Dual or single antiplatelet therapy after coronary surgery for acute coronary syndrome (TACSI trial): Rationale and design of an investigator-initiated, prospective, multinational, registry-based randomized clinical trial.

The TACSI trial (ClinicalTrials.gov Identifier: NCT03560310) tests the hypothesis that 1-year treatment with dual antiplatelet therapy with acetylsalicylic acid (ASA) and ticagrelor is superior to only ASA after isolated coronary artery bypass grafting (CABG) in patients with acute coronary syndrome. The TACSI trial is an investigator-initiated pragmatic, prospective, multinational, multicenter, open-label, registry-based randomized trial with 1:1 randomization to dual antiplatelet therapy with ASA and ticagrelor or ASA only, in patients undergoing first isolated CABG, with a planned enrollment of 2200 patients at Nordic cardiac surgery centers. The primary efficacy end point is a composite of time to all-cause death, myocardial infarction, stroke, or new coronary revascularization within 12 months after randomization. The primary safety end point is time to hospitalization due to major bleeding. Secondary efficacy end points include time to the individual components of the primary end point, cardiovascular death, and rehospitalization due to cardiovascular causes. High-quality health care registries are used to assess primary and secondary end points. The patients will be followed for 10 years. The TACSI trial will give important information useful for guiding the antiplatelet strategy in acute coronary syndrome patients treated with CABG.

Secondary prevention medications after coronary artery bypass grafting and long-term survival: a population-based longitudinal study from the SWEDEHEART registry.

AIMS: To evaluate the long-term use of secondary prevention medications [statins, ß-blockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, and platelet inhibitors] after coronary artery bypass grafting (CABG) and the association between medication use and mortality. METHODS AND RESULTS: All patients who underwent isolated CABG in Sweden from 2006 to 2015 and survived at least 6 months after discharge were included (n = 28 812). Individual patient data from SWEDEHEART and other mandatory nationwide registries were merged. Multivariable Cox regression models using time-updated data on dispensed prescriptions were used to assess associations between medication use and long-term mortality. Statins were dispensed to 93.9% of the patients 6 months after discharge and to 77.3% 8 years later. Corresponding figures for ß-blockers were 91.0% and 76.4%, for RAAS inhibitors 72.9% and 65.9%, and for platelet inhibitors 93.0% and 79.8%. All medications were dispensed less often to patients ≥75 years. Treatment with statins [hazard ratio (HR) 0.56, 95% confidence interval (95% CI) 0.52-0.60], RAAS inhibitors (HR 0.78, 95% CI 0.73-0.84), and platelet inhibitors (HR 0.74, 95% CI 0.69-0.81) were individually associated with lower mortality risk after adjustment for age, gender, comorbidities, and use of other secondary preventive drugs (all P < 0.001). There was no association between ß-blockers and mortality risk (HR 0.97, 95% CI 0.90-1.06; P = 0.54). CONCLUSION: The use of secondary prevention medications after CABG was high early after surgery but decreased significantly over time. The results of this observational study, with inherent risk of selection bias, suggest that treatment with statins, RAAS inhibitors, and platelet inhibitors is essential after CABG whereas the routine use of ß-blockers may be questioned.

Postdischarge major bleeding, myocardial infarction, and mortality risk after coronary artery bypass grafting.

OBJECTIVE: To investigate the incidence and mortality risk associated with postdischarge major bleeding after coronary artery bypass grafting (CABG), and relate this to the incidence of, and mortality risk from, postdischarge myocardial infarction. METHODS: All patients undergoing first-time isolated CABG in Sweden in 2006-2017 and surviving 14 days after hospital discharge were included in a cohort study. Individual patient data from the SWEDEHEART Registry and five other mandatory nationwide registries were merged. Piecewise Cox proportional hazards models were used to investigate associations between major bleeding, defined as hospitalisation for bleeding, with subsequent mortality risk. Similar Cox proportional hazards models were used to investigate the association between postdischarge myocardial infarction and mortality risk. RESULTS: Among 36 633 patients, 2429 (6.6%) had a major bleeding event and 2231 (6.1%) had a myocardial infarction. Median follow-up was 6.0 (range 0-11) years. Major bleeding was associated with higher mortality risk <30 days (adjusted HR (aHR)=20.2 (95% CI 17.3 to 23.5)), 30-365 days (aHR=3.8 (95% CI 3.4 to 4.3)) and >365 days (aHR=1.8 (95% CI 1.7 to 2.0)) after the event. Myocardial infarction was associated with higher mortality risk <30 days (aHR=20.0 (95% CI 16.7 to 23.8)), 30-365 days (aHR=4.1 (95% CI 3.6 to 4.8)) and >365 days (aHR=1.8 (95% CI 1.7 to 2.0)) after the event. CONCLUSIONS: The increase in mortality risk associated with a postdischarge major bleeding after CABG is substantial and is similar to the mortality risk associated with a postdischarge myocardial infarction.

Small calibre biosynthetic bacterial cellulose blood vessels: 13-months patency in a sheep model.

OBJECTIVES: Many patients in need of bypass surgery lack graft material and current synthetic alternatives have poor performance. A 4 mm vascular graft composed of bacterial cellulose (BC) was developed and tested in pilot study in a large animal model. DESIGN: BC is a biopolymer made by the bacteria acetobacter xylinum. BC grafts (n = 16) with 4 cm length and 4 mm internal diameter were implanted bilaterally in the carotid arteries of eight sheep. No long-term antithrombotic therapy was administered. Patency was assessed with ultrasound. Histology, immunohistochemistry, and electron microscopy were performed after explantation. RESULTS: Fifty percent of the grafts occluded within two weeks. One animal died with patent grafts after 14 days. In the three remaining animals 5/6 grafts were patent after nine months. Two animals were followed 13 months after implantation with 3/4 grafts patent at explantation. All patent grafts had confluent endothelial-like cells. CONCLUSIONS: Biosynthetic small calibre vascular grafts made from BC can be patent for up to 13 months in sheep carotid arteries. BC is a potential material for small calibre grafts but patency in animal models needs to be improved before clinical studies can be planned.

Renin-angiotensin system inhibition and outcome after coronary artery bypass grafting: A population-based study from the SWEDEHEART registry.

BACKGROUND: Renin-angiotensin system (RAS) inhibitors are recommended postoperatively to coronary artery bypass grafting (CABG) patients with reduced left ventricular function, diabetes, hypertension or previous myocardial infarction, but not to remaining patients. The aim of the study was to assess the long-term utilization of RAS inhibitors after CABG in patients with and without indication for treatment, and its association with outcome. METHODS: All patients (n = 28,782) not meeting exclusion criterion in Sweden who underwent isolated first time CABG from 2006 to 2015 were included using nationwide registries. The association between treatment and outcome was assessed using adjusted Cox regression models with time-updated data on medications. The primary outcome was major adverse cardiovascular events (MACE), defined as all-cause mortality, stroke and/or myocardial infarction. RESULTS: At baseline 26,284 (91.3%) of the patients had at least one indication for RAS inhibition while 2498 (8.7%) had not. RAS inhibitors were dispensed to 77.0% and 29.7% of patients with and without indication respectively. Dispense declined over time. RAS inhibition was associated with a reduction in MACE in the whole study population (adjusted hazard ratio (aHR) 0.88, 95% confidence interval (95% CI) 0.83-0.93, p < 0.0001), and in patients with (aHR 0.87 95% CI: 0.82-0.93, p < 0.0001) and without indication (aHR 0.75, 95% CI: 0.58-0.98, p = 0.034). CONCLUSIONS: RAS inhibition is underutilized after CABG. The use of RAS inhibitors was associated with a reduction in MACE, both in patients with and without indication for treatment. The results suggest that RAS inhibition is beneficial for all CABG patients. Randomized controlled trials are necessary to confirm this hypothesis.

Comparison of Midterm Outcomes Associated With Aspirin and Ticagrelor vs Aspirin Monotherapy After Coronary Artery Bypass Grafting for Acute Coronary Syndrome.

Importance: Guidelines recommend dual antiplatelet therapy after coronary artery bypass grafting (CABG) for patients with acute coronary syndrome (ACS). However, the evidence for these recommendations is weak. Objective: To compare midterm outcomes after CABG in patients with ACS treated postoperatively with acetylsalicylic acid (ASA) and ticagrelor or with ASA monotherapy. Design, Setting, and Participants: This cohort study used merged data from several national registries of Swedish patients who were diagnosed with ACS and subsequently underwent CABG. All included patients underwent isolated CABG in Sweden between 2012 and 2017 with an ACS diagnosis less than 6 weeks before the procedure, survived 14 days after discharge from hospital, and were treated postoperatively with ASA plus ticagrelor or ASA monotherapy. A multivariable Cox regression model was used for the main analysis, and propensity score-matched models were performed as sensitivity analysis. Data were analyzed between May and September 2020. Exposures: Postoperative antiplatelet treatment, defined as filled prescriptions, with either ASA and ticagrelor or ASA only. Main Outcomes and Measures: Major adverse cardiovascular events (MACE), defined as all-cause mortality, myocardial infarction, and stroke, and major bleeding, at 12 months and at the end of follow-up. Results: A total of 6558 patients (5281 [80.5%] men; mean [SD] age at surgery, 67.6 [9.3] years) were included; 1813 (27.6%) were treated with ASA plus ticagrelor and 4745 (72.4%) were treated with ASA monotherapy. Crude MACE rate was 3.0 per 100 person years (95% CI, 2.5-3.6 per 100 person years) in the ASA plus ticagrelor group and 3.8 per 100 person years (95% CI, 3.5-4.1 per 100 person years) in the ASA group. After adjustment, there was no significant difference in MACE risk between ASA plus ticagrelor vs ASA only, neither during the first 12 months (adjusted hazard ratio [aHR], 0.84; 95% CI, 0.58-1.21; P = .34) or during total follow-up (aHR, 0.89; 95% CI, 0.71-1.11; P = .29). The use of ASA plus ticagrelor was associated with a significantly increased risk for major bleeding during the first 12 months (aHR, 1.90; 95% CI, 1.16-3.13; P = .011). Sensitivity analyses confirmed the results. Conclusions and Relevance: In patients with ACS who survived 2 weeks after CABG, no significant difference in the risk of death or ischemic events could be demonstrated between ASA plus ticagrelor and patients treated with ASA only, while the risk for major bleeding was higher in patients treated with ASA plus ticagrelor. Sufficiently powered prospective randomized trials comparing different antiplatelet therapy strategies after CABG are warranted.

Socioeconomic Factors, Secondary Prevention Medication, and Long-Term Survival After Coronary Artery Bypass Grafting: A Population-Based Cohort Study From the SWEDEHEART Registry.

Background Low income and short education have been found to be independently associated with inferior survival after coronary artery bypass grafting (CABG), whereas the use of secondary prevention medications is associated with improved survival. We investigated whether underusage of secondary prevention medications contributes to the inferior long-term survival in CABG patients with a low income and short education. Methods and Results Patients who underwent CABG in Sweden between 2006 to 2015 and survived at least 6 months after discharge (n=28 448) were included in a population-based cohort study. Individual patient data from 5 national registries, including the SWEDEHEART (Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) registry, covering dispensing of secondary prevention medications (statins, platelet inhibitors, ß-blockers, and RAAS inhibitors), socioeconomic factors, patient characteristics, comorbidity, and long-term mortaity were merged. All-cause mortality risk was estimated using multivariable Cox regression models adjusted for patient characteristics, baseline comorbidities, time-updated secondary prevention medications, and socioeconomic status. Long-term mortality was higher in patients with a low income and short education. Statins and platelet inhibitors were dispensed less often to patients with a low income, both at baseline and after 8 years. The decline in dispensing over time was steeper for low-income patients. Short education was not associated with reduced dispensing of any secondary prevention medication. Use of statins (adjusted hazard ratio=0.57 [95% CI, 0.53-0.61]), RAAS inhibitors (adjusted hazard ratio=0.78 [0.73-0.84]), and platelet inhibitors (adjusted hazard ratio=0.74 [0.68-0.80]) were associated with reduced long-term mortality irrespective of socioeconomic status. Conclusions Secondary prevention medications are dispensed less often after CABG to patients with low income. Underusage of secondary prevention medications after CABG is associated with increased mortality risk independently of income and extent of education.

Postoperative platelet function is associated with severe bleeding in ticagrelor-treated patients.

OBJECTIVES: Preoperative testing of platelet function predicts bleeding risk in cardiac surgery patients treated with dual antiplatelet therapy, but the value of postoperative platelet function testing, reflecting both preoperative antiplatelet therapy and perioperative changes in platelet function, has not been evaluated. METHODS: Seventy-four patients with acute coronary syndrome treated with acetylsalicylic acid and ticagrelor within 5 days before cardiac surgery were included in a prospective observational study. Platelet aggregation induced by adenosine diphosphate, arachidonic acid and thrombin receptor-activating peptide was assessed with multiple electrode impedance aggregometry immediately before surgery and 2 h after weaning off cardiopulmonary bypass. Receiver operating characteristic curves were used to determine any association between platelet aggregation and severe bleeding according to the universal definition of perioperative bleeding in adult cardiac surgery. RESULTS: Severe bleeding occurred in 25 of 74 patients (34%). Preoperative and postoperative adenosine diphosphate-induced platelet aggregations were associated with bleeding, with comparable areas under the receiver operating characteristic curve [0.77 (95% confidence interval 0.65-0.89) vs 0.75 (0.62-0.87)]. Postoperative arachidonic acid- and thrombin receptor-activating peptide-induced aggregation had markedly smaller areas under the curve. There were significant correlations between preoperative and postoperative platelet aggregation induced by adenosine diphosphate (r2 = 0.77, P < 0.001), arachidonic acid (r2 = 0.24, P < 0.001) and thrombin receptor-activating peptide (r2 = 0.21, P < 0.001) but with large interindividual variations. CONCLUSIONS: Poor postoperative platelet function was associated with severe bleeding, with accuracy comparable to that of preoperative platelet function. There was a correlation between preoperative and postoperative platelet function, but the predictability in an individual patient was limited.

A single sequential snake saphenous vein graft versus separate left and right vein grafts in coronary artery bypass surgery: a population-based cohort study from the SWEDEHEART registry†.

OBJECTIVES: Our goal was to compare short- and midterm outcomes after coronary artery bypass grafting (CABG) using 2 different revascularization strategies. METHODS: A total of 6895 patients were included who had CABG in Sweden from 2009 to 2015 using the left internal mammary artery to the left anterior descending artery and either a single sequential saphenous vein graft connecting the left and right coronary territories to the aorta (snake graft, n = 2122) or separate vein grafts to both territories (n = 4773). Data were obtained from the Swedish Web System for Enhancement of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) and the Swedish Patient Registry. The groups were compared using adjusted logistic regression for short-term (30-day) and Cox regression and flexible parametric survival models for midterm outcomes. Primary outcome was a composite of all-cause mortality, myocardial infarction (MI), reangiography and new revascularization. The median follow-up time was 35 months. RESULTS: At 30 days, the incidences of the composite end point [odds ratio (OR) 1.31, 95% confidence interval (CI) 1.03-1.68; P = 0.03] and reangiography (OR 1.51, 95% CI 1.07-2.14; P = 0.02) were higher in the snake group. There was also a trend towards higher mortality (OR 1.47, 95% CI 0.97-2.22; P = 0.07). The event rates during the complete follow-up period were 6.5 (5.9-7.2) and 5.7 (5.3-6.1) per 100 person-years for the snake group and the separate vein group, respectively. At the midterm follow-up, no significant difference between the groups could be shown for the composite end point [hazard ratio (HR) 1.08, 95% CI 0.95-1.22; P = 0.24], mortality (HR 0.95, 95% CI 0.79-1.14; P = 0.56), MI (HR 1.11, 95% CI 0.88-1.41; P = 0.39) or new revascularization (HR 1.19, 95% CI 0.94-1.50; P = 0.15), whereas reangiography remained more common in the snake group (HR 1.25, 95% CI 1.05-1.48; P = 0.01). CONCLUSIONS: Snake grafts were associated with a higher rate of early postoperative complications, possibly reflecting a more demanding surgical technique, whereas midterm outcomes were comparable. Based on these data, one strategy cannot be recommended over the other.

Adrenaline enhances in vitro platelet activation and aggregation in blood samples from ticagrelor-treated patients.

BACKGROUND: Temporarily improved platelet reactivity may reduce the bleeding in patients on antiplatelet therapy who have ongoing bleeding or who are in need of acute surgery. Adrenaline can bind to adrenergic α2A-receptors on platelets and potentially enhance platelet reactivity. OBJECTIVE: To assess if adrenaline can improve adenosine diphosphate (ADP)-induced platelet aggregation and activation in blood samples from patients on dual antiplatelet therapy with acetylsalicylic acid (ASA) and the ADP-receptor antagonist ticagrelor. METHODS: Blood samples were collected from a total of forty acute coronary syndrome patients on dual antiplatelet therapy with ASA and ticagrelor. ADP-induced platelet aggregation (by impedance aggregometry) and activation (by flow cytometry) were assessed before and after supplementation with adrenaline and/or platelet concentrate. RESULTS: Adrenaline supplementation (770 nmol L-1) increased median ADP-induced aggregation from 15 (25-75th percentiles: 10-20) to 26 (18-38) aggregation units. The effect was independent of concomitant platelet supplementation. Adrenaline also increased ADP-induced platelet activation: from 40% (36-54%) to 83% (74-88%) platelets with active fibrinogen receptor (binding PAC-1) and from 13% (7-21%) to 35% (18-50%) P-selectin-expressing platelets. CONCLUSIONS: Adrenaline potentiated ADP-induced platelet aggregation and activation in blood samples from ticagrelor-treated patients. Adrenaline infusion may be a new method to enhance platelet function in ticagrelor-treated patients who are in need of acute surgery or have ongoing bleeding. In vivo studies are needed to confirm the present results.

Platelet function recovery after ticagrelor withdrawal in patients awaiting urgent coronary surgery.

Objective: Dual antiplatelet therapy with ticagrelor and aspirin is associated with an increased risk of perioperative bleeding complications. Current guidelines recommend therefore discontinuation of ticagrelor 5 days before surgery to allow sufficient recovery of platelet function. It is not known how the time to recovery varies between individual patients after discontinuation of ticagrelor. Methods: Twenty-five patients accepted for urgent coronary artery bypass surgery and treated with ticagrelor and aspirin were included in a prospective observational study. Platelet aggregation was evaluated with impedance aggregometry at five timepoints 12-96 h after discontinuation of ticagrelor. In a subset of patients ( n = 15), we also tested the ex vivo efficacy of platelet concentrate supplementation on platelet aggregation. Results: There was a gradual increase in mean adenosine diphosphate-induced platelet aggregation after discontinuation of ticagrelor. After 72 h, mean aggregation was 38 ±23 aggregation units (U), which is above a previously suggested cut-off of 22 U, when patients can be operated without increased bleeding risk. However, there was a large interindividual variability (range 4‒88 U at 72 h) and 6/24 patients (25%) had <22 U after 72 h. Ex vivo administration of platelet concentrate did not improve adenosine diphosphate-induced aggregation at any timepoint after ticagrelor discontinuation. Conclusions: Adenosine diphosphate-induced aggregation was acceptable after 72 h in the majority of patients but with a large interindividual variability. Due to the large variability, platelet function testing may prove to be a valuable tool in timing of surgery in patients with ongoing or recently stopped ticagrelor treatment. Adenosine diphosphate-induced aggregation was not improved by addition of platelet concentrate.

Hemofiltration in ex vivo lung perfusion-a study in experimentally induced pulmonary edema.

OBJECTIVES: Ex vivo lung perfusion (EVLP) can potentially reduce pulmonary edema. In a pig model with induced pulmonary edema, we evaluated the effect of hemofiltration (HF) during EVLP on lung function, perfusate oncotic pressure, and lung weight. METHODS: In anesthetized pigs (n = 14), pulmonary edema was induced by a balloon in the left atrium, combined with crystalloid infusion (20 mL/kg), for 2 hours. The lungs were harvested, stored cold for 2 hours, and randomized to EVLP, with or without a hemofilter (HF and noHF groups, respectively, n = 7 for each). EVLP was performed with cellular perfusate at a hematocrit of 10% to 15%. Oncotic pressure, lung performance, and weight were measured before and after 180 minutes of EVLP reconditioning with or without HF. RESULTS: After in vivo induction of edema, arterial oxygen tension (Pao2)/inspired oxygen fraction (Fio2), and compliance decreased by 63% and 16%, respectively. Pao2/Fio2 was considerably improved at first evaluation ex vivo in both groups. HF increased oncotic pressure by 43% and decreased lung weight by 15%. The effects were negligible in the noHF group. Compliance decreased in both groups during reconditioning, although less so in the HF group (P < .05). Pao2/Fio2, shunt fraction, and oxygen saturation remained unchanged in both groups. Pulmonary flow index decreased in both groups, and was partially reversed by nitroglycerin. Dorsal atelectatic consolidations were seen in both groups. CONCLUSIONS: In this lung-edema model, EVLP reconditioning with hyperoncotic solution did not affect the degree of lung edema. HF during EVLP increased perfusate oncotic pressure, decreased lung weight with beneficial effects on compliance, but did not improve lung oxygenation capacity.

Pulmonary artery dissection in a patient with undiagnosed pulmonary hypertension--A case report and review of literature.

Pulmonary artery dissection is rare and highly lethal and most reports in the literature are from autopsies. We describe a patient with undiagnosed primary pulmonary hypertension suffering from pulmonary artery dissection that subsequently underwent surgical repair and in addition review the current literature on this topic.

Pressure reflection in the pulmonary circulation in patients with severe mitral regurgitation indicates adverse postoperative outcome.

OBJECTIVES: Severe pulmonary hypertension (PH) is a known risk factor in valvular surgery. In the present study, we hypothesized that the assessment of pressure reflection (PR) in the pulmonary circulation, indicating increased pulmonary vascular resistance, might improve the identification of patients with increased morbidity and mortality following surgery for severe mitral regurgitation. METHODS: A total of 103 patients without atrial fibrillation were divided into three groups: Group 1 (n = 48), patients without PR; Group 2 (n = 36), patients with PR and pulmonary artery systolic pressure (PASP) ≤ 60 mmHg and Group 3 (n = 19), patients with PR and PASP >60 mmHg. Three variables related to PR were selected: the acceleration time in the right ventricular outflow tract (RVOT), the interval between peak velocity in the RVOT and peak tricuspid regurgitant jet velocity and the right ventricular pressure increase after peak RVOT velocity. RESULTS: There were no differences between groups in age, ejection fraction, need for coronary bypass grafting or creatinine. Patients with PR (Groups 2 and 3) had more use of vasoactive drugs (overall P < 0.0001, Group 1 vs Group 2 P = 0.018). The proportion of patients with >24 h in the intensive care unit was 27% in Group 1, 54% in Group 2 and 84% in Group 3 (overall P < 0.0001, Group 1 vs Group 2 P = 0.006). The in-hospital mortality in patients without PR (n = 49) was 0% compared with 10.9% in patients with PR (P = 0.029). CONCLUSIONS: Echocardiography assessment of PR in the pulmonary circulation and severe PH may identify patients with adverse outcome following mitral surgery.

Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development.

The naevoid basal cell carcinoma syndrome (NBCCS) is caused by mutations in the hedgehog receptor PTCH gene. It is characterized by developmental defects and a predisposition to the development of certain tumours, such as basal cell carcinoma, medulloblastoma and meningioma, and potentially fetal rhabdomyomas and embryonal rhabdomyosarcomas. This study aimed to analyse PTCH status in an NBCCS patient with fetal rhabdomyoma and to investigate whether deregulation of hedgehog signalling, as shown by altered expression of hedgehog pathway components and/or genetic imbalances, is a general finding in sporadic rhabdomyomas and rhabdomyosarcomas. The NBCCS patient had a novel PTCH germ-line mutation, 1370insT, and developed a fetal rhabdomyoma that harboured a 30 bp in-frame deletion in the second allele resulting in homozygous inactivation of PTCH. Sporadic rhabdomyomas and rhabdomyosarcomas showed overexpression of PTCH (43/43) and GLI1 (41/43) mRNA, as determined by in situ hybridization, indicating ongoing active hedgehog signalling. Immunohistochemical staining revealed a subgroup of fetal rhabdomyomas and embryonal rhabdomyosarcomas (12/34) lacking PTCH immunoreactivity. Four of nine informative fetal rhabdomyomas and embryonal rhabdomyosarcomas showed loss of heterozygosity (LOH) in the PTCH region with two of these (one fetal rhabdomyoma and one embryonal rhabdomyosarcoma) also showing LOH in the SUFU region. These findings suggest that haploinsufficiency for the two tumour suppressor genes PTCH and SUFU, which are both active in the same signalling pathway, may be important for tumour development. Based on our results we propose that the pathogenesis of rhabdomyoblastic tumours, particularly fetal rhabdomyomas and embryonal rhabdomyosarcomas, involves deregulation of the hedgehog signalling pathway.