Hepatocellular adenoma subtyping by qualitative MRI features and machine learning algorithm of integrated qualitative and quantitative features: a proof-of-concept study.

AIM: To evaluate hepatocellular adenoma (HCA) subtyping using qualitative magnetic resonance imaging (MRI) features and feasibility of differentiating HCA subtypes using machine learning (ML) of qualitative and quantitative MRI features with histopathology as the reference standard. MATERIALS AND METHODS: This retrospective study included 39 histopathologically subtyped HCAs (13 hepatocyte nuclear factor (HNF)-1-alpha mutated [HHCA], 11 inflammatory [IHCA], one beta-catenin-mutated [BHCA], and 14 unclassified [UHCA]) in 36 patients. HCA subtyping by two blinded radiologists using the proposed schema of qualitative MRI features and using the random forest algorithm was compared against histopathology. For quantitative features, 1,409 radiomic features were extracted after segmentation and reduced to 10 principle components. Support vector machine and logistic regression was applied to assess HCA subtyping. RESULTS: Qualitative MRI features with proposed flow chart yielded diagnostic accuracies of 87%, 82%, and 74% for HHCA, IHCA, and UHCA respectively. The ML algorithm based on qualitative MRI features showed AUCs (area under the receiver operating characteristic curve [ROC] curve) of 0.846, 0.642, and 0.766 for diagnosing HHCA, IHCA, and UHCA, respectively. Quantitative radiomic features from portal venous and hepatic venous phase MRI demonstrated AUCs of 0.83 and 0.82, with a sensitivity of 72% and a specificity of 85% in predicting HHCA subtype. CONCLUSIONS: The proposed schema of integrated qualitative MRI features with ML algorithm provided high accuracy for HCA subtyping while quantitative radiomic features provide value for diagnosis of HHCA. The key qualitative MRI features for differentiating HCA subtypes were concordant between the radiologists and the ML algorithm. These approaches appear promising to better inform clinical management for patients with HCA.

Clinical long-term results of radial head arthroplasty in comminuted radial head fractures.

Modern radial head prostheses have recently become more common in the treatment of comminuted radial head fractures. The goal of this study was to evaluate how well the EVOLVE® modular metallic radial head implant prosthetic restores the functional range of motion and stability of the elbow. 30 patients with comminuted radial head fractures received an arthroplasty with an EVOLVE® prosthesis in our institution. 20 of those patients were available for long-term follow-up (mean > 10 years). The outcomes were assessed on the basis of pain, motion, and strength. The overall outcome was scored with functional rating scores. According to the Broberg-Morrey elbow evaluation score, after a mean follow-up period of 10.2 years, ten (50.0%) patients were rated as very good, four (20.0%) as good, six (30.0%) as satisfactory, and none as poor. In the long-term results the Broberg-Morrey score increased from 79 (in short-term results) to 89 points. The Disabilities of the Arm, Shoulder, and Hand (DASH) outcome measure questionnaire showed an average of 16.2 points. Initially, patients had an extension deficit of 20°, which was reduced to 5° at the latest follow-up. In our long-term results, an improvement in the function of the elbow was observed after arthroplasty using a metallic modular radial head implant. Comminuted radial head fractures with elbow instability can be treated effectively with the EVOLVE® radial head prosthesis, which restores stability in acute treatment. Our long-term results after 10.2 years demonstrate good functional outcome and low major complication rate. IV.

Acceptance of physical activity monitoring in cancer patients during radiotherapy, the GIROfit phase 2 pilot trial.

Background: In radiotherapy the timely identification of patients needing intervention and supportive care due to side effects is an important task especially in the outpatient setting. Activity trackers as an increasingly used lifestyle device may enable physicians to monitor patient's physical activity (PA) and to intervene early during the course of radiotherapy. Objective: The primary aim of this trial was to assess patient acceptance of PA monitoring in an outpatient setting and to correlate changes in PA with toxicity and changes in quality of life. Methods: Patients undergoing radio(chemo-)therapy with a curative intent were eligible to participate in this prospective pilot phase II trial. Patients were instructed to wear a commercially available activity tracker during the course of radiotherapy and four weeks afterwards. Quality of life (QoL) and fatigue was scored using the Functional assessment of Chronic Illness Therapy questionnaire. A linear regression was performed to determine baseline activity and changes in step counts during radiotherapy. Results: We included 23 patients in this trial. Two withdrew consent before the start of treatment, two patients were excluded after prophylactic feeding tube placement and prolonged recovery. Compliance in the remaining 19 patients was high, with availability of step-counts on 92% of the days. Baseline step counts were 6274 for breast cancer patients and 3621 for patients with other entities. Decreasing activity during radiotherapy coincided with the development of side effects and declines in quality of life. Conclusions: Activity trackers as tool to monitor PA during and after radiotherapy were accepted by a majority of the patients included in the current trial. Observed changes in PA correlated with patient reported side effects and QoL in some of the patients.

Tranexamic acid reduced blood transfusions in acute burn surgery: A retrospective case-controlled trial.

OBJECTIVE: Early excision and grafting of burn wounds are key for reducing prevalence of infection and sepsis. However, it is associated with massive blood loss and patients frequently require large numbers of blood transfusions. This study aimed to evaluate the effect of tranexamic acid (TXA) on blood transfusion requirements in acute burn surgery. METHODS: Patients admitted to the burn intensive care unit between January 2018 and May 2021 and received TXA before first surgery for wound excision and grafting were matched in a 1:2 ratio to patients that did not receive TXA (confounders age,sex,total body surface area (TBSA) burned). Primary endpoint of the analysis was the total number of transfused units of red blood cells (RBC) intra- and postoperatively up to 48 h. Fresh frozen plasma (FFP) and platelets were evaluated. Endpoints were compared between groups using van Elteren tests adjusting for strata variable age, gender, TBSA. RESULTS: Twenty-six TXA patients were matched with 52 control patients resulting in similar distributions of gender (77.9%(TXA)vs. 82.7%(control) males, p=0.542), age (51.7±21.3vs.48.3 ±17.4years,p = 0.459) and %TBSA burned (33.5%(IQR34)vs. 38.5% (IQR 30.5),p = 1.000). TXA group received significantly less RBC units intraoperatively (2.5(IQR 2.0)vs.4.0 units (IQR4.0), p = 0.038) and in total (4.0(IQR3.0)vs.6.0(IQR4.0),p = 0.017). TXA patients also received less blood products in general (RBC, FFP, platelets) in each period and in total. We found no significant difference in length of stay (24.0(IQR26.0)vs.33.0 days (IQR 0.5),p = 0.367) or mortality (15.4%vs.21.2%, p = 0.542). DISCUSSION: This study shows that necessity for blood transfusions in acute burn surgery may be reduced significantly by administration of TXA perioperatively. Randomized-controlled trials are needed to prove these findings.

Early introduction of exercise prevents insulin resistance in postnatal overfed rats

Early childhood obesity increases the risk of developing metabolic diseases. We examined the early introduction of exercise in small-litter obese-induced rats (SL) on glucose metabolism in the epididymal adipose tissue (AT) and soleus muscle (SM). On day 3 post-birth, pups were divided into groups of ten or three (SL). On day 22, rats were split into sedentary (S and SLS) and exercise (E and SLE) groups. The rats swam three times/week carrying a load for 30 min. In the first week, they swam without a load; in the 2nd week, they carried a load equivalent to 2% of their body weight; from the 3rd week to the final week, they carried a 5% body load. At 85 days of age, an insulin tolerance test was performed in some rats. At 90 days of age, rats were killed, and blood was harvested for plasma glucose, cholesterol, and triacylglycerol measurements. Mesenteric, epididymal, retroperitoneal, and brown adipose tissues were removed and weighed. SM and AT were incubated in the Krebs-Ringer bicarbonate buffer, 5.5 mM glucose for 1 h with or without 10 mU/mL insulin. Comparison between the groups was performed by 3-way ANOVA followed by the Tukey post-hoc test. Sedentary, overfed rats had greater body mass, more visceral fat, lower lactate production, and insulin resistance. Early introduction of exercise reduced plasma cholesterol and contained the deposition of white adipose tissue and insulin resistance. In conclusion, the early introduction of exercise prevents the effects of obesity on glucose metabolism in adulthood in this rat model.

Bullous systemic lupus erythematosus: An uncommon manifestation in pediatric population. / Lupus eritematoso sistémico buloso: Una manifestación infrecuente en población pediátrica.

INTRODUCTION: Bullous systemic lupus erythematosus (BSLE) is an autoimmune subepidermal blistering disease se condary to the presence of autoantibodies against type VII collagen of the basement membrane zone. It is considered a variant of Systemic Lupus Erythematosus (SLE) and is uncommon in the pediatric population. OBJECTIVE: To describe the case of a pediatric patient with a bullous eruption compati ble with BSLE. CLINICAL CASE: A 16-year-old female patient of Mapuche descent with history of SLE diagnosed at age 10, undergoing treatment. She consulted due to a six-week history of a generalized bullous eruption with no systemic symptoms. Biopsy for histology and direct immunofluorescence (DIF) confirmed the diagnosis of BSLE. The patient responded favorably to dapsone 100 mg/day (associated with her baseline treatment), without new reactivations after 8 years of follow-up. Con clusion: BSLE is an infrequent manifestation of SLE. The clinical presentation is similar to other bullous dermatoses, but the histopathology and DIF in correlation with the presence of SLE confirm the diagnosis. Although indigenous ancestry is associated with SLE high-risk alleles, studies regarding the association of BSLE in this ethnic group are still lacking.

The Use of Semi-Absorbable Mesh and its Impact on Donor-Site Morbidity and Patient-Reported Outcomes in DIEP Flap Breast Reconstruction.

BACKGROUND: This study aimed to evaluate the impact of semi-absorbable mesh on donor-site morbidity and patient-reported outcomes in deep inferior epigastric perforator (DIEP) flap breast reconstruction. METHODS: We conducted a retrospective cohort study of all patients who had DIEP flap breast reconstruction in our department from July 2007 to March 2019. Patients were invited to a comparative follow-up visit and grouped according to donor-site closure: primary fascial closure (the no-mesh group) and fascial reinforcement with semi-absorbable mesh in a subfascial position (the mesh group). The primary outcome of interest was donor-site morbidity, including bulging, hernia formation and rectus abdominis muscle strength. We also surveyed, surgical site complications and patient-reported outcomes using Patient and Observer Scar Assessment Scale v2.0 and BREAST-Q© version 2.0. RESULTS: A total of 191 patients had received DIEP flap breast reconstruction. Eighty-five patients (44.5%) with 108 DIEP flaps (53 patients in the mesh group and 32 patients in the no-mesh group) were included in the study. The mean BMI of the patients was significantly higher in the mesh group (mesh group, 26.9 vs. no-mesh group, 25.0, with p = 0.03). The incidence of hernia was significantly reduced in the mesh group (mesh group, 2.8% vs. no-mesh group, 13.5%, with p = 0.03). The incidence of bulging and the extent of rectus abdominis muscle strength were similar for both groups. Operative surgical site complications were reduced in the mesh group (mesh group, 7.5% vs. no-mesh group, 18.8%). There was no difference in patients' physical well-being and satisfaction with the donor site between groups. Patient-reported scar outcome was significantly better in the no-mesh group (p < 0.001). CONCLUSION: Our novel method of donor-site closure with semi-absorbable mesh in a subfascial position for reinforcement of the anterior rectus fascia on the DIEP donor site is safe. It has no negative impact on surgical site complications and patient-reported outcomes, while reducing the incidence of hernias on the donor-site in DIEP flap breast reconstruction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

[Extracorporeal Lung Support in Thoracic Surgery: Basics and Pathophysiology]. / ECMO in der Thoraxchirurgie: Grundlagen und Pathophysiologie.

Extracorporeal lung support (ECLS) is of increasing importance in general thoracic surgery. Different modes of ECLS may be applied in several situations throughout the perioperative phase and are adapted to the individual patient's needs and the planned surgical procedures. ECLS is not a static procedure and should be always evaluated according to the present condition of the patient. Therefore, it is essential to understand the pathophysiology of the disease and the different ECLS modes, as well as the different cannulation options, in order to be able to use the different escalation and de-escalation techniques in accordance with the clinical situation.

Random-pattern versus perforator-based adipocutaneous skin paddles for postoperative monitoring of free muscle flaps-a comparative retrospective cohort study.

INTRODUCTION: Free microvascular muscle flaps represent well-established reconstructive options for complex soft tissue defects. However, due to their lack of cutaneous capillary beds, they are difficult to monitor postoperatively. To this end, random and axial-pattern adipocutaneous skin paddles are often included. The objective of the study was to compare the impact of random-pattern versus perforator-based adipocutaneous skin paddles on operative efficacy and muscle flap safety. METHODS: Between August 2014 and July 2016, a total of 120 free muscle flaps were included in this retrospective monocentric cohort study. Based on their skin-paddle type, they were either grouped into a 'perforator-based' (group Pb) or 'random-pattern' (group Rp) cohort. The electronic medical records and operative reports of all patients were subsequently reviewed and patient, defect, and flap characteristics of both groups were compared. The effect of the competing skin paddle types on the overall operative time, incidences of flap loss or microvascular complications, and total length of hospital stay were then assessed. RESULTS: Group Pb comprised 72 flaps, whereas 48 flaps constituted group Rp. Patient, defect, and flap characteristics were similar between both groups. Groups Pb and Rp were comparable regarding patient age (group Pb: 61 (10-90) vs. Rp: 59 (13-81), p = 0.556), ASA (American Society of Anesthesiologists) class (group Pb: 3 (1-4) vs. Rp 3 (1-3), p = 0.977), and comorbidities, summarized by the Charlson comorbidity index (CCI; group Pb: 1 (0-4 vs. Rp: 1 (0-5), p = 0.295). Both types of monitoring skin paddles were equally reliable. There was no significant difference in the mean operation time between both groups (group Pb: 373 ±â€¯122 min vs. Rp: 342 ±â€¯84 min, p = 0.124). In-patient treatment after flap surgery and total length of hospital stay were significantly shorter in group Pb (group Pb: 24 ±â€¯10 days vs. Rp: 32 ±â€¯17 days, p = 0.002 and group Pb: 39 ±â€¯15 vs. Rp: 48 ±â€¯24, p = 0.022). CONCLUSION: Perforator-based skin paddles are a reliable tool for postoperative perfusion monitoring of free muscle flaps and help avoid additional surgical interventions as opposed to their random-pattern counterparts. Thus, the overall and postoperative length of hospital stay is significantly reduced.

ICF-based multidisciplinary rehabilitation program for complex regional pain syndrome of the hand: efficacy, long-term outcomes, and impact of therapy duration.

BACKGROUND: Complex regional pain syndrome (CRPS) is a rare but feared complication in hand surgery. Although multimodal therapy concepts are recommended, there is only low evidence on efficacy of such approaches. Furthermore, recommendations regarding therapy duration are lacking. Aim of this study was to validate the efficacy of an International Classification of Functioning, Disability and Health (ICF)-based multidisciplinary rehabilitation concept for treatment of CRPS of the hand and to find correlations between therapy duration and outcome measures. METHODS: Patients with CRPS of the hand after occupational trauma that underwent an ICF-based rehabilitation program between 2010 and 2014 were included in this retrospective study. Besides demographic data, outcomes included pain (VAS), range of motion assessed by fingertip-to-palm-distance (PTPD) and fingernail-to-table-distance (FTTD) as well as strength in grip, 3-point pinch and lateral pinch. All measures were gathered at admission to and discharge from inpatient rehabilitation therapy as well as at follow-up. Statistical analysis included paired t-test, ANOVA and Pearson's correlation analysis. RESULTS: Eighty-nine patients with a mean age of 45 years were included in this study. Duration of rehabilitation therapy was 53 days on average. All outcomes improved significantly during rehabilitation therapy. Pain decreased from 6.4 to 2.2. PTPD of digit 2 to 5 improved from 2.5, 2.8, 2.6, and 2.3 cm to 1.3, 1.4, 1.2, and 1.1 cm, respectively. FTTD of digit 2 to 5 decreased from 1.5, 1.7, 1.5, and 1.6 cm to 0.6, 0.8, 0.7, and 0.7 cm, respectively. Strength ameliorated from 9.5, 3.7, 2.7 kg to 17.9, 5.6, 5.0 kg in grip, lateral pinch, and 3-point pinch, respectively. Improvement in range of motion significantly correlated with therapy duration. 54% of patients participated at follow-up after a mean of 7.5 months. Outcome measures at follow-up remained stable compared to discharge values without significant differences. CONCLUSION: The ICF-based rehabilitation concept is a reliable and durable treatment option for CRPS of the hand. Range of motion improved continuously with therapy duration and thus may serve as an indicator for optimum length of therapy.

Combination of the PI3K inhibitor Idelalisib with the conventional cytostatics cytarabine and dexamethasone leads to changes in pathway activation that induce anti-proliferative effects in B lymphoblastic leukaemia cell lines.

BACKGROUND: The introduction of combined conventional cytostatics and pathway-specific inhibitors has opened new treatment options for several cancer types including hematologic neoplasia such as leukaemias. As the detailed understanding of the combination-induced molecular effects is often lacking, the identification of combination-induced molecular mechanisms bears significant value for the further development of interventional approaches. METHODS: Combined application of conventional cytostatic agents (cytarabine and dexamethasone) with the PI3K-inhibitor Idelalisib was analysed on cell-biologic parameters in two acute pro-B lymphoblastic leukaemia (B-ALL) cell lines. In particular, for comparative characterisation of the molecular signatures induced by the combined and mono application, whole transcriptome sequencing was performed. Emphasis was placed on pathways and genes exclusively regulated by drug combinations. RESULTS: Idelalisib + cytostatics combinations changed pathway activation for, e.g., "Retinoblastoma in cancer", "TGF-b signalling", "Cell cycle" and "DNA-damage response" to a greater extent than the two cytostatics alone. Analyses of the top-20 regulated genes revealed that both combinations induce characteristic gene expression changes. CONCLUSION: A specific set of genes was exclusively deregulated by the drug combinations, matching the combination-specific anti-proliferative cell-biologic effects. The addition of Idelalisib suggests minor synergistic effects which are rather to be classified as additive.

Endovascular Thrombectomy of Calcified Emboli in Acute Ischemic Stroke: A Multicenter Study.

BACKGROUND AND PURPOSE: Large intracranial vessel occlusion due to calcified emboli is a rare cause of major stroke. We assessed the prevalence, imaging appearance, the effectiveness of mechanical thrombectomy, and clinical outcome of patients with large-vessel occlusion due to calcified emboli. MATERIALS AND METHODS: We performed a retrospective analysis of clinical and procedural data of consecutive patients who underwent mechanical thrombectomy due to calcified emboli in 7 European stroke centers. RESULTS: We screened 2969 patients, and 40 patients matched the inclusion criteria, accounting for a prevalence of 1.3%. The mean maximal density of the thrombus was 327 HU (range, 150-1200 HU), and the mean thrombus length was 9.2 mm (range, 4-20 mm). Four patients had multiple calcified emboli, and 2 patients had an embolic event during an endovascular intervention. A modified TICI score of ≥2b was achieved in 57.5% (23/40), with minimal-to-no reperfusion (modified TICI 0-1) in 32.5% (13/40) and incomplete reperfusion (modified TICI 2a) in 10% (4/40). Excellent outcome (mRS 0-1) was achieved in only 20.6%, functional independence (mRS 0-2) in 26.5% and 90-day mortality was 55.9%. CONCLUSIONS: Acute ischemic stroke with large-vessel occlusion due to calcified emboli is a rare entity in patients undergoing thrombectomy, with considerably worse angiographic outcome and a higher mortality compared with patients with noncalcified thrombi. Good functional recovery at 3 months can still be achieved in about a quarter of patients.

Pulsatile tinnitus due to an aneurysmatic diverticulum of the jugular bulb treated with the Woven EndoBridge device.

Tinnitus is a common symptom with an incidence of 4-20%. Pulsatile tinnitus represents a minor subgroup of less than 10% of all patients suffering from tinnitus. Pulsatile tinnitus - different from permanent mostly idiopathic tinnitus is mainly caused by physical sources related to vascular pathologies resulting in a change in blood volume and pressure or an alteration of the vessel lumen. Differential diagnosis for pulsatile tinnitus include dural arteriovenous fistulas, glomus tumors of the jugular foramen and the middle ear or atherosclerotic diseases of the carotid artery in the petrous or cavernous segment. Anomalies of the dural sinuses and the jugular bulb have been described as rare sources of synchronized tinnitus. The Woven EndoBridge (WEB, Microvention, Tustin, CA) is an intraaneurysmal flow diverter for the treatment of broad-based arterial aneurysms with a high safety and effectiveness profile. The initial version of the WEB with a dual layer structure evolved to a single layer structure in two different versions (WEB SL, WEB SLS). The WEB system does not require a concomitant antiplatelet therapy compared to other intraluminal devices as extra-aneurysmal flow-diverters or intracranial stents. Here we describe a case of an aneurysmatic diverticulum of the jugular bulb in a patient with ipsilateral pulsatile tinnitus treated with a WEB device.

Assessments of activities of daily living after arthroscopic SLAP repair with knot-tying versus knotless suture anchors.

PURPOSE: The clinical influence of knot-tying or knotless anchor systems for the arthroscopic repair of SLAP lesions (superior labrum lesion from anterior to posterior) remain unclear. MATERIALS AND METHODS: In a retrospective cohort analysis, 61 of 78 (78.2%) patients with isolated symptomatic SLAP II lesions were examined with a minimum of 24 months after arthroscopic SLAP repair compared to a control group: 28 patients with knot-tying anchors (group I, G1; 28.95 ± 9.48 years, 23 male/5 female), 33 with knotless anchors (group II, G2; 31 ± 10.09 years, 26 male/7 female) and 140 healthy volunteers (group III, G3; 30.9 ± 8.9 years, 109 male/31 female). The clinical assessment included an examination and estimated parameters of ADL (activities of daily living), the CS (Constant score), ASES (American Shoulder and Elbow score), DASH (disability of arm-shoulder hand) and the RS (Rowe score). RESULTS: The ROM analysis recorded no significant differences for the external rotation in 0° abduction (G1 63.75° ± 15.55° versus = vs G2 65.30° ± 18.15°; pERG1 vs G2 = 0.72). The clinical outcomes revealed significantly decreased pain status in G1 for the O'brien test and in G2 for the Palm-up test, whereas Yergason test showed similar pain levels (pO'brien = 0.03; ppalm up = 0.02; pyergason > 0.5). The pulley associated rotator cuff tests revealed a significantly inferior force status in G2 compared to G1 (plift-off = 0.005, pJobe = 0.02) whereas the further rotator cuff assessments were equal. In general, the intervention group showed increased pain level and functional deficits compared to the G3. The score analysis detected no significant differences with PCSG1 vs G2, PASESG1 vs G2, PDASHG1 vs G2 and PRSG1 vs G2 all > 0.05 and significant impairments compared to G3 in all scores pG1/G2 vs G3 < 0.05 (CSG1 = 88.28 ± 14.42, CSG2=92.73 ± 9.24, CSG3 = 96.2 ± 4.96; ASESG1 = 81.10 ± 21.69, ASESG2 = 85.35 ± 17.12, ASESG3 = 94.95 ± 10.39,; DASHG1= 35.75 ± 13.44, DASHG2 = 36.03 ± 17.55, DASHG3 = 27.13 ± 6.52; RSG1 = 90.71 ± 9.88, RSG2 = 88.33 ± 11.22, RSG3= 92.96 ± 11.27). CONCLUSIONS: The clinical assessment revealed for both anchor systems similar outcomes but showed general underestimated impairments after the SLAP repair surgery compared to the healthy control. The clinical status only marginally differed between both techniques, wherefore the present assessment of ADL allowed no recommendation of one of these two specific surgery technique for SLAP repair.

Lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 inhibitors.

Lipoprotein(a) (Lp(a)) is an internationally accepted independent atherogenic risk factor. Details about its synthesis, many aspects of composition and clearance from the bloodstream are still unknown. LDL receptor (LDLR) (and probably other receptors) play a role in the elimination of Lp(a) particles. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors increase the number of available LDLRs and in this way very effectively reduce the LDL cholesterol (LDL-C) concentrations. As shown in controlled studies using PCSK9 inhibitors, Lp(a) levels are decreased by 20 to 30%, though in some patients no effect was observed. So far, it has not been clarified whether this decrease is associated with an effect on the incidence of cardiovascular events (CVEs). In two recently published well-performed secondary prevention studies (FOURIER with evolocumab, ODYSSEY OUTCOMES with alirocumab) baseline Lp(a) levels were shown to have an impact on CVEs independently of baseline LDL-C concentrations. The rather modest PCSK9 inhibitor-induced decrease of Lp(a) was associated with a reduction of CVEs in both studies, even after adjusting (ODYSSEY OUTCOMES) for demographic variables (age, sex, race, region), baseline Lp(a), baseline LDL-C, change in LDL-C, and clinical variables (time from acute coronary syndrome, body mass index, diabetes, smoking history). The largest decrease of CVEs was seen in patients with relatively low concentrations of both LDL-C and Lp(a) (FOURIER). These findings will probably have an influence on the use of PCSK9 inhibitors in patients with high Lp(a) concentrations.

Gonadoblastoma Y locus genes expressed in germ cells of individuals with dysgenetic gonads and a Y chromosome in their karyotypes include DDX3Y and TSPY.

STUDY QUESTION: Which Y genes mapped to the 'Gonadoblastoma Y (GBY)' locus on human Y chromosome are expressed in germ cells of individuals with some Differences of Sexual Development (DSD) and a Y chromosome in their karyotype (DSD-XY groups)? SUMMARY ANSWER: The GBY candidate genes DDX3Y and TSPY are expressed in the germ cells of DSD-XY patients from distinct etiologies: patients with mixed gonadal dysgenesis (MGD) and sex chromosome mosaics (45,X0/46,XY; 46,XX/46,XY); patients with complete androgen insensitivity (CAIS), patients with complete gonadal dysgenesis (CGD; e.g. Swyer syndrome). WHAT IS KNOWN ALREADY: A GBY locus was proposed to be present on the human Y chromosome because only DSD patients with a Y chromosome in their karyotype have a high-although variable-risk (up to 55%) for germ cell tumour development. GBY was mapped to the proximal part of the short and long Y arm. TSPY located in the proximal part of the short Y arm (Yp11.1) was found to be a strong GBY candidate gene. It is expressed in the germ cells of DSD-XY patients with distinct etiologies but also in foetal and pre-meiotic male spermatogonia. However, the GBY region extends to proximal Yq11 and therefore includes probably more than one candidate gene. STUDY DESIGN, SIZE, DURATION: Protein expression of the putative GBY candidate gene in proximal Yq11, DDX3Y, is compared with that of TSPY in serial gonadal tissue sections of 40 DSD-XY individuals from the three DSD patient groups (MGD, Complete Androgen Insensitivity Syndrome [CAIS], CGD) with and without displaying malignancy. Expression of OCT3/4 in the same tissue samples marks the rate of pluripotent germ cells. PARTICIPANTS/MATERIALS, SETTING, METHOD: A total of 145 DSD individuals were analysed for the Y chromosome to select the DSD-XY subgroup. PCR multiplex assays with Y gene specific marker set score for putative microdeletions in GBY Locus. Immunohistochemical experiments with specific antisera mark expression of the GBY candidate proteins, DDX3Y, TSPY, in serial sections of the gonadal tissue samples; OCT3/4 expression analyses in parallel reveal the pluripotent germ cell fraction. MAIN RESULTS AND THE ROLE OF CHANCE: Similar DDX3Y and TSPY protein expression patterns were found in the germ cells of DSD-XY patients from each subgroup, independent of age. In CAIS patients OCT3/4 expression was often found only in a fraction of these germ cells. This suggest that GBY candidate proteins are also expressed in the non-malignant germ cells of DSD-XY individuals like in male spermatogonia. LIMITATIONS, REASONS FOR CAUTION: Variation of the expression profiles of GBY candidate genes in the germ cells of some DSD-XY individuals suggests distinct transcriptional and translational control mechanisms which are functioning during expression of these Y genes in the DSD-XY germ cells. Their proposed GBY tumour susceptibility function to transform these germ cells to pre-malignant GB/Germ Cell Neoplasia in Situ (GB/GCNIS) cells seems therefore to be limited and depending on their state of pluripotency. WIDER IMPLICATIONS OF THE FINDINGS: These experimental findings are of general importance for each individual identified in the clinic with DSD and a Y chromosome in the karyotype. To judge their risk of germ cell tumour development, OCT3/4 expression analyses on their gonadal tissue section is mandatory to reveal the fraction of germ cells still being pluripotent. Comparative expression analysis of the GBY candidate genes can be helpful to reveal the fraction of germ cells with genetically still activated Y chromosomes contributing to further development of malignancy if at high expression level. STUDY FUNDING/COMPETING INTEREST(S): This research project was supported by a grant (01GM0627) from the BMBF (Bundesministerium für Bildung und Forschung), Germany to P.H.V. and B.B. The authors have no competing interests.

Radiation Pneumonitis after Intensity-Modulated Radiotherapy for Esophageal Cancer: Institutional Data and a Systematic Review.

Radiation pneumonitis (RP) is a serious complication that can occur after thoracic radiotherapy. The goal of this study is to investigate the incidence of RP after radiochemotherapy with intensity modulated radiotherapy (IMRT) in patients with esophageal cancer and correlate this with dose volume histogram (DVH) related parameters. For this purpose, the clinical course of 73 patients was evaluated and irradiation doses to the lungs were extracted from radiotherapy treatment plans. Furthermore, a systematic review on this topic was conducted across PubMed. In our institutional cohort, Common Terminology Criteria for Adverse Events (CTCAE) grade II or higher RP occurred in four patients (5.5%). The systematic review identified 493 titles of which 19 studies reporting 874 patients qualified for the final analysis. No grade IV or V RP after radiochemotherapy with IMRT for esophageal cancer was reported in the screened literature. Grade II or higher RP is reported in 6.6% of the patients. A higher incidence can be seen with increasing values for lung V20. In conclusion, our institutional data and the literature consistently show a low incidence of symptomatic RP after radiochemotherapy in patients with esophageal cancer treated with IMRT. However, efforts should be made to keep the lung V20 below 23% and specific caution is warranted in patients with pre-existing lung conditions.

E-cadherin, actin, microtubules and FAK dominate different spheroid formation phases and important elements of tissue integrity.

Spheroids resemble features of tissues and serve as model systems to study cell-cell and cell-ECM interactions in non-adhesive three-dimensional environments. Although it is generally accepted that mature spheroids resemble tissue properties very well, no studies relate different phases in the spheroid formation processes that contribute to tissue integrity. Tissue integrity involves the cellular processes adhesion formation, adhesion reinforcement, rearrangement as well as proliferation. They maintain the structure and function of tissues and, upon dysregulation, contribute to malignancy. We investigated spheroid formation dynamics in cell lines of different metastatic potential. We dissected spheroid formation into phases of aggregation, compaction and growth to identify the respective contributions of E-cadherin, actin, microtubules and FAK. E-cadherin, actin and microtubules drive the first two phases. Microtubules and FAK are involved in the proliferation phase. FAK activity correlates with the metastatic potential of the cells. A robust computational model based on a very large number of experiments reveals the temporal resolution of cell adhesion. Our results provide novel hypotheses to unveil the general mechanisms that contribute to tissue integrity.

[Inflammatory bowel diseases : Crohn's disease and ulcerative colitis]. / Chronisch-entzündliche Darmerkrankungen : Morbus Crohn und Colitis ulcerosa.

Inflammatory bowel diseases (IBD) are complex diseases. Epidemiological studies suggest rising incidences in industrialized countries. The article is based on a literature search in PubMed and is oriented on the current guidelines published by the European Crohn's and Colitis Organisation. IBD are characterized by chronic diarrhoea, abdominal pain and peranal haemorrhage. Extraintestinal manifestations commonly affect joints, skin, eyes and bile tracts. Early diagnosis and therapeutic intervention determine individual patient outcome. Medical treatment currently includes aminosalicylates, corticosteroids, thiopurines, calcineurin inhibitors and biologicals. IBDs require anti-inflammatory and if necessary immunosuppressive therapy. Due to extraintestinal complications and the possible need for surgical intervention, an interdisciplinary approach is important.