Platelet Transfusion before CVC Placement in Patients with Thrombocytopenia.

BACKGROUND: Transfusion guidelines regarding platelet-count thresholds before the placement of a central venous catheter (CVC) offer conflicting recommendations because of a lack of good-quality evidence. The routine use of ultrasound guidance has decreased CVC-related bleeding complications. METHODS: In a multicenter, randomized, controlled, noninferiority trial, we randomly assigned patients with severe thrombocytopenia (platelet count, 10,000 to 50,000 per cubic millimeter) who were being treated on the hematology ward or in the intensive care unit to receive either one unit of prophylactic platelet transfusion or no platelet transfusion before ultrasound-guided CVC placement. The primary outcome was catheter-related bleeding of grade 2 to 4; a key secondary outcome was grade 3 or 4 bleeding. The noninferiority margin was an upper boundary of the 90% confidence interval of 3.5 for the relative risk. RESULTS: We included 373 episodes of CVC placement involving 338 patients in the per-protocol primary analysis. Catheter-related bleeding of grade 2 to 4 occurred in 9 of 188 patients (4.8%) in the transfusion group and in 22 of 185 patients (11.9%) in the no-transfusion group (relative risk, 2.45; 90% confidence interval [CI], 1.27 to 4.70). Catheter-related bleeding of grade 3 or 4 occurred in 4 of 188 patients (2.1%) in the transfusion group and in 9 of 185 patients (4.9%) in the no-transfusion group (relative risk, 2.43; 95% CI, 0.75 to 7.93). A total of 15 adverse events were observed; of these events, 13 (all grade 3 catheter-related bleeding [4 in the transfusion group and 9 in the no-transfusion group]) were categorized as serious. The net savings of withholding prophylactic platelet transfusion before CVC placement was $410 per catheter placement. CONCLUSIONS: The withholding of prophylactic platelet transfusion before CVC placement in patients with a platelet count of 10,000 to 50,000 per cubic millimeter did not meet the predefined margin for noninferiority and resulted in more CVC-related bleeding events than prophylactic platelet transfusion. (Funded by ZonMw; PACER Dutch Trial Register number, NL5534.).

Immediate versus Postponed Intervention for Infected Necrotizing Pancreatitis.

BACKGROUND: Infected necrotizing pancreatitis is a potentially lethal disease that is treated with the use of a step-up approach, with catheter drainage often delayed until the infected necrosis is encapsulated. Whether outcomes could be improved by earlier catheter drainage is unknown. METHODS: We conducted a multicenter, randomized superiority trial involving patients with infected necrotizing pancreatitis, in which we compared immediate drainage within 24 hours after randomization once infected necrosis was diagnosed with drainage that was postponed until the stage of walled-off necrosis was reached. The primary end point was the score on the Comprehensive Complication Index, which incorporates all complications over the course of 6 months of follow-up. RESULTS: A total of 104 patients were randomly assigned to immediate drainage (55 patients) or postponed drainage (49 patients). The mean score on the Comprehensive Complication Index (scores range from 0 to 100, with higher scores indicating more severe complications) was 57 in the immediate-drainage group and 58 in the postponed-drainage group (mean difference, -1; 95% confidence interval [CI], -12 to 10; P = 0.90). Mortality was 13% in the immediate-drainage group and 10% in the postponed-drainage group (relative risk, 1.25; 95% CI, 0.42 to 3.68). The mean number of interventions (catheter drainage and necrosectomy) was 4.4 in the immediate-drainage group and 2.6 in the postponed-drainage group (mean difference, 1.8; 95% CI, 0.6 to 3.0). In the postponed-drainage group, 19 patients (39%) were treated conservatively with antibiotics and did not require drainage; 17 of these patients survived. The incidence of adverse events was similar in the two groups. CONCLUSIONS: This trial did not show the superiority of immediate drainage over postponed drainage with regard to complications in patients with infected necrotizing pancreatitis. Patients randomly assigned to the postponed-drainage strategy received fewer invasive interventions. (Funded by Fonds NutsOhra and Amsterdam UMC; POINTER ISRCTN Registry number, ISRCTN33682933.).

The Value of Biological and Conditional Factors for Staging of Patients with Resectable Pancreatic Cancer Undergoing Upfront Resection: A Nationwide Analysis.

BACKGROUND: Novel definitions suggest that resectability status for pancreatic ductal adenocarcinoma (PDAC) should be assessed beyond anatomical criteria, considering both biological and conditional factors. This has, however, yet to be validated on a nationwide scale. This study evaluated the prognostic value of biological and conditional factors for staging of patients with resectable PDAC. PATIENTS AND METHODS: A nationwide observational cohort study was performed, including all consecutive patients who underwent upfront resection of National Comprehensive Cancer Network resectable PDAC in the Netherlands (2014-2019) with complete information on preoperative carbohydrate antigen (CA) 19-9 and Eastern Cooperative Oncology Group (ECOG) performance status. PDAC was considered biologically unfavorable (RB+) if CA19-9 ≥ 500 U/mL and favorable (RB-) otherwise. ECOG ≥ 2 was considered conditionally unfavorable (RC+) and favorable otherwise (RC-). Overall survival (OS) was assessed using Kaplan-Meier and Cox-proportional hazard analysis, presented as hazard ratios (HRs) with 95% confidence interval (CI). RESULTS: Overall, 688 patients were analyzed with a median overall survival (OS) of 20 months (95% CI 19-23). OS was 14 months (95% CI 10 months-median not reached) in 20 RB+C+ patients (3%; HR 1.61, 95% CI 0.86-2.70), 13 months (95% CI 11-15) in 156 RB+C- patients (23%; HR 1.86, 95% CI 1.50-2.31), and 21 months (95% CI 12-41) in 47 RB-C+ patients (7%; HR 1.14, 95% CI 0.80-1.62) compared with 24 months (95% CI 22-27) in 465 patients with RB-C- PDAC (68%; reference). CONCLUSIONS: Survival after upfront resection of anatomically resectable PDAC is worse in patients with CA19-9 ≥ 500 U/mL, while performance status had no impact. This supports consideration of CA19-9 in preoperative staging of resectable PDAC.

First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5): an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group.

BACKGROUND: Patients with initially unresectable colorectal cancer liver metastases might qualify for local treatment with curative intent after reducing the tumour size by induction systemic treatment. We aimed to compare the currently most active induction regimens. METHODS: In this open-label, multicentre, randomised, phase 3 study (CAIRO5), patients aged 18 years or older with histologically confirmed colorectal cancer, known RAS/BRAFV600E mutation status, WHO performance status of 0-1, and initially unresectable colorectal cancer liver metastases were enrolled at 46 Dutch and one Belgian secondary and tertiary centres. Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by predefined criteria. Randomisation was done centrally with the minimisation technique via a masked web-based allocation procedure. Patients with right-sided primary tumour site or RAS or BRAFV600E mutated tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B). Patients with left-sided and RAS and BRAFV600E wild-type tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles. Patients were stratified by resectability of colorectal cancer liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAFV600E mutation status (for groups A and B). Bevacizumab was administered intravenously at 5 mg/kg. Panitumumab was administered intravenously at 6 mg/kg. FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m2 with folinic acid at 400 mg/m2, followed by bolus fluorouracil at 400 mg/m2 intravenously, followed by continuous infusion of fluorouracil at 2400 mg/m2. FOLFOX consisted of oxaliplatin at 85 mg/m2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI. FOLFOXIRI consisted of irinotecan at 165 mg/m2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m2 with folinic acid at 400 mg/m2, followed by continuous infusion of fluorouracil at 3200 mg/m2. Patients and investigators were not masked to treatment allocation. The primary outcome was progression-free survival, analysed on a modified intention-to-treat basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic colorectal cancer, or previous liver surgery for colorectal cancer liver metastases). The study is registered with ClinicalTrials.gov, NCT02162563, and accrual is complete. FINDINGS: Between Nov 13, 2014, and Jan 31, 2022, 530 patients (327 [62%] male and 203 [38%] female; median age 62 years [IQR 54-69]) were randomly assigned: 148 (28%) patients to group A, 146 (28%) patients to group B, 118 (22%) patients to group C, and 118 (22%) patients to group D. Groups C and D were prematurely closed for futility. 521 patients were included in the modified intention-to-treat population (147 in group A, 144 in group B, 114 in group C, and 116 in group D). The median follow-up at the time of this analysis was 51·1 months (95% CI 47·7-53·1) in groups A and B and 49·9 months (44·5-52·5) in in groups C and D. Median progression-free survival was 9·0 months (95% CI 7·7-10·5) in group A versus 10·6 months (9·9-12·1) in group B (stratified hazard ratio [HR] 0·76 [95% CI 0·60-0·98]; p=0·032), and 10·8 months (95% CI 9·9-12·6) in group C versus 10·4 months (9·8-13·0) in group D (stratified HR 1·11 [95% CI 0·84-1·48]; p=0·46). The most frequent grade 3-4 events in groups A and B were neutropenia (19 [13%] patients in group A vs 57 [40%] in group B; p<0·0001), hypertension (21 [14%] vs 20 [14%]; p=1·00), and diarrhoea (five [3%] vs 28 [19%]; p<0·0001), and in groups C and D were neutropenia (29 [25%] vs 24 [21%]; p=0·44), skin toxicity (one [1%] vs 29 [25%]; p<0·0001), hypertension (20 [18%] vs eight [7%]; p=0·016), and diarrhoea (five [4%] vs 18 [16%]; p=0·0072). Serious adverse events occurred in 46 (31%) patients in group A, 75 (52%) patients in group B, 41 (36%) patients in group C, and 49 (42%) patients in group D. Seven treatment-related deaths were reported in group B (two due to multiorgan failure, and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), one in group C (multiorgan failure), and three in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis). INTERPRETATION: In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAFV600E mutated primary tumour. In patients with a left-sided and RAS and BRAFV600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab, but was associated with more toxicity. FUNDING: Roche and Amgen.

Algorithm-based care versus usual care for the early recognition and management of complications after pancreatic resection in the Netherlands: an open-label, nationwide, stepped-wedge cluster-randomised trial.

BACKGROUND: Early recognition and management of postoperative complications, before they become clinically relevant, can improve postoperative outcomes for patients, especially for high-risk procedures such as pancreatic resection. METHODS: We did an open-label, nationwide, stepped-wedge cluster-randomised trial that included all patients having pancreatic resection during a 22-month period in the Netherlands. In this trial design, all 17 centres that did pancreatic surgery were randomly allocated for the timing of the crossover from usual care (the control group) to treatment given in accordance with a multimodal, multidisciplinary algorithm for the early recognition and minimally invasive management of postoperative complications (the intervention group). Randomisation was done by an independent statistician using a computer-generated scheme, stratified to ensure that low-medium-volume centres alternated with high-volume centres. Patients and investigators were not masked to treatment. A smartphone app was designed that incorporated the algorithm and included the daily evaluation of clinical and biochemical markers. The algorithm determined when to do abdominal CT, radiological drainage, start antibiotic treatment, and remove abdominal drains. After crossover, clinicians were trained in how to use the algorithm during a 4-week wash-in period; analyses comparing outcomes between the control group and the intervention group included all patients other than those having pancreatic resection during this wash-in period. The primary outcome was a composite of bleeding that required invasive intervention, organ failure, and 90-day mortality, and was assessed by a masked adjudication committee. This trial was registered in the Netherlands Trial Register, NL6671. FINDINGS: From Jan 8, 2018, to Nov 9, 2019, all 1805 patients who had pancreatic resection in the Netherlands were eligible for and included in this study. 57 patients who underwent resection during the wash-in phase were excluded from the primary analysis. 1748 patients (885 receiving usual care and 863 receiving algorithm-centred care) were included. The primary outcome occurred in fewer patients in the algorithm-centred care group than in the usual care group (73 [8%] of 863 patients vs 124 [14%] of 885 patients; adjusted risk ratio [RR] 0·48, 95% CI 0·38-0·61; p<0·0001). Among patients treated according to the algorithm, compared with patients who received usual care there was a decrease in bleeding that required intervention (47 [5%] patients vs 51 [6%] patients; RR 0·65, 0·42-0·99; p=0·046), organ failure (39 [5%] patients vs 92 [10%] patients; 0·35, 0·20-0·60; p=0·0001), and 90-day mortality (23 [3%] patients vs 44 [5%] patients; 0·42, 0·19-0·92; p=0·029). INTERPRETATION: The algorithm for the early recognition and minimally invasive management of complications after pancreatic resection considerably improved clinical outcomes compared with usual care. This difference included an approximate 50% reduction in mortality at 90 days. FUNDING: The Dutch Cancer Society and UMC Utrecht.

Endoscopic Versus Surgical Step-Up Approach for Infected Necrotizing Pancreatitis (ExTENSION): Long-term Follow-up of a Randomized Trial.

BACKGROUND & AIMS: Previous randomized trials, including the Transluminal Endoscopic Step-Up Approach Versus Minimally Invasive Surgical Step-Up Approach in Patients With Infected Pancreatic Necrosis (TENSION) trial, demonstrated that the endoscopic step-up approach might be preferred over the surgical step-up approach in patients with infected necrotizing pancreatitis based on favorable short-term outcomes. We compared long-term clinical outcomes of both step-up approaches after a period of at least 5 years. METHODS: In this long-term follow-up study, we reevaluated all clinical data on 83 patients (of the originally 98 included patients) from the TENSION trial who were still alive after the initial 6-month follow-up. The primary end point, similar to the TENSION trial, was a composite of death and major complications. Secondary end points included individual major complications, pancreaticocutaneous fistula, reinterventions, pancreatic insufficiency, and quality of life. RESULTS: After a mean follow-up period of 7 years, the primary end point occurred in 27 patients (53%) in the endoscopy group and in 27 patients (57%) in the surgery group (risk ratio [RR], 0.93; 95% confidence interval [CI], 0.65-1.32; P = .688). Fewer pancreaticocutaneous fistulas were identified in the endoscopy group (8% vs 34%; RR, 0.23; 95% CI, 0.08-0.83). After the initial 6-month follow-up, the endoscopy group needed fewer reinterventions than the surgery group (7% vs 24%; RR, 0.29; 95% CI, 0.09-0.99). Pancreatic insufficiency and quality of life did not differ between groups. CONCLUSIONS: At long-term follow-up, the endoscopic step-up approach was not superior to the surgical step-up approach in reducing death or major complications in patients with infected necrotizing pancreatitis. However, patients assigned to the endoscopic approach developed overall fewer pancreaticocutaneous fistulas and needed fewer reinterventions after the initial 6-month follow-up. Netherlands Trial Register no: NL8571.

Intersurgeon Variability in Local Treatment Planning for Patients with Initially Unresectable Colorectal Cancer Liver Metastases: Analysis of the Liver Expert Panel of the Dutch Colorectal Cancer Group.

BACKGROUND: Consensus on resectability criteria for colorectal cancer liver metastases (CRLM) is lacking, resulting in differences in therapeutic strategies. This study evaluated variability of resectability assessments and local treatment plans for patients with initially unresectable CRLM by the liver expert panel from the randomised phase III CAIRO5 study. METHODS: The liver panel, comprising surgeons and radiologists, evaluated resectability by predefined criteria at baseline and 2-monthly thereafter. If surgeons judged CRLM as resectable, detailed local treatment plans were provided. The panel chair determined the conclusion of resectability status and local treatment advice, and forwarded it to local surgeons. RESULTS: A total of 1149 panel evaluations of 496 patients were included. Intersurgeon disagreement was observed in 50% of evaluations and was lower at baseline than follow-up (36% vs. 60%, p < 0.001). Among surgeons in general, votes for resectable CRLM at baseline and follow-up ranged between 0-12% and 27-62%, and for permanently unresectable CRLM between 3-40% and 6-47%, respectively. Surgeons proposed different local treatment plans in 77% of patients. The most pronounced intersurgeon differences concerned the advice to proceed with hemihepatectomy versus parenchymal-preserving approaches. Eighty-four percent of patients judged by the panel as having resectable CRLM indeed received local treatment. Local surgeons followed the technical plan proposed by the panel in 40% of patients. CONCLUSION: Considerable variability exists among expert liver surgeons in assessing resectability and local treatment planning of initially unresectable CRLM. This stresses the value of panel-based decisions, and the need for consensus guidelines on resectability criteria and technical approach to prevent unwarranted variability in clinical practice.

Risk Factors for Cholangitis After Pancreatoduodenectomy: A Systematic Review.

BACKGROUND: Cholangitis is a late complication after pancreatoduodenectomy with considerable clinical impact and is difficult to treat. The aim of this systematic review was to provide an overview of the literature identifying risk factors for postoperative cholangitis. METHODS: A systematic search of the databases PUBMED and EMBASE was performed to identify all studies reporting on possible risk factors for cholangitis following pancreatoduodenectomy. Data on patient, peri- and postoperative characteristics were collected. Risk of bias assessment was done according to the methodological index for non-randomized studies (MINORS) criteria. RESULTS: In total, 464 studies were identified. Eight studies met the inclusion criteria for this analysis. The definition of postoperative cholangitis was inconsistent, with four studies using the Tokyo Guidelines, whereas other studies used different definitions. Data on 26 potential risk factors concerning the patient, peri- and postoperative characteristics were analyzed. Five factors were significantly associated with cholangitis in two or more studies: high body mass index, duration of surgery, benign disease, postoperative pancreatic fistula, and postoperative serum alkaline phosphatase. CONCLUSION: Multiple potential risk factors for postoperative cholangitis were identified, with large discrepancies between studies. Prospective research, with consensus on the definition, is required to determine the true relevance of these risk factors.

Outcomes of Irreversible Electroporation for Perihilar Cholangiocarcinoma: A Prospective Pilot Study.

PURPOSE: To investigate the safety and efficacy of percutaneous or open irreversible electroporation (IRE) in a prospective cohort of patients with locally advanced, unresectable perihilar cholangiocarcinoma (PHC). MATERIALS AND METHODS: In a multicenter Phase I/II study, patients with unresectable PHC due to extensive vascular involvement or N2 lymph node metastases or local recurrence after resection for PHC were included and treated by open or percutaneous IRE combined with palliative chemotherapy (current standard of care). The primary outcome was the number of major adverse events occurring within 90 d after IRE (grade ≥3), and the upper limit was predefined at 60%. Secondary outcomes included technical success rate, hospital stay, and overall survival (OS). RESULTS: Twelve patients (mean age, 63 y ± 12) were treated with IRE. The major adverse event rate was 50% (6 of 12 patients), and no 90-d mortality was observed. All procedures were technically successful, with no intraprocedural adverse events requiring additional interventions. The median OS from diagnosis was 21 mos (95% confidence interval, 15-27 mos), with a 1-y survival rate of 75% after IRE. CONCLUSIONS: Percutaneous IRE in selected patients with locally advanced PHC seems feasible, with a major adverse event rate of 50%, which was below the predefined upper safety limit in this prospective study. Future comparative research exploring the efficacy of IRE is warranted.

Added value of 3T MRI and the MRI-halo sign in assessing resectability of locally advanced pancreatic cancer following induction chemotherapy (IMAGE-MRI): prospective pilot study.

BACKGROUND: Restaging of locally advanced pancreatic cancer (LAPC) after induction chemotherapy using contrast-enhanced computed tomography (CE-CT) imaging is imprecise in evaluating local tumor response. This study explored the value of 3 Tesla (3 T) contrast-enhanced (CE) and diffusion-weighted (DWI) magnetic resonance imaging (MRI) for local tumor restaging. METHODS: This is a prospective pilot study including 20 consecutive patients with LAPC with RECIST non-progressive disease on CE-CT after induction chemotherapy. Restaging CE-CT, CE-MRI, and DWI-MRI were retrospectively evaluated by two abdominal radiologists in consensus, scoring tumor size and vascular involvement. A halo sign was defined as replacement of solid perivascular (arterial and venous) tumor tissue by a zone of fatty-like signal intensity. RESULTS: Adequate MRI was obtained in 19 patients with LAPC after induction chemotherapy. Tumor diameter was non-significantly smaller on CE-MRI compared to CE-CT (26 mm vs. 30 mm; p = 0.073). An MRI-halo sign was seen on CE-MRI in 52.6% (n = 10/19), whereas a CT-halo sign was seen in 10.5% (n = 2/19) of patients (p = 0.016). An MRI-halo sign was not associated with resection rate (60.0% vs. 62.5%; p = 1.000). In the resection cohort, patients with an MRI-halo sign had a non-significant increased R0 resection rate as compared to patients without an MRI-halo sign (66.7% vs. 20.0%; p = 0.242). Positive and negative predictive values of the CE-MRI-halo sign for R0 resection were 66.7% and 66.7%, respectively. CONCLUSIONS: 3 T CE-MRI and the MRI-halo sign might be helpful to assess the effect of induction chemotherapy in patients with LAPC, but its diagnostic accuracy has to be evaluated in larger series.

Increased Hepatic Microvascular Density, Oxygenation, and VEGF in the Hypertrophic Lobe following Portal Vein Embolization in Rabbits.

INTRODUCTION: The microvascular events following portal vein embolization (PVE) are poorly understood despite the pivotal role of the microcirculation in liver regeneration and tumor progression. We aimed to assess the changes in hepatic microvascular perfusion and neo-angiogenesis after experimental PVE. METHODS: PVE of the cranial liver lobes was performed in 12 New Zealand White rabbits divided into 2 groups of permanent (P-PVE) and reversible PVE (R-PVE), respectively. Hepatobiliary scintigraphy and CT were used to evaluate hepatic function and volume. Hepatic microcirculation was assessed using a handheld vital microscope (Cytocam) to measure microvascular density (total vessel density; TVD) before PVE, right after PVE, and 20 min after PVE, as well as at 14 days (D14 post-PVE) and 35 days (D35 post-PVE). Additionally, on D35, microvascular PO2 and liver parenchymal VEGF were assessed. RESULTS: Eleven rabbits were included after PVE (R-PVE, n = 5; P-PVE, n = 6). TVD in the nonembo-lized (hypertrophic) lobes was higher than in the embolized (atrophic) lobes of the P-PVE group at D35 post-PVE (36.7 ± 7.2 vs. 23.4 ± 4.9 mm/mm2; p < 0.05). In the R-PVE group, TVD in the nonembolized lobes was not increased at D35. Function and volume were increased in the nonembolized lobes of the P-PVE group compared to the embolized lobes, but not in the R-PVE group. Likewise, the mmicrovascular PO2 and VEGF staining rate were higher in the nonembolized lobes of the P-PVE group at D35 post-PVE. DISCUSSION/CONCLUSION: Successful volumetric and functional hypertrophy of the nonembolized lobe was accompanied by microvascular alterations featuring increased neo-angiogenesis, microvascular density, and microvascular oxygen pressure following P-PVE.

Survival Benefit Associated With Resection of Locally Advanced Pancreatic Cancer After Upfront FOLFIRINOX Versus FOLFIRINOX Only: Multicenter Propensity Score-matched Analysis.

OBJECTIVE: This study compared median OS after resection of LAPC after upfront FOLFIRINOX versus a propensity-score matched cohort of LAPC patients treated with FOLFIRINOX-only (ie, without resection). BACKGROUND: Because the introduction of FOLFIRINOX chemotherapy, increased resection rates in LAPC patients have been reported, with improved OS. Some studies have also reported promising OS with FOLFIRINOX-only treatment in LAPC. Multicenter studies assessing the survival benefit associated with resection of LAPC versus patients treated with FOLFIRINOX-only are lacking. METHODS: Patients with non-progressive LAPC after 4 cycles of FOLFIRINOX treatment, both with and without resection, were included from a prospective multicenter cohort in 16 centers (April 2015-December 2019). Cox regression analysis identified predictors for OS. One-to-one propensity score matching (PSM) was used to obtain a matched cohort of patients with and without resection. These patients were compared for OS. RESULTS: Overall, 293 patients with LAPC were included, of whom 89 underwent a resection. Resection was associated with improved OS (24 vs 15 months, P < 0.01), as compared to patients without resection. Before PSM, resection, Charlson Comorbidity Index, and Response Evaluation Criteria in Solid Tumors (RECIST) response were predictors for OS. After PSM, resection remained associated with improved OS [Hazard Ratio (HR) 0.344, 95% confidence interval (0.222-0.534), P < 0.01], with an OS of 24 versus 15 months, as compared to patients without resection. Resection of LAPC was associated with improved 3-year OS (31% vs 11%, P < 0.01). CONCLUSIONS: Resection of LAPC after FOLFIRINOX was associated with increased OS and 3-year survival, as compared to propensity-score matched patients treated with FOLFIRINOX-only.

Irreversible Electroporation to Treat Unresectable Colorectal Liver Metastases (COLDFIRE-2): A Phase II, Two-Center, Single-Arm Clinical Trial.

Background Irreversible electroporation (IRE), an ablative technique that uses high-voltage electrical pulses, has shown promise for eradicating tumors near critical structures, including blood vessels and bile ducts. Purpose To investigate the efficacy and safety of IRE for colorectal liver metastases (CRLMs) unsuitable for resection or thermal ablation because of proximity to critical structures and for further systemically administered treatments. Materials and Methods Between June 2014 and November 2018, participants with fluorine 18 (18F) fluorodeoxyglucose (FDG) PET-avid CRLMs measuring 5.0 cm or smaller, unsuitable for partial hepatectomy and thermal ablation, underwent percutaneous or open IRE (ClinicalTrials.gov identifier: NCT02082782). Follow-up included tumor marker assessment and 18F-FDG PET/CT imaging. For the primary end point to be met, at least 50% of treated participants had to be alive without local tumor progression (LTP) at 12 months, defined as LTP-free survival. Secondary aims were safety, technical success, local control allowing for repeat procedures, disease-free status, and overall survival. Results A total of 51 participants (median age, 67 years [interquartile range, 62-75 years]; 37 men) underwent IRE. Of these 51 participants, 50 with a total of 76 CRLMs (median tumor size, 2.2 cm; range, 0.5-5.4 cm) were successfully treated in 62 procedures; in one participant, treatment was stopped prematurely because of pulse-induced cardiac arrhythmia. With a per-participant 1-year LTP-free survival of 68% (95% CI: 59, 84) according to competing risk analysis, the primary end point was met. Local control following repeat procedures was achieved in 74% of participants (37 of 50). Median overall survival from first IRE was 2.7 years (95% CI: 1.6, 3.8). Twenty-three participants experienced a total of 34 adverse events in 25 of the 62 procedures (overall complication rate, 40%). One participant (2%), who had an infected biloma after IRE, died fewer than 90 days after the procedure (grade 5 adverse event). Conclusion Irreversible electroporation was effective and relatively safe for colorectal liver metastases 5.0 cm or smaller that were unsuitable for partial hepatectomy, thermal ablation, or further systemic treatment. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Goldberg in this issue.

Predicting overall survival and resection in patients with locally advanced pancreatic cancer treated with FOLFIRINOX: Development and internal validation of two nomograms.

BACKGROUND AND OBJECTIVES: Patients with locally advanced pancreatic cancer (LAPC) are increasingly treated with FOLFIRINOX, resulting in improved survival and resection of tumors that were initially unresectable. It remains unclear, however, which specific patients benefit from FOLFIRINOX. Two nomograms were developed predicting overall survival (OS) and resection at the start of FOLFIRINOX for LAPC. METHODS: From our multicenter, prospective LAPC registry in 14 Dutch hospitals, LAPC patients starting first-line FOLFIRINOX (April 2015-December 2017) were included. Stepwise backward selection according to the Akaike Information Criterion was used to identify independent baseline predictors for OS and resection. Two prognostic nomograms were generated. RESULTS: A total of 252 patients were included, with a median OS of 14 months. Thirty-two patients (13%) underwent resection, with a median OS of 23 months. Older age, female sex, Charlson Comorbidity Index ≤1, and CA 19.9 < 274 were independent factors predicting a better OS (c-index: 0.61). WHO ps >1, involvement of the superior mesenteric artery, celiac trunk, and superior mesenteric vein ≥ 270° were independent factors decreasing the probability of resection (c-index: 0.79). CONCLUSIONS: Two nomograms were developed to predict OS and resection in patients with LAPC before starting treatment with FOLFIRINOX. These nomograms could be beneficial in the shared decision-making process and counseling of these patients.

Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma.

Circulating tumor DNA (ctDNA) is assumed to reflect tumor burden and has been suggested as a tool for prognostication and follow-up in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the prognostic value of ctDNA and its relation with tumor burden has yet to be substantiated, especially in mPDAC. In this retrospective analysis of prospectively collected samples, cell-free DNA from plasma samples of 58 treatment-naive mPDAC patients was isolated and sequenced using a custom-made pancreatobiliary NGS panel. Pathogenic mutations were detected in 26/58 (44.8%) samples. Cross-check with droplet digital PCR showed good agreement in Bland-Altman analysis (p = 0.217, nonsignificance indicating good agreement). In patients with liver metastases, ctDNA was more frequently detected (24/37, p < 0.001). Tumor volume (3D reconstructions from imaging) and ctDNA variant allele frequency (VAF) were correlated (Spearman's ρ = 0.544, p < 0.001). Median overall survival (OS) was 3.2 (95% confidence interval [CI] 1.6-4.9) versus 8.4 (95% CI 1.6-15.1) months in patients with detectable versus undetectable ctDNA (p = 0.005). Both ctDNA VAF and tumor volume independently predicted OS after adjustment for carbohydrate antigen 19.9 and treatment regimen (hazard ratio [HR] 1.05, 95% CI 1.01-1.09, p = 0.005; HR 1.00, 95% CI 1.01-1.05, p = 0.003). In conclusion, our study showed that ctDNA detection rates are higher in patients with larger tumor volume and liver metastases. Nevertheless, measurements may diverge and, thus, can provide complementary information. Both ctDNA VAF and tumor volume were strong predictors of OS.

Percutaneous Irreversible Electroporation in Locally Advanced and Recurrent Pancreatic Cancer (PANFIRE-2): A Multicenter, Prospective, Single-Arm, Phase II Study.

Background Patients with locally advanced pancreatic cancer have a dismal prognosis, with a median overall survival (OS) of 12-14 months with systemic therapies. Irreversible electroporation (IRE), a nonthermal ablative technique, may prolong survival of patients with locally advanced pancreatic cancer. Purpose To investigate the safety and efficacy of percutaneous IRE for locally advanced pancreatic cancer and locally recurring pancreatic cancer in a prospective phase II trial. Materials and Methods Between December 2012 and September 2017, participants with locally advanced pancreatic cancer or postresection local recurrence were prospectively treated with percutaneous CT-guided IRE (ClinicalTrials.gov identifier: NCT01939665). The primary end point was median OS from diagnosis. The target median OS was 11.6 months for participants receiving no induction chemotherapy or gemcitabine-based induction chemotherapy and 14.9 months for those receiving induction 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). Results Fifty participants (25 men and 25 women; median age, 61 years [interquartile range, 56-69 years]; 40 with locally advanced pancreatic cancer and 10 with local recurrence) were included. Median OS measured by using the Kaplan-Meier method was 17 months from diagnosis of locally advanced pancreatic cancer (95% confidence interval [CI]: 15 months, 19 months) and 10 months from IRE (95% CI: 8 months, 11 months). In the locally advanced pancreatic cancer group, 18 participants received no therapy or gemcitabine-based induction chemotherapy and 22 received FOLFIRINOX. The median OS from diagnosis was 17 months for both groups (95% CI: 7 months, 28 months and 15 months, 18 months, respectively; P = .26). For participants with postresection local recurrence, the median OS was 16 months from diagnosis of recurrence (95% CI: 11 months, 22 months) and 9 months from IRE (95% CI: 2 months, 16 months). After IRE, local recurrence developed in 23 of the 50 participants (46%). Tumor volume of 37 cm3 or greater (hazard ratio [HR], 2.9; P = .02), pre-IRE carbohydrate antigen 19-9 (CA 19-9) level of 2000 U/mL or greater (HR, 12.1; P = .001), and decrease in CA 19-9 level of 50% or less 3 months after IRE (HR, 3.1; P = .01) were predictors of worse survival. Fourteen minor and 21 major complications occurred in 29 of the 50 participants (58%). Two participants died less than 90 days after IRE; one of these deaths was likely related to IRE. Conclusion The target median overall survival with CT-guided percutaneous irreversible electroporation was exceeded in participants with locally advanced pancreatic cancer (17 months) and those with local recurrence (16 months). © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Goldberg in this issue.

Value of CT-Guided Percutaneous Irreversible Electroporation Added to FOLFIRINOX Chemotherapy in Locally Advanced Pancreatic Cancer: A Post Hoc Comparison.

PURPOSE: To compare survival after CT-guided percutaneous irreversible electroporation (IRE) and folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) chemotherapy versus FOLFIRINOX only in patients with locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: A post hoc comparison was performed of data derived from a prospective IRE-FOLFIRINOX cohort and a retrospective FOLFIRINOX-only cohort. All patients received a minimum of 3 cycles of FOLFIRINOX for LAPC and were considered eligible for CT-guided percutaneous IRE. Endpoints included overall survival (OS), local and distant progression-free survival, and time to progression (TTP) and were compared using stratified Kaplan-Meier analysis. Patients who received > 8 cycles of FOLFIRINOX before IRE and who had tumors > 6 cm in the FOLFIRINOX-only group were excluded. RESULTS: Of 103 patients with a diagnosis of LAPC, 52 were deemed eligible (n = 30 IRE-FOLFIRINOX and n = 22 FOLFIRINOX-only). Patients in the FOLFIRINOX-only arm had larger tumors (53 mm ± 19 vs 38 mm ± 7, P = .340), had more locoregional lymph node metastases (23% vs 7%, P = .622), and more often received radiotherapy (7 patients vs 2 patients, P = .027); all other baseline characteristics were comparable. Median OS was 17.0 months (range, 5-35 mo; SD = 6) for IRE-FOLFIRINOX versus 12.4 months (range, 3-22 mo; SD = 6) for FOLFIRINOX-only (P = .038). After sensitivity analyses, median OS was 17.2 months (range, 6-27 mo; SD = 6) versus 12.4 months (range, 7-32 mo; SD = 10) (P = .05). Median TTP was longer in the IRE-FOLFIRINOX group: 14.2 months (range, 5-25 mo; SD = 4) versus 5.2 months (range, 2-22; SD = 6) (P = .0001). CONCLUSIONS: In patients with LAPC after FOLFIRINOX chemotherapy, CT-guided percutaneous IRE may improve OS and TTP. This study may facilitate the design of randomized controlled trials to compare survival after IRE-FOLRINOX versus FOLFIRINOX-only.

Mathematical modeling of the thermal effects of irreversible electroporation for in vitro, in vivo, and clinical use: a systematic review.

Introduction: Irreversible electroporation (IRE) is a relatively new ablation method for the treatment of unresectable cancers. Although the main mechanism of IRE is electric permeabilization of cell membranes, the question is to what extent thermal effects of IRE contribute to tissue ablation.Aim: This systematic review reviews the mathematical models used to numerically simulate the heat-generating effects of IRE, and uses the obtained data to assess the degree of mild-hyperthermic (temperatures between 40 °C and 50 °C) and thermally ablative (TA) effects (temperatures exceeding 50 °C) caused by IRE within the IRE-treated region (IRE-TR).Methods: A systematic search was performed in medical and technical databases for original studies reporting on numerical simulations of IRE. Data on used equations, study design, tissue models, maximum temperature increase, and surface areas of IRE-TR, mild-hyperthermic, and ablative temperatures were extracted.Results: Several identified models, including Laplace equation for calculation of electric field distribution, Pennes Bioheat Equation for heat transfer, and Arrhenius model for thermal damage, were applied on various electrode and tissue models. Median duration of combined mild-hyperthermic and TA effects is 20% of the treatment time. Based on the included studies, mild-hyperthermic temperatures occurred in 30% and temperatures ≥50 °C in 5% of the IRE-TR.Conclusions: Simulation results in this review show that significant mild-hyperthermic effects occur in a large part of the IRE-TR, and direct thermal ablation in comparatively small regions. Future studies should aim to optimize clinical IRE protocols, maintaining a maximum irreversible permeabilized region with minimal TA effects.

Intraoperative Imaging Techniques to Visualize Hepatic (Micro)Perfusion: An Overview.

The microcirculation plays a crucial role in the distribution of perfusion to organs. Studies have shown that microcirculatory dysfunction is an independent predictor of morbidity and mortality. Hence, assessment of liver perfusion offers valuable information on the (patho)physiological state of the liver. The current review explores techniques in perfusion imaging that can be used intraoperatively. Available modalities include dynamic contrast-enhanced ultrasound, handheld vital microscopes, indocyanine green fluorescence angiography, and laser contrast speckle imaging. Dynamic contrast-enhanced ultrasound relays information on deep tissue perfusion and is a commonly used technique to assess tumor perfusion. Handheld vital microscopes provide direct visualization of the sinusoidal architectural structure of the liver, which is a unique feature of this technique. Intraoperative fluorescence imaging uses indocyanine green, a dye that is administered intravenously to visualize microvascular perfusion when excited using near-infrared light. Laser speckle contrast imaging produces non-contact large surface-based tissue perfusion imaging free from movement- or pressure-related artefacts. In this review, we discuss the intrinsic advantages and disadvantages of these techniques and their clinical and/or scientific applications.

HyCHEED System for Maintaining Stable Temperature Control during Preclinical Irreversible Electroporation Experiments at Clinically Relevant Temperature and Pulse Settings.

Electric permeabilization of cell membranes is the main mechanism of irreversible electroporation (IRE), an ablation technique for treatment of unresectable cancers, but the pulses also induce a significant temperature increase in the treated volume. To investigate the therapeutically thermal contribution, a preclinical setup is required to apply IRE at desired temperatures while maintaining stable temperatures. This study's aim was to develop and test an electroporation device capable of maintaining a pre-specified stable and spatially homogeneous temperatures and electric field in a tumor cell suspension for several clinical-IRE-settings. A hydraulically controllable heat exchange electroporation device (HyCHEED) was developed and validated at 37 °C and 46 °C. Through plate electrodes, HyCHEED achieved both a homogeneous electric field and homogenous-stable temperatures; IRE heat was removed through hydraulic cooling. IRE was applied to 300 µL of pancreatic carcinoma cell suspension (Mia PaCa-2), after which cell viability and specific conductivity were determined. HyCHEED maintained stable temperatures within ±1.5 °C with respect to the target temperature for multiple IRE-settings at the selected temperature levels. An increase of cell death and specific conductivity, including post-treatment, was found to depend on electric-field strength and temperature. HyCHEED is capable of maintaining stable temperatures during IRE-experiments. This provides an excellent basis to assess the contribution of thermal effects to IRE and other bio-electromagnetic techniques.