Quantitative analysis of contribution of mild and moderate hyperthermia to thermal ablation and sensitization of irreversible electroporation of pancreatic cancer cells.

INTRODUCTION: Irreversible electroporation (IRE) is an ablation modality that applies short, high-voltage electric pulses to unresectable cancers. Although considered a non-thermal technique, temperatures do increase during IRE. This temperature rise sensitizes tumor cells for electroporation as well as inducing partial direct thermal ablation. AIM: To evaluate the extent to which mild and moderate hyperthermia enhance electroporation effects, and to establish and validate in a pilot study cell viability models (CVM) as function of both electroporation parameters and temperature in a relevant pancreatic cancer cell line. METHODS: Several IRE-protocols were applied at different well-controlled temperature levels (37 °C ≤ T ≤ 46 °C) to evaluate temperature dependent cell viability at enhanced temperatures in comparison to cell viability at T = 37 °C. A realistic sigmoid CVM function was used based on thermal damage probability with Arrhenius Equation and cumulative equivalent minutes at 43 °C (CEM43°C) as arguments, and fitted to the experimental data using "Non-linear-least-squares"-analysis. RESULTS: Mild (40 °C) and moderate (46 °C) hyperthermic temperatures boosted cell ablation with up to 30% and 95%, respectively, mainly around the IRE threshold Eth,50% electric-field strength that results in 50% cell viability. The CVM was successfully fitted to the experimental data. CONCLUSION: Both mild- and moderate hyperthermia significantly boost the electroporation effect at electric-field strengths neighboring Eth,50%. Inclusion of temperature in the newly developed CVM correctly predicted both temperature-dependent cell viability and thermal ablation for pancreatic cancer cells exposed to a relevant range of electric-field strengths/pulse parameters and mild moderate hyperthermic temperatures.

Available ablation energies to treat cT1 renal cell cancer: emerging technologies.

PURPOSE: An increasing interest in percutaneous ablation of renal tumors has been caused by the increasing incidence of SRMs, the trend toward minimally invasive nephron-sparing treatments and the rapid development of local ablative technologies. In the era of shared decision making, patient preference for non-invasive treatments also leads to an increasing demand for image-guided ablation. Although some guidelines still reserve ablation for poor surgical candidates, indications may soon expand as evidence for the use of the two most validated local ablative techniques, cryoablation (CA) and radiofrequency ablation (RFA), is accumulating. Due to the collaboration between experts in the field in biomedical engineering, urologists, interventional radiologists and radiation oncologists, the improvements in ablation technologies have been evolving rapidly in the last decades, resulting in some new emerging types of ablations. METHODS: A literature search was conducted to identify original research articles investigating the clinical outcomes of new emerging technologies, percutaneous MWA, percutaneous IRE and SABR, in patients with primary cT1 localized renal cell cancer. RESULTS: Due to the collaboration between experts in the field in biomedical engineering, urologists, interventional radiologists and radiation oncologists, the improvements in ablation technologies have been evolving rapidly in the last decades. New emerging technologies such as microwave ablation (MWA), irreversible electroporation (IRE) and stereotactic ablative radiotherapy (SABR) seem to be getting ready for prime time. CONCLUSION: This topical paper describes the new emerging technologies for cT1 localized renal cell cancer and investigates how they compare to CA and RFA.

Modern work-up and extended resection in perihilar cholangiocarcinoma: the AMC experience.

AIM: Perihilar cholangiocarcinoma (PHC) is a challenging disease and requires aggressive surgical treatment in order to achieve curation. The assessment and work-up of patients with presumed PHC is multidisciplinary, complex and requires extensive experience. The aim of this paper is to review current aspects of diagnosis, preoperative work-up and extended resection in patients with PHC from the perspective of our own institutional experience with this complex tumor. METHODS: We provided a review of applied modalities in the diagnosis and work-up of PHC according to current literature. All patients with presumed PHC in our center between 2000 and 2016 were identified and described. The types of resection, surgical techniques and outcomes were analyzed. RESULTS AND CONCLUSION: Upcoming diagnostic modalities such as Spyglass and combinations of serum biomarkers and molecular markers have potential to decrease the rate of misdiagnosis of benign, inflammatory disease. Assessment of liver function with hepatobiliary scintigraphy provides better information on the future remnant liver (FRL) than volume alone. The selective use of staging laparoscopy is advisable to avoid futile laparotomies. In patients requiring extended resection, selective preoperative biliary drainage is mandatory in cholangitis and when FRL is small (< 50%). Preoperative portal vein embolization (PVE) is used when FRL volume is less than 40% and optionally includes the left portal vein branches to segment 4. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as alternative to PVE is not recommended in PHC. N2 positive lymph nodes preclude long-term survival. The benefit of unconditional en bloc resection of the portal vein bifurcation is uncertain. Along these lines, an aggressive surgical approach encompassing extended liver resection including segment 1, regional lymphadenectomy and conditional portal venous resection translates into favorable long-term survival.

Effect of obeticholic acid on liver regeneration following portal vein embolization in an experimental model.

BACKGROUND: The bile salt-activated transcription factor farnesoid X receptor (FXR) is a key mediator of proliferative bile salt signalling, which is assumed to play a role in the early phase of compensatory liver growth. The aim of this study was to evaluate the effect of a potent FXR agonist (obeticholic acid, OCA) on liver growth following portal vein embolization (PVE). METHODS: Rabbits were allocated to receive daily oral gavage with OCA (10 mg/kg) or vehicle (control group) starting 7 days before PVE (n = 18 per group), and continued until 7 days after PVE. PVE of the cranial liver lobes was performed using polyvinyl alcohol particles and coils on day 0. Caudal liver volume (CLV) was analysed by CT volumetry on days -7, -1, +3 and +7. Liver function was determined by measuring mebrofenin uptake using hepatobiliary scintigraphy. Additional parameters analysed were plasma aminotransferase levels, and histological scoring of haematoxylin and eosin- and Ki-67-stained liver sections. RESULTS: Three days after PVE of the cranial lobes, the increase in CLV was 2·2-fold greater in the OCA group than in controls (mean(s.d.) 56·1(20·3) versus 26·1(15·4) per cent respectively; P < 0·001). This increase remained greater 7 days after PVE (+1·5-fold; P = 0·020). The increase in caudal liver function at day +3 was greater in OCA-treated animals (+1·2-fold; P = 0·017). The number of Ki-67-positive hepatocytes was 1·6-fold higher in OCA-treated animals 3 days after PVE (P = 0·045). Plasma aminotransferase levels and histology did not differ significantly between groups. CONCLUSION: OCA accelerated liver regeneration after PVE in a rabbit model. OCA treatment might increase the efficacy of PVE and, thereby, resectability. Surgical relevance Liver failure is the most feared complication after liver surgery, with no effective treatment options. Liver regeneration is essential to avoid liver failure, and recently bile acid signalling was implicated in the initiation of liver regeneration through the nuclear bile acid receptor farnesoid X receptor (FXR). In this study, the potent FXR agonist obeticholic acid accelerated liver regeneration following portal vein embolization in a rabbit model, in terms of liver volume, liver function and proliferation. Obeticholic acid treatment could enhance the efficacy of portal vein embolization, thereby increasing resectability, and could reduce the interval to surgery. In addition, obeticholic acid might have a place in the prevention of liver failure after liver surgery.

The practice of platelet transfusion prior to central venous catheterization in presence of coagulopathy: a national survey among clinicians.

BACKGROUND: Correction of coagulopathy prior to central venous catheter (CVC) placement is advocated by guidelines, while retrospective studies support restrictive use of transfusion products. STUDY DESIGN AND METHODS: We conducted a mixed vignette and questionnaire web survey to investigate current practice and preferences for CVC placement. Clinical vignettes were used to quantify the tendency to administer platelet concentrate. A positive ß-coefficient is in favour of administering platelet concentrate. RESULTS: Ninety-seven physicians answered the survey questions (36 critical care physicians, 14 haematologists, 20 radiologists and 27 anaesthesiologist). Eighty-six physicians subsequently completed the clinical vignettes (response rate 71%). Preferences in favour of correcting thrombocytopenia prior CVC placement were platelet counts of 10 × 109 /L and 20 × 109 /L (ß = 3·9; ß = 3·2, respectively), the subclavian insertion site (ß = 0·8). An elevated INR (INR = 3; ß = 0·6) and an elevated aPTT (aPTT = 60 s; ß = 0·4) showed a positive trend towards platelet transfusion. Platelet transfusion was less likely in an emergency setting (ß = -0·4). Reported transfusion thresholds for CVC placement varied from <10 × 109 /L to 80 × 109 /L for platelet count, from 1·0 to 10·0 for INR and from 25 s to 150 s for aPTT. Implementation of ultrasound guidance as standard practice was limited. CONCLUSION: Current transfusion practice prior to CVC placement is highly variable. Physicians adjust the decision to correct coagulopathy prior CVC placement based on clinical parameters, insertion site and technique applied.

Non-contrast enhanced navigator-gated balanced steady state free precession magnetic resonance angiography as a preferred magnetic resonance technique for assessment of the thoracic aorta.

AIM: To compare the objective and subjective image quality of non-contrast three-dimensional (3D) navigator-gated balanced steady state free precession magnetic resonance angiography (NC-MRA) and contrast-enhanced magnetic resonance angiography (CE-MRA) along the entire thoracic aorta. MATERIALS AND METHODS: Fifty consecutive patients with thoracic aortic disease underwent NC-MRA and CE-MRA using a 1.5 T MRI system. Vessel sharpness was assessed using signal intensity profiles at five predefined levels of the thoracic aorta. Two readers scored subjective quality. Manual diameter measurements of both readers were used for calculation of interobserver variation. RESULTS: NC-MRA resulted in significantly sharper delineation of the aortic root, ascending aorta, and distal descending aorta compared to CE-MRA. Sharpness was comparable at the level of the arch and proximal descending aorta. NC-MRA resulted in significantly better subjective image quality. Interobserver agreement for diameter measurements was excellent for both techniques. CONCLUSION: NC-MRA resulted in superior image quality for assessment of the thoracic aorta and in better vessel sharpness for assessment of the aortic root and ascending aorta, when compared to CE-MRA. NC-MRA can be considered the MRA technique of choice for the assessment of the thoracic aorta diameters in clinical practice.

Systematic review of outcomes after distal pancreatectomy with coeliac axis resection for locally advanced pancreatic cancer.

BACKGROUND: Pancreatic cancer involving the coeliac axis is considered unresectable by most guidelines, with a median survival of 6-11 months. A subgroup of these patients can undergo distal pancreatectomy with coeliac axis resection, but consensus on the value of this procedure is lacking. The evidence for this procedure, including the impact of preoperative hepatic artery embolization and (neo)adjuvant therapy, was evaluated. METHODS: A systematic review was performed according to the PRISMA guidelines until 27 May 2015. The primary endpoint was overall survival; secondary endpoints included morbidity and radical resection rates. RESULTS: A total of 19 retrospective studies, involving 240 patients, were included. The methodological quality of the studies ranged from poor to moderate. A radical resection was reported in 74·5 per cent (152 of 204), major morbidity in 27 per cent (26 of 96), ischaemic morbidity in 9·0 per cent (21 of 223) and 90-day mortality in 3·5 per cent (4 of 113). Overall, 35·5 per cent of patients (55 of 155) underwent preoperative hepatic artery embolization without an apparent beneficial impact on ischaemic morbidity. Overall, 15·7 per cent (29 of 185) had neoadjuvant and 51·0 per cent (75 of 147) had adjuvant therapy. There was a difference in survival between patient series where less than half of patients had (neo)adjuvant chemotherapy and series where more than half were receiving this treatment: case-weighted median overall survival was 16 (range 9-48) versus 18 (10-26) months respectively (P = 0·002). Overall median survival for the whole study population was 14·4 (range 9-48) months. CONCLUSION: Distal pancreatectomy with coeliac axis resection seems a valuable option for selected patients with pancreatic cancer involving the coeliac axis with acceptable morbidity and mortality, and a median survival of 18 months when combined with (neo)adjuvant therapy.

Use of an absorbable embolization material for reversible portal vein embolization in an experimental model.

BACKGROUND: Portal vein embolization (PVE) is used to increase future remnant liver size in patients requiring major hepatic resection. PVE using permanent embolization, however, predisposes to complications and excludes the use of PVE in living donor liver transplantation. In the present study, an absorbable embolization material containing fibrin glue and different concentrations of the fibrinolysis inhibitor aprotinin was used in an experimental animal model. METHODS: PVE of the cranial liver lobes was performed in 30 New Zealand White rabbits, which were divided into five groups, fibrin glue + 1000, 700, 500, 300 or 150 kunits/ml aprotinin, and were compared with a previous series of permanent embolization using the same experimental set-up. Caudal liver lobe hypertrophy was determined by CT volumetry, and portal recanalization was identified on contrast-enhanced CT images. Animals were killed after 7 or 42 days, and the results were compared with those of permanent embolization. RESULTS: PVE using fibrin glue with aprotinin as embolic material was effective, with 500 kunits/ml providing the optimal hypertrophic response. Lower concentrations of aprotinin (150 and 300 kunits/ml) led to reduced hypertrophy owing to early recanalization of the embolized segments. The regeneration rate over the first 3 days was higher in the group with 500 kunits/ml aprotinin than in the groups with 300 or 150 kunits/ml or permanent embolization. In the 500-kunits/ml group, four of five animals showed recanalization 42 days after embolization, with minimal histological changes in the cranial lobes following recanalization. CONCLUSION: Fibrin glue combined with 500 kunits/ml aprotinin resulted in reversible PVE in 80 per cent of animals, with a hypertrophy response comparable to that achieved with permanent embolization material. Surgical relevance Portal vein embolization (PVE) is used to increase future remnant liver volume in patients scheduled for major liver resection who have insufficient future remnant liver size to perform a safe resection. The current standard is PVE with permanent embolization materials, which renders patients found to have unresectable disease prone to complications owing to the permanently deportalized liver segments. Absorbable embolization might prevent the PVE-associated morbidity and lower the threshold for its application. In this study, PVE using fibrin glue and aprotinin resulted in an adequate hypertrophy response with 80 per cent recanalization after 42 days. Considering the minor histological changes following recanalization of embolized segments and potentially preserved function, reversible PVE might also be applied in living donor liver transplantation.

Systematic review of innovative ablative therapies for the treatment of locally advanced pancreatic cancer.

BACKGROUND: Locally advanced pancreatic cancer (LAPC) is associated with a very poor prognosis. Current palliative (radio)chemotherapy provides only a marginal survival benefit of 2-3 months. Several innovative local ablative therapies have been explored as new treatment options. This systematic review aims to provide an overview of the clinical outcomes of these ablative therapies. METHODS: A systematic search in PubMed, Embase and the Cochrane Library was performed to identify clinical studies, published before 1 June 2014, involving ablative therapies in LAPC. Outcomes of interest were safety, survival, quality of life and pain. RESULTS: After screening 1037 articles, 38 clinical studies involving 1164 patients with LAPC, treated with ablative therapies, were included. These studies concerned radiofrequency ablation (RFA) (7 studies), irreversible electroporation (IRE) (4), stereotactic body radiation therapy (SBRT) (16), high-intensity focused ultrasound (HIFU) (5), iodine-125 (2), iodine-125-cryosurgery (2), photodynamic therapy (1) and microwave ablation (1). All strategies appeared to be feasible and safe. Outcomes for postoperative, procedure-related morbidity and mortality were reported only for RFA (4-22 and 0-11 per cent respectively), IRE (9-15 and 0-4 per cent) and SBRT (0-25 and 0 per cent). Median survival of up to 25·6, 20·2, 24·0 and 12·6 months was reported for RFA, IRE, SBRT and HIFU respectively. Pain relief was demonstrated for RFA, IRE, SBRT and HIFU. Quality-of-life outcomes were reported only for SBRT, and showed promising results. CONCLUSION: Ablative therapies in patients with LAPC appear to be feasible and safe.

Risk factors for bleeding in hepatocellular adenoma.

BACKGROUND: Hepatocellular adenoma (HCA) is a benign hepatic lesion that may be complicated by bleeding, although the risk of bleeding is ill-defined. The aim of this study was to assess risk factors for bleeding in patients diagnosed with HCA. METHODS: Patients with HCA were included prospectively from January 2008 to July 2012. Patient characteristics were noted. Patients underwent dynamic magnetic resonance imaging (MRI) and/or computed tomography (CT) at presentation and during follow-up. Lesion characteristics on (follow-up) imaging were noted, and bleeding was graded as intratumoral (grade I), intrahepatic (grade II) or extrahepatic (grade III). The standard of reference for diagnosis was histopathology, or dynamic MRI and/or CT findings. Possible risk factors were included if mentioned in literature (lesion size, body mass index), or based on clinical experience (lesion location, visible vessels on imaging). RESULTS: A total of 45 patients (median age 39 (range 22-60) years; 44 women) with 195 lesions (median size 24 (10-250) mm) were evaluated. Bleeding occurred in 29 patients (64 per cent) and in 42 lesions (21.5 per cent) with a median size of 62 (10-160) mm. Size was a risk factor for bleeding (P < 0.001), with an increased number of bleeding events in lesions of 35 mm or more. Exophytic lesions (protruding from liver) had more bleeding (16 of 24, 67 per cent) than intrahepatic (9 of 82, 11 per cent) or subcapsular (17 of 89, 19 per cent) lesions (P < 0.001). Lesions in segments II and III had more bleeds than those in the right liver (11 of 32 versus 31 of 163; P = 0.049), as did lesions in which peripheral or central arteries were visualized on imaging (10 of 13 versus 32 of 182 lesions with no visible vascularization; P < 0.001). CONCLUSION: Risk factors for bleeding of HCA include diameter of 35 mm or more, visualization of lesional arteries, location in the left lateral liver, and exophytic growth.

Increase in future remnant liver function after preoperative portal vein embolization.

BACKGROUND: Preoperative portal vein embolization (PVE) is performed in patients with insufficient future remnant liver (FRL) to allow safe resection. Although many studies have demonstrated an increase in FRL volume after PVE, little is known about the increase in FRL function. This study evaluated the increase in FRL function after PVE using (99m) Tc-labelled mebrofenin hepatobiliary scintigraphy (HBS) with single photon emission computed tomography (SPECT) and compared this with the increase in FRL volume. METHODS: In 24 patients, computed tomography volumetry and (99m) Tc-labelled mebrofenin HBS with SPECT were performed before and 3-4 weeks after PVE to measure FRL volume, standardized FRL and FRL function. A hypothetical model was used to assess safe resectability after PVE. The limit for safe resection for FRL function was set at an uptake of 2·69 per cent per min per m². For FRL volume and standardized FRL, 25 or 40 per cent of total liver volume was used, depending on the presence of underlying liver disease. RESULTS: After PVE, FRL function increased significantly more than FRL volume. The correlation between the increase in FRL volume and FRL function was poor. Using the hypothetical model, seven patients did not achieve a sufficient increase in FRL function to allow safe resection 3-4 weeks after PVE, compared with 12 and nine patients based on FRL volume and standardized FRL respectively. CONCLUSION: The increase in FRL function after PVE is more pronounced than the increase in FRL volume, suggesting that the necessary waiting time until resection may be shorter than indicated by volumetric parameters.

Predictive Factors for Hypertrophy of the Future Liver Remnant After Portal Vein Embolization: A Systematic Review.

This systematic review was conducted to determine factors that are associated with the degree of hypertrophy of the future liver remnant following portal vein embolization. An extensive search on September 15, 2020, and subsequent literature screening resulted in the inclusion of forty-eight articles with 3368 patients in qualitative analysis, of which 18 studies were included in quantitative synthesis. Meta-analyses based on a limited number of studies showed an increase in hypertrophy response when additional embolization of segment 4 was performed (pooled difference of medians = - 3.47, 95% CI - 5.51 to - 1.43) and the use of N-butyl cyanoacrylate for portal vein embolization induced more hypertrophy than polyvinyl alcohol (pooled standardized mean difference (SMD) = 0.60, 95% CI 0.30 to 0.91). There was no indication of a difference in degree of hypertrophy between patients who received neo-adjuvant chemotherapy and those who did not receive pre-procedural systemic therapy(pooled SMD = - 0.37, 95% CI - 1.35 to 0.61), or between male and female patients (pooled SMD = 0.19, 95% CI - 0.12 to 0.50).The study was registered in the International Prospective Register of Systematic Reviews on April 28, 2020 (CRD42020175708).

Radiofrequency ablation and chemotherapy versus chemotherapy alone for locally advanced pancreatic cancer (PELICAN): study protocol for a randomized controlled trial.

BACKGROUND: Approximately 80% of patients with locally advanced pancreatic cancer (LAPC) are treated with chemotherapy, of whom approximately 10% undergo a resection. Cohort studies investigating local tumor ablation with radiofrequency ablation (RFA) have reported a promising overall survival of 26-34 months when given in a multimodal setting. However, randomized controlled trials (RCTs) investigating the effect of RFA in combination with chemotherapy in patients with LAPC are lacking. METHODS: The "Pancreatic Locally Advanced Unresectable Cancer Ablation" (PELICAN) trial is an international multicenter superiority RCT, initiated by the Dutch Pancreatic Cancer Group (DPCG). All patients with LAPC according to DPCG criteria, who start with FOLFIRINOX or (nab-paclitaxel/)gemcitabine, are screened for eligibility. Restaging is performed after completion of four cycles of FOLFIRINOX or two cycles of (nab-paclitaxel/)gemcitabine (i.e., 2 months of treatment), and the results are assessed within a nationwide online expert panel. Eligible patients with RECIST stable disease or objective response, in whom resection is not feasible, are randomized to RFA followed by chemotherapy or chemotherapy alone. In total, 228 patients will be included in 16 centers in The Netherlands and four other European centers. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, RECIST response, CA 19.9 and CEA response, toxicity, quality of life, pain, costs, and immunomodulatory effects of RFA. DISCUSSION: The PELICAN RCT aims to assess whether the combination of chemotherapy and RFA improves the overall survival when compared to chemotherapy alone, in patients with LAPC with no progression of disease following 2 months of systemic treatment. TRIAL REGISTRATION: Dutch Trial Registry NL4997 . Registered on December 29, 2015. ClinicalTrials.gov NCT03690323 . Retrospectively registered on October 1, 2018.

Effect of structured use of preoperative portal vein embolization on outcomes after liver resection of perihilar cholangiocarcinoma.

BACKGROUND: Portal vein embolization (PVE) is performed to reduce the risk of liver failure and subsequent mortality after major liver resection. Although a cut-off value of 2·7 per cent per min per m2 has been used with hepatobiliary scintigraphy (HBS) for future remnant liver function (FRLF), patients with perihilar cholangiocarcinoma (PHC) potentially benefit from an additional cut-off of 8·5 per cent/min (not corrected for body surface area). Since January 2016 a more liberal approach to PVE has been adopted, including this additional cut-off for HBS of 8·5 per cent/min. The aim of this study was to assess the effect of this approach on liver failure and mortality. METHODS: This was a single-centre retrospective study in which consecutive patients undergoing liver resection under suspicion of PHC in 2000-2015 were compared with patients treated in 2016-2019, after implementation of the more liberal approach. Primary outcomes were postoperative liver failure (International Study Group of Liver Surgery grade B/C) and 90-day mortality. RESULTS: Some 191 patients with PHC underwent liver resection. PVE was performed in 6·4 per cent (9 of 141) of the patients treated in 2000-2015 and in 32 per cent (16 of 50) of those treated in 2016-2019. The 90-day mortality rate decreased from 16·3 per cent (23 of 141) to 2 per cent (1 of 50) (P = 0·009), together with a decrease in the rate of liver failure from 19·9 per cent (28 of 141) to 4 per cent (2 of 50) (P = 0·008). In 2016-2019, 24 patients had a FRLF greater than 8·5 per cent/min and no liver failure or death occurred, suggesting that 8·5 per cent/min is a reliable cut-off for patients with suspected PHC. CONCLUSION: The major decrease in liver failure and mortality rates in recent years and the simultaneous increased use of PVE suggests an important role for PVE in reducing adverse outcomes after surgery for PHC.

ANTECEDENTES: La embolización de la vena porta (portal vein embolization, PVE) se realiza para reducir el riesgo de insuficiencia hepática y de mortalidad asociada después de una resección hepática mayor. Aunque con la gammagrafía hepato-biliar (hepato-biliary scintigraphy, HBS) se ha utilizado un punto de corte de 2,7%/min/m2 para la función hepática remanente futura (future remnant liver function, FRLF), los pacientes con colangiocarcinoma perihilar (perihilar cholangiocarcinoma, PHC) se beneficiarían potencialmente de un punto de corte adicional de 8,5%/min (no corregido para el área de superficie corporal). Desde enero de 2016, se adoptó un enfoque más liberal para la PVE, incluyendo este punto de corte adicional para la HBS de 8,5%/min. El objetivo de este estudio fue evaluar el efecto de este enfoque sobre la insuficiencia hepática y la mortalidad. MÉTODOS: Se trata de un estudio retrospectivo de un solo centro, en el que los pacientes consecutivos sometidos a resección hepática por sospecha de PHC entre 2000-2016 se compararon con los pacientes tratados entre 2016-2019, después de la implementación de un enfoque más liberal. Los objetivos primarios fueron la insuficiencia hepática postoperatoria (ISGLS grado B/C) y la mortalidad a los 90 días. RESULTADOS: Un total de 191 pacientes con PHC se sometieron a resección hepática. Se realizó PVE en el 6% (9/141) de los pacientes antes de 2016 y en el 32% (16/50) de los pacientes después de 2016. La mortalidad disminuyó del 16% (23/141) al 2% (1/50) (P = 0,009), junto con una disminución de la insuficiencia hepática del 20% (28/141) al 4% (2/50) (P = 0,008). Después de 2016, 20 pacientes tuvieron un FRLF > 8,5%/min y no se produjo insuficiencia hepática o mortalidad, lo que sugiere que el 8,5%/min es un punto de corte fiable para los pacientes con sospecha de PHC. CONCLUSIÓN: La disminución marcada de la insuficiencia hepática y de la mortalidad en los últimos años y el aumento simultáneo del uso de la PVE, sugiere que la PVE ha jugado un importante papel en el descenso de los resultados adversos después de la cirugía para el PHC.

Myeloid Dendritic Cells Are Enriched in Lymph Node Tissue of Early Rheumatoid Arthritis Patients but not in At Risk Individuals.

Lymph nodes (LNs) are highly organized structures where specific immune responses are initiated by dendritic cells (DCs). We investigated the frequency and distribution of human myeloid (mDCs) and plasmacytoid (pDCs) in LNs and blood during the earliest phases of rheumatoid arthritis (RA). We included 22 RA-risk individuals positive for IgM rheumatoid factor and/or anti-citrullinated protein antibodies, 16 biological-naïve RA patients and 8 healthy controls (HCs). DC subsets (CD1c+ mDCs and CD304+ pDCs) in LN tissue and paired peripheral blood were analyzed using flow cytometry and confocal microscopy. In blood of RA patients a significant decreased frequency of pDCs was found, with a similar trend for mDCs. In contrast, mDC frequencies were higher in RA compared with HCs and RA-risk individuals, especially in LN. Frequency of mDCs seemed higher in LNs compared to paired blood samples in all donors, while pDCs were higher in LNs only in RA patients. As expected, both mDCs and pDCs localized mainly in T-cell areas of LN tissue. In conclusion, compared with RA-risk individuals, mDCs and pDCs were enriched in the LN tissue of early-RA patients, while their frequency in RA-risk individuals was comparable to HCs. This may suggest that other antigen-presenting cells are responsible for initial breaks of tolerance, while mDCs and pDCs are involved in sustaining inflammation.

[Nephrogenic systemic fibrosis possibly caused by gadolinium-containing contrast agent]. / Nefrogene systemische fibrose, mogelijk veroorzaakt door gadoliniumhoudend contrastmiddel.

A 34-year-old woman with terminal renal insufficiency presented with thickening and hardening of the skin of the extremities, resulting in contractures of the joints and severe disability. Serology revealed no signs of autoimmune disease, apart from a positive result for antinuclear antibodies. Histological evaluation of a skin biopsy showed marked fibrosis of the entire dermis, extending into the subcutaneous fat, with CD34-positive fibrocytes. The clinical features resembled a recently reported new disorder: nephrogenic systemic fibrosis (NSF). This disease causes fibrotic changes in the skin and other organs in patients with (pre)terminal renal insufficiency. The cause of the disease is still unknown, although there are strong indications that exposure to gadolinium-containing contrast agents plays a role in the pathogenesis. To prevent more patients from developing NSF, the Dutch Medicines Evaluation Board has changed the clinical indications for the use of gadolinium-containing contrast agents in patients with kidney disease: gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist) may not be used in patients with severe renal failure or patients that will undergo or have already undergone liver transplantation. Caution is advised in patients with moderate renal insufficiency; this also applies to the other registered gadolinium-containing contrast agents.

[A patient with repeated, life-threatening gastro-intestinal haemorrhages treated by means of medication, open surgery, endoscopic surgery, intervention radiology and conservative methods]. / Een patiënt met recidiverende levensbedreigende darmbloedingen behandeld met medicamenteuze, chirurgische, endoscopische, interventieradiologische en conservatieve methoden.

A 56-year-old man with Henoch Schönlein purpura vasculitis suffered from repeated and multiple life-threatening gastrointestinal haemorrhages. Over recent years a number of interventions for the treatment of gastrointestinal haemorrhaging have become available; choosing which option to use can present difficulties. The available interventions are carried out by different disciplines and include haemostatic drugs, endoscopic intervention, intervention radiology, and surgery. In this patient, following a severe drop in haemoglobin levels, CT and angiography revealed active bleeding in the distal jejunum. Transarterial embolization by means of a coiling procedure halted the bleeding. The patient was also given tranexamic acid, a fibrinolysis inhibitor. More episodes of bleeding subsequently followed which necessitated further coiling procedures, two bowel resections, the endoscopic clipping of a bleeding artery, treatment with the recombinant activated factor VII (rFVIIa) at a dosage of 90 microg/kg, as well as conservative treatment with multiple transfusions of filtered erythrocytes and fresh plasma. The patient eventually recovered.

Correction: Time-Dependent Impact of Irreversible Electroporation on Pancreas, Liver, Blood Vessels and Nerves: A Systematic Review of Experimental Studies.

[This corrects the article DOI: 10.1371/journal.pone.0166987.].

Membranous duodenal stenosis: initial experience with balloon dilatation in four children.

INTRODUCTION: We present a novel approach to the treatment of membranous duodenal stenosis (MDS). To our knowledge this is the first paper to describe balloon dilatation for this entity. MATERIAL AND METHODS: Four children, 2 boys and 2 girls, aged between 8 and 28 days, underwent duodenal balloon dilatation. Balloon dilatation was performed under general anaesthesia using standard angiography balloons per os. Balloon diameters ranged from 6 to 14 mm. RESULTS: All balloon dilatations were successful. None of the procedures showed procedural or post-procedural complications. None of the patients subsequently required surgical intervention. To date all children are doing well. DISCUSSION: The initial experience with balloon dilation of MDS showed a 100% success rate, without procedural or post-procedural complications. The results obtained in this small group of patients suggest that the use of balloon dilatation in cases of MDS may be a safe technique that can be readily performed by an experienced interventional radiologist.

Time-Dependent Impact of Irreversible Electroporation on Pancreas, Liver, Blood Vessels and Nerves: A Systematic Review of Experimental Studies.

INTRODUCTION: Irreversible electroporation (IRE) is a novel ablation technique in the treatment of unresectable cancer. The non-thermal mechanism is thought to cause mostly apoptosis compared to necrosis in thermal techniques. Both in experimental and clinical studies, a waiting time between ablation and tissue or imaging analysis to allow for cell death through apoptosis, is often reported. However, the dynamics of the IRE effect over time remain unknown. Therefore, this study aims to summarize these effects in relation to the time between treatment and evaluation. METHODS: A systematic search was performed in Pubmed, Embase and the Cochrane Library for original articles using IRE on pancreas, liver or surrounding structures in animal or human studies. Data on pathology and time between IRE and evaluation were extracted. RESULTS: Of 2602 screened studies, 36 could be included, regarding IRE in liver (n = 24), pancreas (n = 4), blood vessels (n = 4) and nerves (n = 4) in over 440 animals (pig, rat, goat and rabbit). No eligible human studies were found. In liver and pancreas, the first signs of apoptosis and haemorrhage were observed 1-2 hours after treatment, and remained visible until 24 hours in liver and 7 days in pancreas after which the damaged tissue was replaced by fibrosis. In solitary blood vessels, the tunica media, intima and lumen remained unchanged for 24 hours. After 7 days, inflammation, fibrosis and loss of smooth muscle cells were demonstrated, which persisted until 35 days. In nerves, the median time until demonstrable histological changes was 7 days. CONCLUSIONS: Tissue damage after IRE is a dynamic process with remarkable time differences between tissues in animals. Whereas pancreas and liver showed the first damages after 1-2 hours, this took 24 hours in blood vessels and 7 days in nerves.