Circulating immune-related proteins associated with immune checkpoint inhibitor efficacy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Most patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint inhibitor treatment. However, the phase II study CheckPAC (NCT02866383) showed a clinical benefit (CB) rate of 37% and a response rate of 14% in patients with metastatic PDAC receiving stereotactic radiation therapy and nivolumab with or without ipilimumab. Translational studies were initiated to characterize the patients who would benefit from this treatment. Here, we evaluated the association between treatment outcome and 92 circulating immuno-oncology-related proteins in patients from the CheckPAC trial. MATERIALS AND METHODS: The study included 78 patients with chemoresistant metastatic PDAC treated with nivolumab ± ipilimumab combined with radiotherapy. Proteins were measured in serum samples collected at baseline and on treatment with the use of the Olink Target 96 Immuno-Oncology panel. A cohort of 234 patients with metastatic PDAC treated with first-line chemotherapy were also included. RESULTS: High levels of Fas ligand (FASLG) and galectin 1 (Gal-1) and low levels of C-C motif chemokine 4 were associated with CB. High FASLG and Gal-1 were associated with longer progression-free survival in univariable analysis. In the multivariable Cox regression analysis, the association was significant for Gal-1 (P < 0.001) but not significant for FASLG (P = 0.06). A focused unsupervised hierarchal clustering analysis, including T-cell activation and immune checkpoint-related proteins, identified clusters of patients with higher CB rate and higher tumor expression of leukocyte or T-cell markers (CD3, CD45, granzyme B). Thirty-six proteins increased significantly during immunotherapy. Several proteins (including FASLG, checkpoint proteins, and immune activation markers) increased independently of response during immunotherapy but did not increase in the cohort of patients treated with chemotherapy. CONCLUSIONS: Circulating levels of immune-related proteins like FASLG and Gal-1 might be used to predict the efficacy of checkpoint inhibitors in patients with metastatic PDAC.

PO-20 - Crosstalk between the lectin pathway and haemostasis in patients with pulmonary cancer.

INTRODUCTION: Recent research has focused on the complement system in cancer, including the lectin pathway of complement activation. Mannose-binding lectin (MBL), a key activator of the lectin pathway, can bind to tumor cell surfaces in vitro, and lectin pathway activation is increased in several types of cancer. The exact role of the complement system in cancer is currently discussed. However, one possible consequence of the increased complement activation could be contribution to the increased thrombosis risk which cancer patients experience. Proteins of the lectin pathway can activate coagulation and impair fibrinolysis in vitro, but the significance of this in a clinical setting is not well understood. AIM: We aim to investigate associations between lectin pathway and haemostatic activation in patients with lung cancer undergoing thoracoscopic surgery. MATERIALS AND METHODS: Patients with lung cancer (n=60) eligible for thoracoscopic tumor resection were included as part of a randomized controlled trial, the COPPVATS project (EudraCT no: 2012-002409-23), conducted at the Department of Thoracic Surgery, Aarhus University Hospital. Exclusion criteria were arterial or venous thrombosis within the last three months, other systemic disease than cancer, and anticoagulant treatment prior to inclusion. Blood samples were obtained the day before surgery, perioperatively, and on the 1st and 2nd postoperative days. Laboratory analyses on the complement system include MBL, MBL-associated protease (MASP)-1 and -2, MBL-MASP complex, ficolin-1, -2, and -3 and complement factor C3b. Haemostasis was evaluated with routine coagulation parameters (INR, APTT, fibrinogen, fibrin d-dimer), platelet function, and tissue factor-induced thrombin generation. RESULTS: Recruitment of the study subjects is concluded, and laboratory work is in progress. The complement analyses and data processing will be performed during early spring 2016, so that results will be ready for presentation on the conference. CONCLUSIONS: The present project will provide new knowledge on lectin pathway activation and the pathogenesis of thrombosis in cancer patients. In the long term, this will help improve the individual risk assessment and lead to new studies on thromboprophylaxis and treatment in conditions with increased complement activation.

Inflammatory myofibroblastic tumours of the respiratory system and the impact of the varying patterns.

Inflammatory fibroblastic tumours are very rare. They are mostly located in the respiratory system. We present three cases of patients with fibroblastic tumours. The diversity of inflammatory fibroblastic tumours in the respiratory system and the surgical considerations are discussed. Our recommendation is that treatment should include a complete resection to prevent local recurrence and malignant transformation, and follow-up review should reflect the procedure carried out, especially in terms of the anatomical location and the extent of the surgical procedure performed.

Precision and accuracy of point-of-care testing coagulometers used for self-testing and self-management of oral anticoagulation therapy.

BACKGROUND: Oral anticoagulation therapy is monitored by the use of the International Normalized Ratio (INR). Patients who perform self-testing or self-management use a point-of-care testing (POCT) coagulometer (INR monitor) to estimate their INRs. A precondition for a correct dosage of coumarins is a correct INR estimation, and the method and apparatus used for providing the INR measurements are crucial in this context. Several studies have been published regarding the precision and accuracy of these POCT coagulometers, and have led to diverse conclusions. It is difficult and challenging to perform an overview of the literature, owing to the vast amount of papers, with differences in design, statistical analysis, etc. OBJECTIVES: The aim of this systematic review was to analyze the current literature, especially regarding the precision and accuracy of the POCT coagulometers, to provide recommendations for clinical use and quality control, and to point out areas for future research. METHODS: We included a total of 22 studies, of which four were characterized as high-quality studies. RESULTS: The precision of the POCT coagulometers was generally adequate for clinical use. Their performance in terms of accuracy has to be viewed in the context of the inherent inaccuracies of INR measurements. CONCLUSIONS: The accuracy of POCT coagulometers seems, in this respect, to be generally acceptable, and they can be used in a clinical setting.

International Normalized Ratio (INR), coagulation factor activities and calibrated automated thrombin generation - influence of 24 h storage at ambient temperature.

International Normalized Ratio (INR) measurements are used to monitor oral anticoagulation therapy with coumarins. Single coagulation factor activities and calibrated automated thrombin (CAT) generation are considered as more advanced methods for evaluating overall haemostatic capacity. The aims were to assess the variability of INR, coagulation factor activities, and CAT, during 24 h of storage of blood samples at ambient temperature. A total of 24 patients on stable coumarin treatment were followed prospectively for 6 weeks. INR was analyzed at 0, 6 and 24 h after blood sampling and 1-stage clotting activity of coagulation factors II, VII, IX, and X as well as CAT generation was recorded after 0 and 24 h respectively. Statistical analyses included Bland-Altman plot, 95% limits of agreement, and a variability test using a mixed effect model. The level of INR remained statistically unchanged from 0 to 6 and 24 h of storage. Coagulation factor activities and CAT revealed no significant difference induced by 24 h of storage, although the limits of agreement were wide. Patients' individual INR, coagulation factor activities, and CAT generation were not significantly influenced by 24 h storage of blood samples, but for the CAT generation analyses a trend toward time dependency was detected.

Self-management of oral anticoagulant therapy for mechanical heart valve patients.

OBJECTIVE: Self-management of oral anticoagulant therapy (OAT) has shown good results on a short-term basis. We hypothesize that self-management of OAT provides a better quality of treatment than conventional management also on a long-term basis. The aim of this study was to assess the quality of self-management of OAT in patients with mechanical heart valve prostheses on a 4-year perspective in a prospective, non-randomized study. DESIGN: Twenty-four patients with mechanical heart valves and on self-managed OAT were followed for up to 4 years. A matched, retrospectively selected group of conventionally managed heart valve patients (control group) was used as reference. RESULTS: The median observation time was 1175 days (range: 174-1428 days). The self-managed patients were within therapeutic INR target range for a mean of 78.0% (range: 36.1%-93.9%) of the time compared with 61.0% (range 37.4%-2.9%) for the control group. CONCLUSION: Self-management of OAT is a feasible and safe concept for selected patients with mechanical heart valve prostheses also on a long-term basis. It provides at least as good and most likely better quality of anticoagulant therapy than conventional management assessed by time within the therapeutic International Normalized Ratio (INR) target range.

Self-management of oral anticoagulation in children with congenital heart disease.

OBJECTIVE: The concept of self-management of oral anticoagulation has been shown to entail better quality of treatment than conventional management when assessed in selected adults. We have extended the concept of self-management to include children with congenital cardiac disease, hypothesizing self-management of oral anticoagulation is also possible in this subset of patients. Our aim was to assess the quality of self-management. METHODS: We trained 14 children aged from 2.2 to 15.6 years, with a mean age of 9.7 years, and their parents, in domiciliary analysis of the International Normalized Ratio and necessary adjustment of dosage of coumarin. The curriculum for training lasted for 27 weeks, and the patients and their parents were followed for a period of up to 31 months by weekly measurement of the values obtained for the International Normalized Ratio. RESULTS: The patients were observed over a mean of 547 days, with a range from 214 to 953 days. The patients were within the therapeutic targetted range of the International Normalized Ratio for a median of 65.5% of the time, with a range from 17.6% to 90.4%. None of the patients experienced thromboembolic or bleeding complications requiring doctoral intervention. All the patients and their parents expressed full satisfaction with the treatment. CONCLUSION: Self-management of oral anticoagulation provides a good quality of treatment, which is feasible and safe in selected children with congenital cardiac disease.

Inhibition of nitric oxide synthesis improves left ventricular contractility in neonatal pigs late after cardiopulmonary bypass.

BACKGROUND: Following neonatal open heart surgery a nadir occurs in left ventricular function six to 12 hours after cardiopulmonary bypass. Although initiated by intraoperative events, little is known about the mechanisms involved. OBJECTIVE: To evaluate the involvement of nitric oxide in this late phase dysfunction in piglets. DESIGN: Piglets aged 2 to 3 weeks (4-5 kg) underwent cardiopulmonary bypass (1 h) and cardioplegic arrest (0.5 h) and then remained ventilated with inotropic support. Twelve hours after bypass, while receiving dobutamine (5 microg/kg/min), the left ventricular response to non-selective nitric oxide synthase inhibition (l-N(G)-monomethylarginine (l-NMMA)) was evaluated using load dependent and load independent indices (E(es), the slope of the end systolic pressure-volume relation; M(w), the slope of the stroke work-end diastolic volume relation; [dP/dt(max)](edv), the slope of the dP/dt(max)-end diastolic volume relation), derived from left ventricular pressure-volume loops generated by conductance and microtip pressure catheters. RESULTS: 10 pigs received 7.5 mg l-NMMA intravenously and six of these received two additional doses (37.5 mg and 75 mg). E(es) (mean (SD)) increased with all three doses, from 54.9 (40.1) mm Hg/ml (control) to 86.3 (69.5) at 7.5 mg, 117.9 (65.1) at 37.5 mg, and 119 (80.4) at 75 mg (p < 0.05). At the two highest doses, [dP/dt(max)](edv) increased from 260.8 (209.3) (control) to 470.5 (22.8) at 37.5 mg and 474.1 (296.6) at 75 mg (p < 0.05); and end diastolic pressure decreased from 16.5 (5.6) mm Hg (control) to 11.3 (5.0) at 37.5 mg and 11.4 (4.9) at 75 mg (p < 0. 05). CONCLUSIONS: In neonatal pigs 12 hours after cardiopulmonary bypass with ischaemic arrest, low dose l-NMMA improved left ventricular function, implying that there is a net deleterious cardiac action of nitric oxide at this time.

Venous saturation monitoring: reliability of the Bentley SM-0200 OxySAT with and without use of a cuvette.

In-line venous saturation monitoring is a useful method of quality management during extracorporeal circulation (ECC). The Bentley SM-0200 OxySAT meter was tested with and without the use of the recommended cuvette. The study consisted of an in vitro part, where extremely low saturations could be safely measured, and an in vivo part, carried out under routine ECC conditions. The results show that the OxySAT may be used with or without a cuvette, and that it needs calibration for optimal accuracy in either case.

In vivo analysis of dynamic tensile stresses at arterial end-to-end anastomoses. Influence of suture-line and graft on anastomotic biomechanics.

OBJECTIVE: to determine the influence of an anastomotic suture line and a graft on dynamic tensile stresses of vascular end-to-end anastomoses in vivo. MATERIAL AND METHODS: the abdominal aorta of twelve 35-kg pigs was used as an experimental model. Simultaneous recordings of internal arterial diameter and pressure were performed on each pig at 3 successive stages: (1) The genuine artery (REF), (2) artery-artery (A-A) and (3) graft-artery (G-A) anastomosis at 1-mm increments in the immediate perianastomotic area. Thereby, RD (relative distension), CC (compliance coefficient), E(p)(dynamic pressure-strain elastic modulus) and hysteresis loop areas could be calculated for every measuring point. RESULTS: the graft was significantly stiffer than REF. A-A and G-A anastomoses were significantly less compliant than REF. Maximum E(p), minimum CC and hysteresis loop areas were found at the anastomotic line due to minimum anastomotic RD. Downstream of the G-A anastomosis, the RD, CC, E(p)and loop areas were significantly different from REF, but significantly different from A-A. CONCLUSION: an animal model for acute studies of mechanical properties of vascular end-to-end anastomoses was developed. The main determinant for anastomotic biomechanics was the suture-line itself.

[Self management of peroral anticoagulant therapy in patients with artificial heart valves]. / Selvstyring af peroral antikoagulationsbehandling hos patienter med kunstige hjerteklapper.

Twenty-one heart valve operated patients (age 19-70 years) were trained in self-managed oral anticoagulant therapy using a home coagulometer (CoaguChek). Twenty patients accomplished between eight and 29 (median 24) months of self management and were fully capable of self management after 30 weeks of training. No patients experienced major bleeds or thrombo-embolic events. A control group of 20 patients from our department was matched, retrospectively, to the study group. The self-managing patients were within the therapeutic INR range 78% of the study period compared to 54% for the control patients. All self-managing patients had their median INR-value within the therapeutic range, versus only 14 in the control group. Self-management of oral anticoagulant therapy seems feasible for selected patients.

The effect of changing excitation frequency on parallel conductance in different sized hearts.

OBJECTIVE: An important component of the ventricular volume measured using the conductance catheter technique is due to parallel conductance (Vc), which results from the extension of the electric field beyond the ventricular blood pool. Parallel conductance volume is normally estimated using the saline dilution method (Vc(saline dilution)), in which the conductivity of blood in the ventricle is transiently increased by injection of hypertonic saline. A simpler alternative has been reported by Gawne et al. [12]. Vc(dual frequency) is estimated from the difference in total conductance measured at two exciting frequencies and the method is based on the assumption that parallel conductance is mainly capacitive and hence is negligible at low frequency. The objective of this study was to determine whether the dual frequency technique could be used to substitute the saline dilution method to estimate Vc in different sized hearts. METHODS: The accuracy and linearity of a custom-built conductance catheter (CC) system was initially assessed in vitro. Subsequently, a CC and micromanometer were inserted into the left ventricle of seven 5 kg pigs (group 1) and six 50 kg pigs (group 2). Cardiac output was determined using thermodilution (group 1) and an ultrasonic flow probe (group 2) from which the slope coefficient (alpha) was determined. Steady state measurements and Vc estimated using saline dilution were performed at frequencies in the range of 5-40 kHz. All measurements were made at end-expiration. Finally, Vc was estimated from the change in end-systolic conductance between 5 kHz and 40 kHz using the dual frequency technique of Gawne et al. [12]. RESULTS: There was no change in measured volume of a simple insulated cylindrical model when the stimulating frequency was varied from 5-40 kHz. Vc(saline dilution) varied significantly with frequency in group 1 (8.63 +/- 2.74 ml at 5 kHz; 11.51 +/- 2.65 ml at 40 kHz) (p = 0.01). Similar results were obtained in group 2 (69.43 +/- 27.76 ml at 5 kHz; 101.24 +/- 15.21 ml at 40 kHz) (p < 0.001). However, the data indicate that the resistive component of the parallel conductance is substantial (Vc at 0 Hz estimated as 8.01 ml in group 1 and 62.3 ml in group 2). There was an increase in alpha with frequency in both groups but this did not reach significance. The correspondence between Vc(dual frequency) and Vc(saline dilution) methods was poor (group 1 R2 = 0.69; group 2 R2 = 0.22). CONCLUSION: At a lower excitation frequency of 5 kHz a smaller percentage of the electric current extends beyond the blood pool so parallel conductance is reduced. While parallel conductance is frequency dependent, it has a substantial resistive component. The dual frequency method is based on the assumption that parallel conductance is negligible at low frequencies and this is clearly not the case. The results of this study confirm that the dual frequency technique cannot be used to substitute the saline dilution technique.

Latissimus dorsi cardiomyoplasty: a chronic experimental porcine model. Feasibility study of cardiomyoplasty in Danish Landrace pigs and Göttingen minipigs.

Cardiomyoplasty is an experimental treatment for end-stage heart failure. We hypothesized that the porcine latissimus dorsi muscle (LDM) in an experimental porcine model is a suitable surrogate for a clinically relevant evaluation of this concept. Fourteen Danish Landrace (DL) pigs and six Göttingen minipigs (GM) were studied. The LDM was evaluated immediately after surgical dissection and in various phases: phase 1 (n = 4)--outcome of a partial vascular isolation (vascular delay), 2 to 3 weeks prior to heart wrapping in DL pigs; phase 2 (n = 6)--long-term flap survival of nonstimulated LDM cardiomyoplasty in DL pigs; phase 3 (n = 6)--outcome of nonstimulated cardiomyoplasty in GM; phase 4--one DL pig had dynamic cardiomyoplasty performed and was subjected to low-intensity LDM stimulation for 8 months. Isolation of the LDM of DL pigs and GM as a pedicled graft had no acute deleterious impact on the global blood supply. In phase 1a, partial vascular isolation and in situ recovery of the LDM resulted in a muscle encapsulated in fibrotic tissue, which hampered a later heart wrap. In phase 1b, a less extensive dissection diminished fibrosis and allowed subsequent wrapping. In phase 2, after 6 weeks of nonstimulated LDM cardiomyoplasty, the LDM of DL pigs was viable, with excellent heart-muscle integration. In phase 3, the same procedure applied in GM yielded the same result as that in DL pigs, but with a higher success rate owing to the learning phase.

Self management of oral anticoagulant therapy after heart valve replacement.

OBJECTIVE: Patients with mechanical heart valves require lifelong oral anticoagulant treatment which entails frequent blood sampling and dosage adjustment. The purpose of this study was to investigate the feasibility of letting heart valve operated patients manage blood specimen analysis and dosage adjustment themselves. METHODS: A total of 21 patients were enrolled in the study and followed for at least 9 months postoperatively. Immediately after the heart valve operation they were trained in operating a CoaguChek international normal ratio (INR) monitor to analyze capillary whole blood samples. Subsequently training in dosage adjustment was accomplished and all patients were considered fully capable of self management after 30 weeks. In the training period, parallel laboratory INR measurements were made at 3-4 week intervals for reference. A control group of 20 patients was matched, respectively, to the study group. The INR target range was 2.0-3.0. RESULTS: Out of the 21 study patients 19 continued self management beyond 9 months. The median INR value obtained with the monitor was within therapeutic target range for all study patients and only 15 out of 20 control patients were within this range. The mean systematic deviation between laboratory and CoaguChek INR was 7.8% but each patient had a constant characteristic deviation from -11 to +21%. The study patients were within therapeutic target range 77% of the time compared with 53% for the control patients. CONCLUSIONS: Self management of oral anticoagulation is feasible for selected patients and constitutes a significant service improvement compared with conventional management. The CoaguChek monitor seems sufficiently accurate and reliable for self testing and the treatment quality is comparable or even better than conventional management. Assessment of the rate of bleeding and thrombo-embolic events shall be settled in studies comprising larger number of patients.