, they displayed a significantly higher proliferative capacity ex vivo that was inversely correlated with the PD-1 expression. Therefore, CD39+ CD8+ TILs, including those co-expressing the CD103 (a marker of T resident memory [TRM] cells), were defined as partially dysfunctional T cells that correlate with tumor patients with initial progression stages. Interestingly, our results identified for the first time a single nucleotide polymorphism (SNP rs10748643 A>G), as a genetic factor associated with CD39 expression in CD8+ TILs. Finally, we demonstrated that compounds inhibiting CD39-related ATPases improved CD39+ CD8+ T-cell effector function ex vivo, and that CD39+ CD8+ TILs displayed effective suppression function in vitro. Overall these data suggest that the SNP analysis may represent a suitable predictor of CD39+ CD8+ T-cell expression in cancer patients, and propose the modulation of CD39 as a new strategy to restore partially exhausted CD8+ TILs.

Intrapancreatic accessory spleen false positive to 68Ga-Dotatoc: case report and literature review.

BACKGROUND: Intrapancreatic accessory spleen (IPAS) is an uncommon finding of pancreatic mass. Differential diagnosis with pancreatic tumor, especially with non-functional neuroendocrine tumor (NF-NET), may be very hard and sometimes it entails unnecessary surgery. A combination of CT scan, MRI, and nuclear medicine can confirm the diagnosis of IPAS. 68-Ga-Dotatoc PET/CT is the gold standard in NET diagnosis and it can allow to distinguish between IPAS and NET. CASE PRESENTATION: A 69-year-old man was admitted to our hospital for an incidental nodule in the tail of the pancreas with focal uptake of 68-Ga-dotatate at PET/CT. NET was suspected and open distal splenopancreatectomy was performed. Pathologic examination revealed an IPAS. CONCLUSION: This is the second IPAS case in which a positive 68Ga-Dotatoc uptake led to a false diagnosis of pancreatic NET. Here is a proposal of a literature review.

Minimally invasive pancreatoduodenectomy is associated with a higher incidence of postoperative venous thromboembolism when compared to the open approach: A systematic review and meta-analysis.

BACKGROUND: Despite the increased use of minimally invasive approaches for pancreatoduodenectomy (PD), the association between surgical approach and venous thromboembolism (VTE) risk is still unknown. This study aims to compare VTE rates following open (OPD) and minimally invasive pancreatoduodenectomy (MIPD). METHOD: MEDLINE, Web of Sciences and EMBASE databases were searched to identify eligible studies. Studies were considered suitable if the incidence of postoperative VTE in open and minimally invasive (laparoscopic or robotic) pancreatic surgery was reported. The review was conducted following the PRISMA guidelines. RESULTS: Five studies including 12 984 patients met the inclusion criteria and were considered for meta-analysis. A total of 11 060 patients underwent OPD and 1924 MIPD. Overall, patients who underwent OPD had a lower rate of VTE compared to MIPD (3.6 % vs 4.6 %, OR (95 % CI) = 0.66 (0.52-0.85), p < 0.001). Subgroup analysis showed similar results for pulmonary embolism (PE) (1.1 % in OPD vs 1.9 % in MIPD, OR (95 % CI) = 0.54 (0.36-0.80), p 0.002) and deep venous thrombosis (DVT) (1.3 % in OPD vs 3.1 % in MIPD, OR (95 % CI) = 0.48 (0.29-0.79), p 0.004). CONCLUSION: Patients who undergo minimally invasive pancreatoduodenectomy have a higher incidence of postoperative VTE when compared to open pancreatoduodenectomy.

A machine learning predictive model for recurrence of resected distal cholangiocarcinoma: Development and validation of predictive model using artificial intelligence.

INTRODUCTION: Distal Cholangiocarcinoma (dCCA) represents a challenge in hepatobiliary oncology, that requires nuanced post-resection prognostic modeling. Conventional staging criteria may oversimplify dCCA complexities, prompting the exploration of novel prognostic factors and methodologies, including machine learning algorithms. This study aims to develop a machine learning predictive model for recurrence after resected dCCA. MATERIAL AND METHODS: This retrospective multicentric observational study included patients with dCCA from 13 international centers who underwent curative pancreaticoduodenectomy (PD). A LASSO-regularized Cox regression model was used to feature selection, examine the path of the coefficient and create a model to predict recurrence. Internal and external validation and model performance were assessed using the C-index score. Additionally, a web application was developed to enhance the clinical use of the algorithm. RESULTS: Among 654 patients, LNR (Lymph Node Ratio) 15, neural invasion, N stage, surgical radicality, and differentiation grade emerged as significant predictors of disease-free survival (DFS). The model showed the best discrimination capacity with a C-index value of 0.8 (CI 95 %, 0.77%-0.86 %) and highlighted LNR15 as the most influential factor. Internal and external validations showed the model's robustness and discriminative ability with an Area Under the Curve of 92.4 % (95 % CI, 88.2%-94.4 %) and 91.5 % (95 % CI, 88.4%-93.5 %), respectively. The predictive model is available at https://imim.shinyapps.io/LassoCholangioca/. CONCLUSIONS: This study pioneers the integration of machine learning into prognostic modeling for dCCA, yielding a robust predictive model for DFS following PD. The tool can provide information to both patients and healthcare providers, enhancing tailored treatments and follow-up.

Pulsed Electric Fields in Oncology: A Snapshot of Current Clinical Practices and Research Directions from the 4th World Congress of Electroporation.

The 4th World Congress of Electroporation (Copenhagen, 9-13 October 2022) provided a unique opportunity to convene leading experts in pulsed electric fields (PEF). PEF-based therapies harness electric fields to produce therapeutically useful effects on cancers and represent a valuable option for a variety of patients. As such, irreversible electroporation (IRE), gene electrotransfer (GET), electrochemotherapy (ECT), calcium electroporation (Ca-EP), and tumour-treating fields (TTF) are on the rise. Still, their full therapeutic potential remains underappreciated, and the field faces fragmentation, as shown by parallel maturation and differences in the stages of development and regulatory approval worldwide. This narrative review provides a glimpse of PEF-based techniques, including key mechanisms, clinical indications, and advances in therapy; finally, it offers insights into current research directions. By highlighting a common ground, the authors aim to break silos, strengthen cross-functional collaboration, and pave the way to novel possibilities for intervention. Intriguingly, beyond their peculiar mechanism of action, PEF-based therapies share technical interconnections and multifaceted biological effects (e.g., vascular, immunological) worth exploiting in combinatorial strategies.

Irreversible Electroporation for Liver Metastases from Colorectal Cancer: A Systematic Review.

BACKGROUND: Irreversible electroporation (IRE) is a non-thermal form of ablation based on the delivery of pulsed electrical fields. It has been used to treat liver lesions, particularly those in proximity to major hepatic vasculature. The role of this technique in the portfolio of treatments for colorectal hepatic metastases has not been clearly defined. This study undertakes a systematic review of IRE for treatment of colorectal hepatic metastases. METHODS: The study protocol was registered with the PROSPERO register of systematic reviews (CRD42022332866) and reports in compliance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA). The Ovid MEDLINE®, EMBASE, Web of Science and Cochrane databases were queried in April 2022. The search terms 'irreversible electroporation', 'colon cancer', 'rectum cancer' and 'liver metastases' were used in combinations. Studies were included if they provided information on the use of IRE for patients with colorectal hepatic metastases and reported procedure and disease-specific outcomes. The searches returned 647 unique articles and the exclusions left a total of eight articles. These were assessed for bias using the methodological index for nonrandomized studies (MINORS criteria) and reported using the synthesis without meta-analysis guideline (SWiM). RESULTS: One hundred eighty patients underwent treatment for liver metastases from colorectal cancer. The median transverse diameter of tumours treated by IRE was <3 cm. Ninety-four (52%) tumours were adjacent to major hepatic inflow/outflow structures or the vena cava. IRE was undertaken under general anaesthesia with cardiac cycle synchronisation and with the use of either CT or ultrasound for lesion localisation. Probe spacing was less than 3.2 cm for all ablations. There were two (1.1%) procedure-related deaths in 180 patients. There was one (0.5%) post-operative haemorrhage requiring laparotomy, one (0.5%) bile leak, five (2.8%) post-procedure biliary strictures and a zero incidence of post-IRE liver failure. CONCLUSIONS: This systematic review shows that IRE for colorectal liver metastases can be accomplished with low procedure-related morbidity and mortality. Further prospective study is required to assess the role of IRE in the portfolio of treatments for patients with liver metastases from colorectal cancer.

It is the lymph node ratio that determines survival and recurrence patterns in resected distal cholangiocarcinoma. A multicenter international study.

BACKGROUND: Distal cholangiocarcinoma (dCC) is still associated with a poor overall survival (OS). This study aims to investigate the impact of novel prognostic scores in comparison with more traditional ones. METHODS: Multicentric retrospective analysis of patients who underwent a pancreatoduodenectomy (PD) for dCC. An unadjusted analysis was used to identify predictors of decreased survival. Significant variables were introduced in a multivariable model that assessed OS, recurrence-free survival (RFS), early recurrence (defined as a recurrence within the first 12 months from the PD), local and distant recurrence. Prognostic scores evaluated included the TNM staging system, the lymph-node ratio (LNR), the platelet-lymphocyte ratio (PLR), the neutrophil-lymphocyte ratio (NLR) and the systemic inflammation index (SII). RESULTS: The study included 232 patients with resected dCC. The optimal cut-off value for LNR was 15% (LNR15). On the unadjusted analysis T stage (p = 0.012), N stage (p < 0.001), LNR15 (p < 0.001), grade (p < 0.001), perineural invasion (p < 0.001) and the R1 status of resection margin (p = 0.001) accounted for the decreased OS. No significant association between survival and PLR, NLR and SII were found. On the multivariable analysis only LNR15, perineural invasion and R1 were independent predictors of decreased RFS (p = 0.003, p = 0.021 and p = 0.009, respectively) and OS (p = 0.001, p = 0.016 and p = 0.013, respectively). Additionally, LNR15 was an independent predictor of early recurrence (p = 0.003) and both LNR15 and R1 were associated with increased local (p < 0.001 and p = 0.010) and distant recurrence (p < 0.001 and p = 0.003). CONCLUSIONS: LNR15 is an independent predictor of DFS, OS, early, local and distal recurrence, combined with the status of the resection margin and perineural invasion.

A rare case of metachronous neuroendocrine tumor after a colorectal adenocarcinoma: qualitative critical review of synchronous and metachronous gastrointestinal NET.

Gastrointestinal neuroendocrine tumor (NET) associated with a metachronous intestinal adenocarcinoma is rare. We report the case of a 71-year-old man with an ileal NET. Patient has previously undergone a left colectomy for sigmoid cancer. We report a complete review both of the metachronous and synchronous NET. A comprehensive systematic literature search in PubMed, EMBASE, and MEDLINE identified a total of 35 relevant studies. This study includes an analysis of review articles, case reports, case series, retrospective studies and population-based studies. In the English literature to date, there are 21 case reports (19 synchronous cases and 2 metachronous cases), 3 case series and 3 review articles, and less than 10 retrospective studies or population-based studies. A total of 31 patients in 24 articles were included in the study: 28 patients with a synchronous gastrointestinal NET and colorectal adenocarcinoma and 3 patients with metachronous gastrointestinal NET and colorectal adenocarcinoma. The incidence of synchronous cancer (particularly for colorectal and gastric cancer) with a gastrointestinal NET ranges from 10 to 50%, while for the metachronous ones it is still unclear. This is the third metachronous case report and the first descriptive case of gastrointestinal NET diagnosed 2 years after a colorectal adenocarcinoma. An endoscopic follow-up program for gastrointestinal NET patients and/or for first-degree relatives of NET patients appears recommendable.

Short course radiotherapy and delayed surgery for locally advanced rectal cancer in frail patients: is it a valid option?

OBJECTIVE: The endpoint of the present study was to evaluate the outcomes of short-course radiotherapy (SCRT) and SCRT with delayed surgery (SCRT-DS) on a selected subgroup of frail patients with locally advanced middle/low rectal adenocarcinoma. METHODS: From January 2008 to December 2018, a total of 128 frail patients with locally advanced middle-low rectal adenocarcinoma underwent SCRT and subsequent restaging for eventual delayed surgery. Rates of complete pathological response, down-staging, disease free survival (DFS) and overall survival (OS) were analyzed. RESULTS: 128 patients completed 5 × 5 Gy pelvic radiotherapy. 69 of these were unfit for surgery; 59 underwent surgery 8 weeks (average time: 61 days) after radiotherapy. Downstaging of T occurred in 64% and down-staging of N in 50%. The median overall survival (OS) of SCRT alone was 19.5 months. The 1-year, 2-year, 3-year and 5-year OS was 48%, 22%, 14% and 0% respectively. In the surgical group, the median disease-free survival (DFS) and median OS were, respectively, 67 months (95% CI 49.8-83.1 months) and 72.1 months (95% CI 57.5-86.7 months). The 1, 2, 3, 5-year OS was 88%, 75%, 51%, 46%, respectively. Post-operative morbidity was 22%, mortality was 3.4%. CONCLUSIONS: Frail patients with advanced rectal cancer are often "unfit" for long-term neoadjuvant chemoradiation. A SCRT may be considered a valid option for this group of patients. Once radiotherapy is completed, patients can be re-evaluated for surgery. If feasible, SCRT and delayed surgery is the best option for frail patients.

Wnt3a/ß-Catenin Signaling Conditions Differentiation of Partially Exhausted T-effector Cells in Human Cancers.

In this study, we investigated the role of the Wnt/ß-catenin signaling pathway in antitumor immune responses. We report that the concentration of secreted Wnt3a was significantly higher in conditioned medium from tumor or nontumor tissues obtained from all hepatocellular carcinoma or colorectal cancer patients tested, than in serum of healthy donors or patients. In addition, both Wnt3a and ß-catenin were overexpressed by tumor-infiltrating and nontumor-infiltrating CD4+ or CD8+ T cells. The majority of these T cells expressed a dysfunctional effector memory Eomes+T-bet-phenotype that we defined as partially exhausted, because they performed effector functions (in terms of interferon-γ and tumor necrosis factor-α production, as well as CD107a mobilization) despite their PD-1 expression. Wnt3a/ß-catenin signaling in T naïve cells in vitro recapitulated the T-cell setting in vivo Indeed, the differentiation of cultured T naïve cells was arrested, producing cells that resembled the EomeshighT-betlowß-cateninhigh T cells with moderate effector functions that infiltrated tumor and nontumor areas. Wnt3a blockade improved the capacity of T naïve cells to differentiate into effector cells in vitro However, Wnt3a blockade did not affect the function and phenotype of differentiated, partially exhausted, tumor-infiltrating T cells ex vivo Taken together, our data suggest that Wnt3a blockade halts the capacity of Wnt/ß-catenin signaling to inhibit the differentiation of T naïve cells, but it does not restore the dysfunction of differentiated T cells, in the tumor setting. Cancer Immunol Res; 6(8); 941-52. ©2018 AACR.