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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC’s immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.

Pancreatic cancer is typically characterized by its aggressive tumor growth and dismal prognosis. Approximately 30% of patients with pancreatic cancer present with locally advanced disease, broadly defined as having a tumor-to-artery interface >180°, having an unreconstructable portal vein or superior mesenteric vein and no signs of metastatic disease. These patients are currently designated to palliative systemic chemotherapy, though median overall survival remains poor (approximately 11 months). Therefore, several innovative local therapies have been investigated as new treatment options for locally advanced pancreatic cancer (LAPC). This article provides an overview of available data with regard to morbidity and oncological outcome of novel local therapies for LAPC.

Irreversible electroporation (IRE) uses short duration, high-voltage electrical pulses to induce cell death via nanoscale defects resulting from altered transmembrane potential. The technique is gaining interest for ablations in unresectable pancreatic and hepatobiliary cancer. Metal stents are often used for palliative biliary drainage in these patients, but are currently seen as an absolute contraindication for IRE due to the perceived risk of direct heating of the metal and its surroundings. This study investigates the thermal and tissue viability changes due to a metal stent during IRE. IRE was performed in a homogeneous tissue model (polyacrylamide gel), without and with a metal stent placed perpendicular and parallel to the electrodes, delivering 90 and 270 pulses (15-35 A, 90 μsec, 1.5 cm active tip exposure, 1.5 cm interelectrode distance, 1000-1500 V/cm, 90 pulses/min), and in-vivo in a porcine liver (4 ablations). Temperature changes were measured with an infrared thermal camera and with fiber-optic probes. Tissue viability after in-vivo IRE was investigated macroscopically using 5-triphenyltetrazolium chloride (TTC) vitality staining. In the gel, direct stent-heating was not observed. Contrarily, the presence of a stent between the electrodes caused a higher increase in median temperature near the electrodes (23.2 vs 13.3°C [90 pulses]; p = 0.021, and 33.1 vs 24.8°C [270 pulses]; p = 0.242). In-vivo, no temperature difference was observed for ablations with and without a stent. Tissue examination showed white coagulation 1mm around the electrodes only. A rim of vital tissue remained around the stent, whereas ablation without stent resulted in complete tissue avitality. IRE in the vicinity of a metal stent does not cause notable direct heating of the metal, but results in higher temperatures around the electrodes and remnant viable tissue. Future studies should determine for which clinical indications IRE in the presence of metal stents is safe and effective.

BackgroundTo analyze long-term oncological outcomes of open and percutaneous thermal ablation in the treatment of patients with colorectal liver metastases (CRLM).MethodsThis assessment from a prospective, longitudinal tumor registry included 329 patients who underwent 541 procedures for 1350 CRLM from January 2010 to February 2021. Three cohorts were formed: 2010–2013 (129 procedures [53 percutaneous]), 2014–2017 (206 procedures [121 percutaneous]) and 2018–2021 (206 procedures [135 percutaneous]). Local tumor progression-free survival (LTPFS) and overall survival (OS) data were estimated using the Kaplan–Meier method. Potential confounding factors were analyzed with uni- and multivariable Cox regression analyses.ResultsLTPFS improved significantly over time for percutaneous ablations (2-year LTPFS 37.7% vs. 69.0% vs. 86.3%, respectively, P < .0001), while LTPFS for open ablations remained reasonably stable (2-year LTPFS 87.1% [2010–2013], vs. 92.7% [2014–2017] vs. 90.2% [2018–2021], P = .12). In the latter cohort (2018–2021), the open approach was no longer superior regarding LTPFS (P = .125). No differences between the three cohorts were found regarding OS (P = .088), length of hospital stay (open approach, P = .065; percutaneous approach, P = .054), and rate and severity of complications (P = .404). The rate and severity of complications favored the percutaneous approach in all three cohorts (P = .002).ConclusionOver the last 10 years efficacy of percutaneous ablations has improved remarkably for the treatment of CRLM. Oncological outcomes seem to have reached results following open ablation. Given its minimal invasive character and shorter length of hospital stay, whenever feasible, percutaneous procedures may be favored over an open approach.

Abstract Purpose of ReviewBased on good local control rates and an excellent safety profile, guidelines consider thermal ablation the gold standard to eliminate small unresectable colorectal liver metastases (CRLM). However, efficacy decreases exponentially with increasing tumour size. The preferred treatment for intermediate-size unresectable CRLM remains uncertain. This systematic review and meta-analysis compare safety and efficacy of local ablative treatments for unresectable intermediate-size CRLM (3–5 cm).Recent FindingsWe systematically searched for publications reporting treatment outcomes of unresectable intermediate-size CRLM treated with thermal ablation, irreversible electroporation (IRE) or stereotactic ablative body-radiotherapy (SABR). No comparative studies or randomized trials were found. Literature to assess effectiveness was limited and there was substantial heterogeneity in outcomes and study populations. Per-patient local control ranged 22–90% for all techniques; 22–89% (8 series) for thermal ablation, 44% (1 series) for IRE, and 67–90% (1 series) for SABR depending on radiation dose.SummaryFocal ablative therapy is safe and can induce long-term disease control, even for intermediate-size CRLM. Although SABR and tumuor-bracketing techniques such as IRE are suggested to be less susceptible to size, evidence to support any claims of superiority of one technique over the other is unsubstantiated by the available evidence. Future prospective comparative studies should address local-tumour-progression-free-survival, local control rate, overall survival, adverse events, and quality-of-life.

Purpose Peripheral arterial calcification is an important predictor of outcomes after both conservative and endovascular treatment. Digital subtraction angiography (DSA)-based calcification scores are limited by low sensitivity and inter-observer agreement. The Peripheral Arterial Calcium Scoring System (PACSS) assesses the severity of target lesion calcification. The newly introduced modified PACSS (mPACSS) also evaluates target vessel calcification. This study aimed to assess the inter- and intra-observer reliability of PACSS and mPACSS on computed tomography angiography (CTA) in (infra)popliteal endovascular interventions. Methods A random sample of 50 limbs from the prospective multicenter Dutch Chronic Lower Limb-Threatening Ischemia Registry (THRILLER) were included. Three experienced independent raters scored PACSS on CTA. Three months later, one blinded rater assessed the same 50 CTA scans, keeping track of assessment time. The reliability of the original 5-step PACSS, a simplified binary PACSS (0–2 vs 3–4) and the 7-step mPACSS were tested using Cohen’s and Fleiss’ kappa statistics. Results In total, 50 limbs (mean age 70.1 ± 11.0, 29 men) with 41 popliteal and 40 infrapopliteal lesions were scored. Inter-observer agreement of PACSS and binary PACSS were moderate ( κ  = 0.60) and substantial ( κ  = 0.72), respectively, while intra-observer agreement was almost perfect in both scores ( κ  = 0.86). Inter- and intra-observer agreement of mPACSS were moderate ( κ  = 0.48) and substantial ( κ  = 0.77), respectively. Mean assessment time for an experienced rater was 3.43 ± 0.93 min per CTA scan. Conclusion Both the semi-quantitative PACSS and mPACSS scores for (infra)popliteal arteries can be performed reliably on pre-operative CTA. Graphic Abstract

BackgroundIrreversible electroporation (IRE) and stereotactic ablative body radiotherapy (SABR) are cytoreductive therapies for locally advanced pancreatic cancer (LAPC). Both may signify immunogenic cell death. We aimed to compare systemic immune responses between the treatments.MethodsAs part of the randomized phase II CROSSFIRE trial (NCT02791503), comparing the oncological efficacy of IRE to SABR in patients with LAPC, pre- and post-treatment (2 weeks and 3 months) peripheral blood samples were collected. Frequency and activation status of lymphocytic and myeloid subsets were determined using flow cytometry. T cell responses to pancreatic cancer associated with Wilms tumor-1 (WT-1) and survivin tumor antigens were determined by interferon-γ enzyme-linked immunospot assay.ResultsIn total, 20 IRE and 20 SABR-treated participants were analyzed (20 men; median age 65 (IQR 55–70)). IRE induced immediate decreases in systemic regulatory T cell (Treg) and conventional type-1 dendritic cell rates, coinciding with CD4+/CD8+ T cell activation by upregulation of PD-1, which was associated with improved overall survival (OS). SABR similarly induced immediate CD4+/CD8+ T cell activation by upregulation of Ki67 and CD25 but resulted in asynchronously delayed Treg downregulation. SABR also induced a durable increase in CD4+ EM T cells, associated with improved OS. Ablation-induced WT-1 or survivin-specific T cell responses were observed in 9/16 (56%) immune competent participants (IRE n=5, SABR n=4) and were associated with longer OS.ConclusionDistinct immune stimulatory responses associated with improved OS, suggest that SABR might benefit from combined Treg depletion strategies while IRE could benefit from PD-1 checkpoint inhibition.Trial registration numberThe trial was registered on clinical trials.gov (NCT02791503).

The prognosis of metastatic pancreatic ductal adenocarcinoma (mPDAC) remains universally poor, requiring new and innovative treatment approaches. In a subset of oligometastatic PDAC patients, locoregional therapy, in addition to systemic chemotherapy, may improve survival. The aim of this systematic review was to explore and evaluate the current evidence on locoregional treatments for mPDAC. A systematic literature search was conducted on locoregional techniques, including resection, ablation and embolization, for mPDAC with a focus on hepatic and pulmonary metastases. A total of 59 studies were identified, including 63,453 patients. Although subject to significant bias, radical-intent local therapy for both the primary and metastatic sites was associated with a superior median overall survival from metastatic diagnosis or treatment (hepatic mPDAC 7.8–19 months; pulmonary mPDAC 22.8–47 months) compared to control groups receiving chemotherapy or best supportive care (hepatic mPDAC 4.3–7.6 months; pulmonary mPDAC 11.8 months). To recruit patients that may benefit from these local treatments, selection appears essential. Most significant is the upfront possibility of local radical pancreatic and metastatic treatment. In addition, a patient’s response to neoadjuvant systemic chemotherapy, performance status, metastatic disease load and, to a lesser degree, histological differentiation grade and tumor marker CA19-9 serum levels, are powerful prognostic factors that help identify eligible subjects. Although the exact additive value of locoregional treatments for mPDAC patients cannot be distillated from the results, locoregional primary pancreatic and metastatic treatment seems beneficial for a highly selected group of oligometastatic PDAC patients. For definite recommendations, well-designed prospective randomized controlled trials with strict in- and exclusion criteria are needed to validate these results.

PurposeThis study assessed the diagnostic value of CT hepatic arteriography (CTHA) for the intraprocedural detection of previously unknown colorectal liver metastases (CRLM) and the impact on the definitive treatment plan.Materials and MethodsAll patients treated with CTHA-guided percutaneous ablation for CRLM between January 2012 and March 2022 were identified from the Amsterdam Colorectal Liver Met Registry (AmCORE). Radiology reports of the ablative procedure and follow-up imaging were reviewed to see if (a) previously unknown CRLM were detected intra-procedurally and if (b) new CRLM, potentially missed on CTHA, appeared within 6 months following the procedure; three abdominal radiologists re-reviewed the baseline CTHA scans of these patients with early recurrence. To ratify immediate ablations of concomitantly detected CRLM, the upper limit of false positives was predefined at 10%.ResultsOne hundred and fifty-two patients were included. With CTHA, a total of 17 additional tumours in 15 patients were diagnosed and treated immediately, two representing disappeared tumours following systemic chemotherapy. Compared to the conventional contrast-enhanced (ce)CT, ceMRI and 18F-FDG PET-CT, adding CTHA was superior for the detection of CRLM (P < .001). Within 12 months of follow-up 121, new CRLM appeared in 49/152 patients (32.2%); retrospective blinded assessment revealed 56 to already be visible on the baseline CTHA scan (46%); four lesions without substrate on follow-up scans were considered false positives (n = 4/60; 7%). Arterial ring enhancement was the most frequently reported imaging characteristic (n = 45/60; 75%).ConclusionThe subsequent use of CTHA has added value for the detection of previously unknown and vanished CRLM. Taking into account the low number of false positives (7%) and the favourable safety profile of percutaneous ablation, we believe that immediate ablation of typical ring-enhancing supplementary tumours is justified and sufficiently validated.Level of EvidenceLevel 3; individual cross-sectional study with consistently applied reference standard and blinding.

The aim of this study was to assess safety, efficacy and survival outcomes of repeat thermal ablation as compared to repeat partial hepatectomy in patients with recurrent colorectal liver metastases (CRLM). This Amsterdam Colorectal Liver Met Registry (AmCORE) based study of two cohorts, repeat thermal ablation versus repeat partial hepatectomy, analyzed 136 patients (100 thermal ablation, 36 partial hepatectomy) and 224 tumors (170 thermal ablation, 54 partial hepatectomy) with recurrent CRLM from May 2002 to December 2020. The primary and secondary endpoints were overall survival (OS), distant progression-free survival (DPFS) and local tumor progression-free survival (LTPFS), estimated using the Kaplan–Meier method, and complications, analyzed using the chi-square test. Multivariable analyses based on Cox proportional hazards model were used to account for potential confounders. In addition, subgroup analyses according to patient, initial and repeat local treatment characteristics were performed. In the crude overall comparison, OS of patients treated with repeat partial hepatectomy was not statistically different from repeat thermal ablation (p = 0.927). Further quantification of OS, after accounting for potential confounders, demonstrated concordant results for repeat local treatment (hazard ratio (HR), 0.986; 95% confidence interval (CI), 0.517–1.881; p = 0.966). The 1-, 3- and 5-year OS were 98.9%, 62.6% and 42.3% respectively for the thermal ablation group and 93.8%, 74.5% and 49.3% for the repeat resection group. No differences in DPFS (p = 0.942), LTPFS (p = 0.397) and complication rate (p = 0.063) were found. Mean length of hospital stay was 2.1 days in the repeat thermal ablation group and 4.8 days in the repeat partial hepatectomy group (p = 0.009). Subgroup analyses identified no heterogeneous treatment effects according to patient, initial and repeat local treatment characteristics. Repeat partial hepatectomy was not statistically different from repeat thermal ablation with regard to OS, DPFS, LTPFS and complications, whereas length of hospital stay favored repeat thermal ablation. Thermal ablation should be considered a valid and potentially less invasive alternative for small-size (0–3 cm) CRLM in the treatment of recurrent new CRLM. While, the eagerly awaited results of the phase III prospective randomized controlled COLLISION trial (NCT03088150) should provide definitive answers regarding surgery versus thermal ablation for CRLM.