Effects of metoprolol therapy on cardiac gap junction remodelling and conduction in human chronic atrial fibrillation.

BACKGROUND AND PURPOSE: We investigated the influence of metoprolol on gap junction proteins connexin43 (Cx43) and connexin40 (Cx40) in atrial tissue from patients with/without atrial fibrillation (AF). EXPERIMENTAL APPROACH: Left atrial tissue samples from 160 patients with AF or sinus rhythm (SR) with or without metoprolol (mean daily dose: 65.2 ± 9.1 mg·day⁻¹) were analysed for Cx43 and Cx40 by Western blot and immunohistology. Transverse and longitudinal conduction velocities were determined by 64 multi-electrode mapping. KEY RESULTS: Both Cx43 and Cx40 expression were significantly increased in patients with AF versus SR. Cx43-expression in AF was significantly higher in patients receiving metoprolol, while Cx40 expression was unaffected by metoprolol treatment. In AF, the ratio of lateral/polar expression of Cx43 and Cx40 was enhanced due to increased expression at the sides of the cells (lateral) and a loss at the cell poles. This AF-induced increase in lateral/polar expression of Cx43, but not of Cx40, was significantly antagonized by metoprolol treatment. Functionally, in AF patients, transverse conduction velocity in atrial samples was significantly enhanced and this change was also significantly antagonized by metoprolol. CONCLUSIONS AND IMPLICATIONS: AF induced enhanced lateral expression of Cx43 and Cx40 together with enhanced transverse conduction velocity in left atrial tissue. Alterations in localization of Cx43 and conduction changes were both antagonized by metoprolol, showing that pharmacological modulation of gap junction remodelling seems, in principle, possible. This finding may open new approaches to the development of anti-arrythmic drugs.

Activation of cardiomyocytes depending on their proximity to human bone marrow stem cells.

Our study aimed to elucidate whether bone marrow stem cell (BMC) treatment might result in a cellular response in cardiomyocytes IN VITRO. Subconfluent neonatal rat cardiomyocyte cultures were cocultured for three days with Vybrant CM-DiI labeled BMC from human sternal bone marrow and underwent immunohistological staining for the proto-oncogene c-Myc and the cell cycle proteins CDK2, CDK4 and ATF-3. ß-adrenoceptor density was analyzed using [125I]-iodocyanopindolol (ICYP) histoautoradiography. Quantitative analysis of immunohistochemical images revealed significantly increased expression and upregulation of c-Myc, and its downstream targets ATF-3, CDK2 and CDK4 in neighboring cardiomyocytes to BMC, depending on their distance to the BMC compared to cardiomyocytes far from the BMC. Histoautoradiography revealed a significantly higher ß-adrenoceptor density in cardiomyocytes in the immediate vicinity to the BMC. With increasing distance to the BMC, ß-adrenoceptor density in cardiomyocytes declined. Thus, a small number of BMC can affect a larger number of cardiomyocytes by activating an intracellular signaling cascade and enhancing ß-adrenoceptor density.

[Preoperative and postoperative imaging in patients with transposition of the great arteries]. / Prä- und Postoperative Bildgebung bei Patienten mit Transposition der großen Gefäße.

Transposition of the great arteries (TGA) is a rare disease representing not more than 3-5% of all congenital heart diseases. TGA is a cardiac anomaly in which the aorta arises entirely or largely from the morphological right ventricle and the pulmonary artery from the morphological left ventricle. This is called a ventriculo-arterial discordant connection and when accompanied by an atrio-ventricular concordant connection it is called a complete or D-transposition (D-TGA). The terms congenitally corrected TGA (ccTGA) or L-TGA describe an atrio-ventricular discordant connection. In D-TGA survival can only be achieved if additional shunting is simultaneously present, which possibly has to be created post-natal by the so-called Rashkind maneuver.Nowadays, an early anatomic correction using the arterial switch operation is the treatment of choice. Up to the 1980s, an atrial switch operation according to Senning/Mustard was performed. Apart from echocardiography the imaging modality of choice is usually MRI to assess the complex postoperative anatomy, viability of the myocardium and to perform a volumetric and functional assessment, including MR flow measurements. Multidetector computed tomography (MDCT) is used if there are contraindications to MRI or if an assessment of cardiac and especially coronary anatomy is the main interest.

Rupture of the papillary muscle of the tricuspid valve - echocardiographic diagnosis of a rare anomaly leading to critical tricuspid valve regurgitation in the newborn.

We present the case of a male full-term neonate who presented at 4 h of age with severe cyanosis unresponsive to mechanical ventilation and oxygen supplementation. The diagnosis of rupture of the papillary muscle of the tricuspid valve was made by echocardiography. Preoperative stabilization was achieved by adding nitric oxide and extracorporeal membrane oxygenation therapy could be avoided. Corrective surgery was successfully performed on the 7th day of life. Follow-up examination at 2 months of age revealed an excellent postoperative result. Perinatal rupture of the papillary muscle and/or chordae tendineae of the tricuspid valve is exceedingly rare and usually lethal when untreated or diagnosed late. Therefore, timely diagnosis is mandatory for adequate preoperative management and subsequent surgical treatment.

Transcatheter aortic valve closure to treat severe aortic regurgitation in a patient failing stage I palliation for hypoplastic left heart syndrome.

We present a patient with borderline left ventricle, in whom significant aortic regurgitation after failed attempt of biventricular repair with balloon valvuloplasty and consecutive Norwood stage 1 procedure substantially contributed to persisting hemodynamic instability. Transcatheter closure of the aortic valve using an Amplatzer(R) septal occluder was performed and led to clinical stabilization. At medium-term follow-up, there was neither residual aortic regurgitation nor obstruction of the coronary artery origins.

Ischemic and inflammatory lung impairment by extracorporeal circulation: effect of PARP-inhibition by INO1001.

OBJECTIVE: Among the complications after cardiac surgery the development of postoperative pulmonary distress is a serious problem. Typically, the patients leave the operating theatre with good blood gas values and O(2)-saturation, but develop their respiratory problems within the next hours/days. We investigated whether extracorporeal circulation may induce biochemical and histological changes in the lungs which may help to explain this development. METHODS: Piglets (6-10 kg) were anaesthetized using isoflurane and underwent extracorporeal circulation (ECC) with hypothermic (25-28 degrees C) cardioplegic arrest for 90 min followed by 3h reperfusion. An additional group received a poly(ADP-ribose) polymerase (PARP)-Inhibitor, INO1001. Cardiopulmonary monitoring was performed during the whole procedure. Finally, lungs were explanted and investigated by histomorphometry and immunohistology for heat shock protein HSP70 (indicator for cellular damage) and TNFalpha in comparison to normal piglets without ECC. RESULTS: Histologically we found significant swelling of the type I alveocytes (thickness increased from 2.4 to 3.2 microm), interstitial oedema, intra-alveolar erythrocyte (4.8 versus 0.4 erythrocytes/alveole) and granulocyte accumulation and fibrinous exudates. There was a significant up-regulation of TNFalpha and of the cellular repair enzyme HSP70, while in control piglets only minimal levels were observed. INO1001 significantly reduced ECC-induced elevation in TNFalpha and in HSP70. Despite the dramatic changes after heart-lung-machine (HLM), blood gases and gas transport were almost not affected at that time. CONCLUSIONS: ECC can lead to early significant histological and histochemical changes which have similarities with a beginning early stage shock lung, although - at 3h reperfusion - gas transport is still sufficient. INO1001 can partially antagonize these changes.

Catheter interventional treatment of Sano shunt obstruction in patients following modified Norwood palliation for hypoplastic left heart syndrome.

UNLABELLED: Shunts placed between the right ventricle and the pulmonary arteries, called Sano shunts, recently modified Norwood surgery for hypoplastic left heart syndrome. Patients with Sano shunts tend to be more stable thus reducing the interstage mortality of this still challenging complex cardiac anomaly. However, Sano shunt stenosis may develop and is a life threatening complication. We report on our experience in patients with Sano shunt obstruction. PATIENTS: Eight infants presenting with decreasing transcutaneous oxygen saturations (43-63%, median 58%) following modified Norwood procedures were shown to have relevant Sano shunt stenosis. None was suited for early stage two surgery (cavopulmonary Glenn anastomosis). Catheterization was performed at the age of 21 to 112 (median 85) days. Weight was 3.9 to 6.0 (median 4.8) kg. TECHNIQUE: Femoral 5F venous access. Long sheaths were not used. The shunt was entered with a 4F right Judkins catheter and a selective angiography was performed. The stenosis was localized proximal in 5, distal in 1 and proximal and distal in 2 patients. Ten coronary stents were implanted. RESULTS: There were no procedure related complications. Oxygen saturation increased immediately to 75-86% (median 80%) and remained above 70% during follow-up in all. Seven patients had successful stage two surgery 61-288 (median 134) days after stent implantation, one is awaiting this. CONCLUSIONS: Sano shunt obstruction can be treated safely and effectively by stent implantation. Early in-stent restenosis does not seem to be a problem.

Left ventricular diverticulum repair in a newborn.

We report on a male newborn requiring repair of a huge left apical diverticulum leading to progressive heart failure and extensive ventricular arrhythmia. At the age of 11 days, a modified Dor procedure using an autologous endoventricular pericardial patch was performed. Postoperatively, a significant reduction of ventricular extrasystole was evident. One year postoperatively, the infant demonstrates a normal cognitive and somatic development without clinical signs of cardiac failure.

Moderate versus deep hypothermia for arterial switch operation.

BACKGROUND: We evaluated the impact of moderate versus deep intraoperative hypothermia on postoperative morbidity in patients receiving a standard arterial switch operation (ASO). METHODS: 71 newborns underwent ASO from 9/98 onwards. Patients were operated using moderate hypothermia (M, 24 degrees C to 30 degrees C, n=21) or deep hypothermia (D, 16-22 degrees C, n=50). Mean patient age was 9.5 (M) versus 10 (D) days, body weight 3.6+/-0.7 (M) versus 3.8+/-0.9 kg (D), P=n. s. Coronary anatomy was complex in 9.5% (M) versus 16% (D) of patients; additional VSD was present in 23.8 (M) versus 38% (D) of the patients, respectively. Mean follow-up is 2.3+/-1.6 years. RESULTS: Intraoperative rectal temperature was 25+/-2 degrees C (M) and 19+/-2 degrees C (D). Cross-clamping time was 95+/-24 (M) versus 108+/-31 min (D), P=n. s. Conventional ultrafiltration was performed at 114+/-46 (M) versus 129+/-69 ml/kg (D), P=n. s. One patient (D) with complex anatomy suffered myocardial ischemia required ECMO support and died. In-hospital mortality was 1.4%. All other patients were safely weaned from extracorporeal circulation with moderate inotropic support. Secondary chest closure was performed in 33% (M) versus 54 % (D) of the patients. Patients were extubated after 7.4 (M) versus 6 (D) days. There was no renal failure and no other serious complications. CONCLUSIONS: ASO can be safely performed using moderate hypothermia, even with complex anatomy, leading to comparatively good results compared to a conventional approach.

Stent implantation for recurrent interatrial obstruction in an infant with hypoplastic left heart syndrome.

We report the case of a 19-month-old girl with hypoplastic left heart syndrome who, after Norwood stage 1 and 2 procedures, developed recurrent interatrial obstruction and was treated effectively with stent implantation. The stent was explanted electively 14 months after implantation and showed almost no endothelium formation. Therefore, there was no need for redo atrioseptectomy and the surgical intervention could be staged electively.

Leiomyosarcoma--an unusual cause of right ventricular outflow tract obstruction.

A 76-year-old female patient was admitted with progressive dyspnea on exertion, signs of right ventricular failure, and severe pulmonary stenosis. Intraoperatively an infiltrating right ventricular outflow tract (RVOT) tumor was found and xenograft conduit replacement was performed successfully. Histological examination revealed primary cardiac leiomyosarcoma, the patient was discharged and is in good health condition at 9 months' follow-up. Unusual causes of RVOT obstruction should be considered.

Syncope in a child owing to intramural course of the left coronary artery.

UNLABELLED: Coronary abnormalities are a rare cause of syncope or sudden death in childhood or adolescence. We report on a 14-y-old girl who had suffered for many years from repeated syncope after or during exertion. She had to be resuscitated twice. The left coronary artery arose from the right coronary aortic sinus and took a proximal intramural course. After successful reimplantation, the patient has now been free of symptoms for 12 mo. The pitfalls of differential diagnosis of this rare anomaly are discussed. CONCLUSION: Investigation of the coronary anatomy is indicated in otherwise unexplained chest pain, syncope or life-threatening events.

Cardiac malformations associated with the Holt-Oram syndrome--report on a family and review of the literature.

The Holt-Oram syndrome (HOS) is characterized by mild-to-severe congenital cardiac defects and skeletal abnormalities of the upper limb. The most common cardiac disorder is an ostium secundum atrial septal defect (ASD), followed by ventricular septal defect (VSD) and ostium primum ASD. Electrocardiographic abnormalities, such as various degrees of atrioventricular block, have also been reported. In addition, hypoplastic peripheral vessels of the upper limbs have been observed. Here, we will report about a family with three sons having HOS, and we will detail the cardiac spectrum of HOS as reported in the literature.

Prospectively randomized comparison of different mechanical aortic valves.

BACKGROUND: The aim of this prospectively randomized study was to evaluate the hemodynamic and functional outcomes after aortic valve replacement with 3 different bileaflet mechanical valves. METHODS AND RESULTS: Three hundred consecutive patients were randomly assigned to receive ATS (n=100), Carbomedics (n=100), or St Jude Medical Hemodynamic Plus (n=100) mechanical aortic valve replacement. There were no significant differences regarding patient age (average 61+/-8 years), body surface area (1.9+/-0.2 m(2)), left ventricular function (ejection fraction 0.59+/-0.17), and presence of aortic stenosis (90%, 89%, and 91%), respectively. All patients had postoperative as well as 6-month and 1-year follow-ups that included transthoracic echocardiography. Multivariate statistical analysis was performed. Implanted valve sizes were comparable at 24+/-2 (ATS), 23.7+/-1.6 (CM), and 23.6+/-1.9 (SJMHP) mm (NS). At 1-year follow-up, the following incidence of events was noted: death 3/1/1, all non-valve related; stroke 0/1/1; trivial transvalvular incompetence 3/3/2; paravalvular leak 2/3/2; and reoperation 0/1/1, respectively (NS). Transvalvular flow velocities were 2.5/2.6/2.4 m/s postoperatively (P:=0.03) and 2.4/2.4/2.3 m/s at 6-month follow-up, respectively (NS). There was a significant decrease in left ventricular mass for all patients but no significant differences among the groups. CONCLUSIONS: There are no clinically relevant differences among the tested bileaflet aortic valves. Regardless of valve type, there was a low complication rate. On the basis of these findings, all 3 bileaflet prostheses are well suited for aortic valve replacement.

Combined stentless mitral valve implantation and radiofrequency ablation.

BACKGROUND: The aim of this study was to evaluate the results of combined stentless mitral valve (SMV) replacement and intraoperative radiofrequency ablation for chronic atrial fibrillation (IRAAF) to restore physiologic hemodynamic function. METHODS: Since July 1998 12 patients (72+/-4 years, 10 women, mitral stenosis/mitral incompetence 8/4, NYHA 3.3+/-0.4, CI 1.8+/-0.5) had SMV implantation and received additional IRAAF by inducing continuous left atrial lesion lines from the MV annulus to all four pulmonary veins and to the atriotomy. RESULTS: The flexible SMV was implanted at the papillary muscles and at the annulus using a conventional (n = 6) or a minimally invasive approach (n = 6). Sinus rhythm was successfully restored in 10 of 12 patients with 6- and 12-months' follow-up; 2 required DDD-pacemaker implantation. However, in the early postoperative period several interventions including medical treatment (sotalol or amiodarone) in 9 and electrical cardioversion in 7 patients was required. Two patients required reinterventions: 1 cardioversion and 1 amiodarone medication after 3 and 6 months, respectively. At echocardiography the SMV demonstrated good hemodynamic function and atrial contraction. CONCLUSIONS: Restoration of physiologic cardiac function by SMV implantation and IRAAF is advantageous and no further anticoagulation is required.

Hemodynamically optimized temporary cardiac pacing after surgery for congenital heart defects.

Disturbance of normal AV synchrony and dyssynchronous ventricular contraction may be deleterious in patients with otherwise compromised hemodynamics. This study evaluated the effect of hemodynamically optimized temporary dual chamber pacing in patients after surgery for congenital heart disease. Pacing was performed in 23 children aged 5 days to 7.7 years (median 7.3 months) with various postoperative dysrhythmias, low cardiac output, and/or high inotropic support and optimized to achieve the highest systolic and mean arterial pressures. The following four pacing modes were used: (1) AV synchronous or AV sequential pacing with individually optimized AV delay in 11 patients with first- to third-degree AV block; (2) AV sequential pacing using transesophageal atrial pacing in combination with a temporary DDD pacemaker for atrial tracking and ventricular pacing in three patients with third-degree AV block and junctional ectopic tachycardia, respectively, who had poor signal and exit block on atrial epicardial pacing wires; (3) R wave synchronized atrial pacing in eight patients with junctional ectopic tachycardia and impaired antegrade AV conduction precluding the use of atrial overdrive pacing; (4) Atrio-biventricular sequential pacing in two patients. Pressures measured during optimized pacing were compared to baseline values at underlying rhythm (13 patients with first-degree AV block or junctional ectopic tachycardia) or during pacing modes commonly used in the given clinical situation: AAI pacing (1 patient with slow junctional rhythm and first-degree AV block during atrial pacing), VVI pacing (2 patients with third-degree AV block and exit block and poor sensing on epicardial atrial pacing wires) and dual-chamber pacing with AV delays set to 100 ms (atrial tracking) or 150 ms (AV sequential pacing) in 7 patients with second- to third-degree AV block and functional atrial pacing wires. Optimized pacing led to a significant increase in arterial systolic (mean) pressure from 71.5 +/- 12.5 (52.3 +/- 9.0) to 80.5 +/- 12.2 (59.7 +/- 9.1) mmHg (P < 0.001 for both) and a decrease in central venous (left atrial) pressure from 12.3 +/- 3.4 (10.5 +/- 3.2) to 11.0 +/- 3.0 (9.2 +/- 2.7) mmHg (P < 0.001 and < 0.005, respectively). In conclusion, several techniques of individually optimized temporary dual chamber pacing leading to optimal AV synchrony and/or synchronous ventricular contraction were successfully used to improve hemodynamics in patients with heart failure and selected dysrhythmias after congenital heart surgery.

[Extracorporeal membrane oxygenation in the treatment of acute respiratory failure in full-term neonates]. / Pouzití mimotelní membránové oxygenace v terapii akutního respiracního selhání u donosených novorozencu.

OBJECTIVE OF STUDY: Evaluation of success of extracorporeal membrane oxygenation, EMCO) in the treatment of acute respiratory failure in mature neonates. TYPE OF STUDY: Clinical pilot study of the EMCO centre. SETTING: Institute for the Care of Mother and Child, Prague. MATERIAL AND METHOD: In 12 consecutive patients with severe acute respiratory distress syndrome and/or circulatory failure of different etiology who met the indication criteria the method of venoarterial EMCO was used. RESULTS: Venoarterial extracorporeal membrane oxygenation was successful in 75% patients who survived. Four patients died (1x syndrome of cerebral death associated with severe hypoxic-ischaemic encephalopathy, 2x severe irreversible haemorrhage, into the abdominal and thoracic cavity, 1x periventricular intraventricular haemorrhage grade III.). The mean period of EMCO was 71.4 +/- 31.7 hours (range 25-130 hours). On comparison of the surviving group (S) and the non-surviving group (NS) there was a significant difference in the necessity of continuous inotropic adrenaline support during EMCO. In patients who died necropsy confirmed irreversible multiorgan failure. CONCLUSION: In indicated cases extracorporeal membrane oxygenation remains the method of choice in critically ill mature neonates. A prognostically adverse factor is the necessity of inotropic support and haemodialysis during EMCO.

[Occult fibrin production during surgery in cyanotic congenital heart defects and extracorporeal circulation]. / Skrytá produkce fibrinu pri operacích cyanotických vrozených srdecních vad v mimotelním obehu.

In 10 patients with complex cyanotic congenital defects detailed coagulation examinations were made at the beginning and end of the extracorporeal circulation after neutralization of heparin by protamine and the results were compared with a control examination, made before general heparinization, after introduction into general anaesthesia. The authors examined the activated period of blood (ACT) by means of testing tubes with a celite activator (Hemochron) as well as the HR-ACT test with a kaolin activator (Medtronic) for comparison of the results. The authors assessed quantitatively plasma levels of heparin, antithrombin III and fibrinopeptide A which is a sensitive indicator of intravascular coagulation. They assessed also the fibrinogen level and total number of thrombocytes in the blood stream. The degree of haemodilution was recorded as well as the temperature at the periods of assessment. The values of both ACT test were within the range of values above 420 secs., evaluated according to the authors protocol as adequate for total heparinization during operations under conditions of extracorporeal circulation. Despite of this heparin levels lower than those recommended in the literature were found, as well as reduced antithrombin III levels during extracorporeal circulation and a rise of fibronopeptide A levels at the end of extracorporeal circulation which suggest latent fibrin production in the patients. Laboratory results were compared with clinical symptoms of post-operation bleeding. In 50% patients after surgery signs of increased haemorrhage in the surgical field and from thoracic drains were observed, in two patients the surgical wound had to be revised. Laboratory tests revealed in two patients thrombocytopenia after surgery, one patient had a prothrombin test reduced below 45% and in one patient there was a significantly reduced fibrinogen level calling for supplementation of this factor. After improvement of the laboratory results and surgical treatment haemostasis returned to normal. All patients survived the operation and were discharged from hospital to domestic treatment.

[Prenatal diagnosis and therapy of congenital diaphragmatic hernia]. / Prenatální diagnostika a terapie kongenitální diafragmatické hernie.

The diagnosis and treatment of congenital diaphragmatic hernia, CDH, is an interdisciplinary problem. The patient concentration with prenatally diagnosed CDH for comprehensive examination with subsequent decision on the type of delivery improves the prognosis of patients with CDH. Introduction of corticoid therapy in prenatally assessed CDH reduces dysfunction and surfactant deficiency and can reduce the degree of respiratory failure during delivery. In very early prenatally assessed CDH it is possible to consider the possibility of combined corticoid and TRH (thyroxin releasing hormone) treatment of CDH. The authors submit also contemporary possibilities of prenatal intervention treatment of CDH (indication criteria for reconstruction operations of foetal surgery, intrauterine closure of the trachea and artificial laparoschisis). The concentration of patients with postnatally diagnosed CDH and a severe grade of acute respiratory insufficiency in a department with conventional and non-conventional artificial pulmonary ventilation incl. inhalation of NO oe extracorporeal membrane oxygenation, ECMO, is a further step towards optimation of treatment. Continuous evaluation of parameters of pulmonary functions during the pre- and postoperative period may prove that a therapeutic protocol with delayed surgery is useful.

Results of primary and two-stage repair of interrupted aortic arch.

OBJECTIVE: Early results of primary and two-stage repair of interrupted aortic arch have improved. Experience with different surgical approaches should be analysed and compared. METHODS: Forty neonates and infants with interrupted aortic arch underwent primary repair (19 patients) or palliative operation (21 patients). Twenty (50%) patients were followed-up for 5.1+/-4.3 years. All patients were regularly examined with the aim of determining clinical development, presence of residual lesions or complications and need for re-intervention. Aortic arch and the left ventricular outflow tract growth were assessed by echocardiographic examination. Data from hospital and outpatient department records were analysed. RESULTS: The early mortality was 61.9% after palliative operations and 36.8% after the primary repair. Presence of complications (P < 0.001), earlier year of surgery (P < 0.01), bad clinical condition and acidosis (P < 0.05) represented statistically significant risk factors for death in the whole series. In seven (87.5%) out of eight early survivors, after the initial palliative operation, closure of ventricular septal defect and debanding were done, and in three (37.5%) patients, re-operation for aortic arch obstruction was also required. Out of 12 patients, after the primary repair, one required early re-operation for persistent left ventricular outflow tract obstruction and two needed late re-intervention for left bronchus obstruction. In three (25%) patients, after the primary repair, left ventricular outflow tract obstruction with a maximal systolic pressure gradient higher than 30 mmHg developed. At present, all 20 early survivors are alive. Five patients, after palliative operation, are in NYHA class 1, but in three patients, who are in class III or IV, the outcome is influenced by severe complications. All patients after the primary repair are in class I or II. CONCLUSIONS: Our experience confirmed better results after the primary repair of interrupted aortic arch, which was associated with lower mortality, prevalence of severe complications and need for re-intervention. Higher prevalence of subaortic stenosis after primary repair could be explained by patient selection early in our experience. We recommend the primary repair of interrupted aortic arch and associated heart lesions in neonates, however, in unfavourable conditions an individualised surgical approach with initial palliative surgery should be considered.