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Background: Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC. Methods: We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive. Results: PD-1 positive (+) was significantly associated with current smoking status ( P =0.02) and with the presence of KRAS mutations ( P =0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology ( P =0.005) and with presence of EGFR mutations ( P =0.001). In patients treated with EGFR tyrosine kinase inhibitors ( N =95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P =0.01) time to progression (TTP: P <0.0001) and survival (OS: P =0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative ( P =0.01). Conclusions: PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.

Artificial intelligence (AI) has the potential to revolutionize surgery in the coming years. Still, it is essential to clarify what the meaningful current applications are and what can be reasonably expected. This AI-powered review assessed the role of AI in colorectal surgery. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic search of PubMed, Embase, Scopus, Cochrane Library databases, and gray literature was conducted on all available articles on AI in colorectal surgery (from January 1 1997 to March 1 2021), aiming to define the perioperative applications of AI. Potentially eligible studies were identified using novel software powered by natural language processing (NLP) and machine learning (ML) technologies dedicated to systematic reviews. Out of 1238 articles identified, 115 were included in the final analysis. Available articles addressed the role of AI in several areas of interest. In the preoperative phase, AI can be used to define tailored treatment algorithms, support clinical decision-making, assess the risk of complications, and predict surgical outcomes and survival. Intraoperatively, AI-enhanced surgery and integration of AI in robotic platforms have been suggested. After surgery, AI can be implemented in the Enhanced Recovery after Surgery (ERAS) pathway. Additional areas of applications included the assessment of patient-reported outcomes, automated pathology assessment, and research. Available data on these aspects are limited, and AI in colorectal surgery is still in its infancy. However, the rapid evolution of technologies makes it likely that it will increasingly be incorporated into everyday practice.

Background International guidelines recommend at least three months anticoagulation in all patients after acute venous thromboembolism (VTE) and suggest those with unprovoked events be considered for indefinite anticoagulation if the risk of recurrence is high and the risk of bleeding during treatment non-high. Other authors have recently argued against using a dichotomy unprovoked/provoked events to decide on anticoagulation duration and suggest instead using overall risk factors present in each patient as the basis for deciding. Aim This sub-analysis of the WHITE study aimed at assessing the reasons for the treatment decisions taken by doctors in different countries. Results 1240 patients were recruited in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia). Anticoagulation was extended in 51.7% and 49.3% of patients with unprovoked or provoked events (n.s.); stopped in 15.4% versus 28.9% (P < .0001), and changed to antithrombotic drugs (sulodexide or aspirin) in 32.9% versus 21.8% (P < .0001). In the 430 subjects with isolated distal deep vein thrombosis (IDDVT) anticoagulation was stopped in 34.4%, continued in 37.0% (mainly those with post-thrombotic syndrome [PTS]) and switched to antithrombotics in the balance. High risk of recurrence was the most prevalent reason (>83% of cases) given to continue anticoagulation, regardless of nature and site of the index events, followed by risk of bleeding and presence of PTS signs. Conclusion On average, attending physicians estimated the risk of recurrence in real life conditions, and the consequent therapeutic decision, using all the information available, not limiting to the location or nature of the index event.

Purpose The 6‐second cone beam computed tomography (CBCT) acquisition of the Ethos HyperSight (Varian Medical Systems, Inc. Palo Alto, CA, USA) on‐board imaging system offers benefits, but could be too fast to accurately capture an average target position in a free‐breathing lung cancer patient. This study aimed to ascertain whether a 6‐second acquisition is appropriate for regularly breathing patients with varying respiration periods. Additionally, breathing patterns that could lead to clinically impactful inaccuracies for image‐guided radiation therapy (IGRT) shifts were investigated. Methods Nine regular (sinusoidal) breathing patterns with different respiration rates (8–20 breaths‐per‐minute) and amplitudes, along with five irregular breathing patterns including a gasp/cough scenario, were tested using a respiratory motion phantom with a 3 cm diameter spherical target. Once the phantom was aligned using the external chassis to remove any default shifts, the 6‐second CBCTs with Acuros reconstruction were acquired. Rigid registrations were performed using the 4DCT simulation average/untagged reconstructed image as reference to align to target (simulating clinical lung IGRT setup). Sixty‐second CBCTs were also tested to verify the average offsets with conventional practice. The IGRT shifts were compared to 5 mm, a PTV margin typically used for lung tumors. Results Minimal (<1.0 mm) shifts were observed for all regular breathing patterns with both 6‐second and 60‐second CBCT acquisitions. For moderately irregular breathing patterns and the gasp/cough scenario, all shifts were less than 5 mm. Shifts larger than 5 mm were observed in highly irregular breathing patterns, with both 6‐second (14%) and 60‐second (24%) CBCT acquisitions. Statistical tests showed no significant differences (p > 0.05) between the sizes of shifts made with the two CBCT durations. Conclusion The 6‐second CBCT can effectively and reliably localize a mobile target for regular and moderately‐irregular breathers. Cautions should be used for highly irregular breathers, regardless of the duration of CBCT acquisition.

3D printing in medical physics provides opportunities for creating patient‐specific treatment devices and in‐house fabrication of imaging/dosimetry phantoms. This study characterizes several commercial fused deposition 3D printing materials with some containing nonstandard compositions. It is important to explore their similarities to human tissues and other materials encountered in patients. Uniform cylinders with infill from 50 to 100% at six evenly distributed intervals were printed using 13 different filaments. A novel approach rotating infill angle 10o between each layer avoids unwanted patterns. Five materials contained high‐Z/metallic components. A clinical CT scanner with a range of tube potentials (70, 80, 100, 120, 140 kVp) was used. Density and average Hounsfield unit (HU) were measured. A commercial GAMMEX phantom mimicking various human tissues provides a comparison. Utility of the lookup tables produced is demonstrated. A methodology for calibrating print materials/parameters for a desired HU is presented. Density and HU were determined for all materials as a function of tube voltage (kVp) and infill percentage. The range of HU (−732.0–10047.4 HU) and physical densities (0.36–3.52 g/cm3) encompassed most tissues/materials encountered in radiology/radiotherapy applications with many overlapping those of human tissues. Printing filaments doped with high‐Z materials demonstrated increased attenuation due to the photoelectric effect with decreased kVp, as found in certain endogenous materials (e.g., bone). HU was faithfully reproduced (within one standard deviation) in a 3D‐printed mimic of a commercial anthropomorphic phantom section. Characterization of commercially available 3D print materials facilitates custom object fabrication for use in radiology and radiation oncology, including human tissue and common exogenous implant mimics. This allows for cost reduction and increased flexibility to fabricate novel phantoms or patient‐specific devices imaging and dosimetry purposes. A formalism for calibrating to specific CT scanner, printer, and filament type/batch is presented. Utility is demonstrated by printing a commercial anthropomorphic phantom copy.

CD55 has been revealed to have an important role in tumor genesis, and presence of small populations of cells with strong CD55 expression would be sufficient to predict poor prognosis of several tumors. In our study we revealed that CD55 is a novel target of hypoxia-inducible factor HIF-2α in neuroblastoma (NB) cells. We show that HIF-2α expression is sufficient to sustain stem-like features of NB cells, whereas CD55 protein upon HIF-2α expression contributes to growth of colonies and to invasion of cells, but not to stemness features. Interestingly, in NB tissues, CD55 expression is limited to quite a small population of cells that are HIF-2α positive, and the gene expression of CD55 in the NB data set reveals that the presence of CD55 high affects prognosis of NB patients. The functional characterization of CD55-positive populations within heterogeneous NB monoclonal cell lines shows that CD55 has pro-invading and anti-adhesive properties that might provide the basis for the ability of solid tumors to survive as microscopic residual disease. The easy accessibility to CD55 membrane antigen will offer the possibility of a novel antibody approach in the treatment of recurrent tumors and will provide a ready target for antibody-based visualization in NB diagnosis and prognosis.

The aim of this study was to determine the effects of maximal exercise and of physical training on endothelial function (EF) of patients with intermittent claudication (IC). EF, assessed by ultrasonography of the brachial artery, has been measured in 22 male patients with IC before (pre-exercise EF) and after (postexercise EF) maximal treadmill test. Absolute claudication distance (ACD) and ankle brachial index (ABI) have been measured too. The measurements have been repeated after 18 days (3 times weekly, for 6 weeks) of supervised physical training. Before training, the pre-exercise EF was 7.6+/-2.94 and postexercise EF 5.28+/-3.3 (-33.2%) (P<0.01). After training, the pre-exercise EF was 10.3+/-4.04, whilst postexercise EF was 7.79+/-2.56 (-18.97%) (P<0.01). The differences between the pre-exercise value before and after training and between the postexercise value before and after training were significant (P<0.01). ACD and ABI after training increased respectively from 93.95 to 166.55 m and from 0.67 to 0.71 (P<0.001). Endothelial dysfunction takes a relevant part in the pathophysiology of IC, with 2/3 of the patients showing an EF lower than the pathological cut-off. Maximal exercise worsens the EF, according to the trend associated with the acute inflammatory response. All these features suggest that physical activity in IC should not utilize the maximal working load, in order to avoid the high inflammatory activation and the acute complications of atherosclerotic plaque. The supervised physical training, besides confirming itself as the most effective means to increase the walking ability, also proved to be able to improve the EF of these patients, as described about other diseases. It is probable that moderate hemodynamic stress reduces the levels of the inflammatory markers and increases the flow-mediated vasodilation through an ischemic preconditioning. The increased walking ability, associated with the improvement of EF could improve the heavy systemic outcome of claudicant patients, as it has been demonstrated in patients with coronary heart disease. Further prospective survival studies on cardiovascular outcomes of trained claudicant patients are needed.

Chronic venous insufficiency (CVI) is a chronic disease, whose disability has not been appreciated clearly, and several treatment costs are not covered by Public Health Service, probably because its any social impact is not well known. The aim of the study was to assess the impact of CVI on quality of life (QoL), and to compare the sensitivity of more diffused instruments for QoL assessment. One hundred and four patients with CVI received the Italian version of four QoL assessment instruments (MOS SF-36; CIVIQ-2; Euro-QoL 5D and a visual analogical scale). The poorest QoL was adjusted as 0, the best as 100. After filling the questionnaires, patients underwent a clinical and instrumental examination to assess the diagnosis according to the CEAP classification. The QoL is progressively impaired from CEAP class C1 to class C5-6. The SF-36 showed a normal QoL in patients of CEAP class C1 and C2. Class C3 showed a significant (P<0.0018) reduction of QoL (physical role and bodily pain), and the decline was more significant (P<0.0001) in class C4, involving all physical items and several mental ones. Class C5-6 showed very low scores of physical and social functioning, general health and vitality. Physical and emotional scores were better than C4 patients. QoL is progressively impaired in CVI, involving primarily the physical items and the emotional role, with worsening of mental items only in advanced stages. This early involvement of physical items underlines how CVI is not an esthetic problem, but, a disease. Its impact on the lifestyle and QoL is similar to that of other chronic diseases (diabetes, cancer, chronic pulmonary disease), reaching in the class C5-6 the poorest level, similar to heart failure.

Purpose Demonstrate a novel phantom design using a remote camera imaging method capable of concurrently measuring the position of the x‐ray isocenter and the magnetic resonance imaging (MRI) isocenter on an MR‐linac. Methods A conical frustum with distinct geometric features was machined out of plastic. The phantom was submerged in a small water tank, and aligned using room lasers on a MRIdian MR‐linac (ViewRay Inc., Cleveland, OH). The phantom physical isocenter was visualized in the MR images and related to the DICOM coordinate isocenter. To view the x‐ray isocenter, an intensified CMOS camera system (DoseOptics LLC., Hanover, NH) was placed at the foot of the treatment couch, and centered such that the optical axis of the camera was coincident with the central axis of the treatment bore. Two or four 8.3mm x 24.1cm beams irradiated the phantom from cardinal directions, producing an optical ring on the conical surface of the phantom. The diameter of the ring, measured at the peak intensity, was compared to the known diameter at the position of irradiation to determine the Z‐direction offset of the beam. A star‐shot method was employed on the front face of the frustum to determine X‐Y alignment of the MV beam. Known shifts were applied to the phantom to establish the sensitivity of the method. Results Couch translations, demonstrative of possible isocenter misalignments, on the order of 1mm were detectable for both the radiotherapy and MRI isocenters. Data acquired on the MR‐linac demonstrated an average error of 0.28mm(N=10, R2=0.997, σ=0.37mm) in established Z displacement, and 0.10mm(N=5, σ=0.34mm) in XY directions of the radiotherapy isocenter. Conclusions The phantom was capable of measuring both the MRI and radiotherapy treatment isocenters. This method has the potential to be of use in MR‐linac commissioning, and could be streamlined to be valuable in daily constancy checks of isocenter coincidence.

Chronic venous disease encompasses a range of venous disorders, including those involving the lower limbs resulting from venous hypertension. The spectrum of chronic venous disease signs and symptoms shows variable severity, ranging from mild (aching, pain, and varicose veins) to severe (venous ulcers). The pathophysiology of chronic venous disease is characterized by venous hypertension, which triggers endothelial dysfunction and inflammation leading to microcirculatory and tissue damage, and eventually to varicose veins and venous ulcers. Sulodexide is an orally active mixture of glycosaminoglycan (GAG) polysaccharides with established antithrombotic and profibrinolytic activity. The agent is used in the treatment of a number of vascular disorders with increased risk of thrombosis, including intermittent claudication, peripheral arterial occlusive disease and post-myocardial infarction. Sulodexide differs from heparin because it is orally bioavailable and has a longer half-life and a smaller effect on systemic clotting and bleeding. An increasing body of preclinical evidence shows that sulodexide also exerts anti-inflammatory, endothelial-protective, and pleiotropic effects, supporting its potential efficacy in the treatment of chronic venous disease. Clinical studies of sulodexide have shown that the agent is associated with significant improvements in the clinical signs and symptoms of venous ulcers, and is therefore a recommended therapy in combination with local wound care and bandages for patients with persistent venous leg ulcers. Preliminary evidence supports the use of sulodexide in the prevention of recurrent deep venous thrombosis. Sulodexide was generally safe and well tolerated in clinical trials, without hemorrhagic complications. Sulodexide therefore appears to be a favorable option for the treatment of all stages of chronic venous disease and for the prevention of disease progression.