Pazopanib in advanced vascular sarcomas: an EORTC Soft Tissue and Bone Sarcoma Group (STBSG) retrospective analysis.

BACKGROUND: Pazopanib is a multitargeted tyrosine kinase inhibitor approved for the treatment of patients with selective subtypes of advanced soft tissue sarcoma (STS) who have previously received standard chemotherapy including anthracyclines. Data on the efficacy in vascular sarcomas are limited. The main objective of this study was to investigate the activity of pazopanib in vascular sarcomas. PATIENTS AND METHODS: A retrospective study of patients with advanced vascular sarcomas, including angiosarcoma (AS), epithelioid hemangioendothelioma (HE) and intimal sarcoma (IS) treated with pazopanib in real life practice at EORTC centers as well as patients treated within the EORTC phase II and III clinical trials (62043/62072) was performed. Patient and tumor characteristics were collected. Response was assessed according to RECIST 1.1. and survival analysis was performed. RESULTS: Fifty-two patients were identified, 40 (76.9%), 10 (19.2%) and two (3.8%) with AS, HE and IS, respectively. The response rate was eight (20%), two (20%) and two (100%) in the AS, HE and IS subtypes, respectively. There was no significant difference in response rate between cutaneous and non-cutaneous AS and similarly between radiation-associated and non-radiation-associated AS. Median progression-free survival (PFS) and median overall survival (OS; from commencing pazopanib) were three months (95% CI 2.1-4.4) and 9.9 months (95% CI 6.5-11.3) in AS, respectively. CONCLUSION: The activity of pazopanib in AS is comparable to its reported activity in other STS subtypes. In this study, the activity of pazopanib was similar in cutaneous/non-cutaneous and in radiation/non-radiation-associated AS. In addition, pazopanib showed promising activity in HE and IS, worthy of further evaluation.

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06).

BACKGROUND: Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. PATIENTS AND METHODS: In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. RESULTS: The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. CONCLUSIONS: Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT00544700.

Safety, clinical outcome, and fracture rate of femoropopliteal stenting using a 4F compatible delivery system.

OBJECTIVE: To determine the safety, clinical outcome, and fracture rate of femoropopliteal interventions using 4F stents. METHODS: Between January 2010 and December 2011, 112 symptomatic patients were treated by stent implantation. Ten patients were lost to follow up; therefore, 102 patients (62 men; mean age 66.4 ± 10.1 years) were retrospectively analyzed. The indication for femoropopliteal revascularization was severe claudication (Rutherford-Becker score = 3) in 63 (62%) patients and chronic critical limb ischemia (Rutherford-Becker score = 4-6) in 39 (38%). Follow up included palpation of peripheral pulses and measurement of ankle brachial index. In patients with suspected in-stent restenosis duplex ultrasonography was performed. In 2013, patients were asked to return for a fluoroscopic examination of the stents. RESULTS: 114 lesions (Trans-Atlantic InterSociety Consensus-C and D, n = 45) were treated with 119 stents (Astron Pulsar, n = 42; Pulsar-18, n = 77). Lesions were long (≥100 mm) in 49 cases and heavily calcified in 35. Stents were long (≥120 mm) in 46 cases. Ten stents were partially overlapped. The technical and clinical success rates were 100%. Two puncture related complications were noted, neither of which required surgical repair. Eleven patients died (myocardial infarction, n = 4; stroke, n = 2; cancer, n = 5) and nine patients underwent major amputation (above knee, n = 4). The primary patency rate was 83% at 6 months and 80% at 12 months. The primary assisted patency rate was 97% at 6 months and 94% at 12 months. The secondary patency rate was 86% at 6 months and 85% at 12 months. The prevalence of fractures was 26% (type III and IV, 10%) after an average follow up of 25 months. CONCLUSION: Femoropopliteal stenting using a 4F compatible delivery system can be accomplished with a low complication rate, acceptable fracture rate, and with similar 12 month patency and revascularization rates as their 6F counterparts.

SAKK57/16 Nab-paclitaxel and Gemcitabine in Soft Tissue Sarcoma (NAPAGE): a phase I/II trial.

BACKGROUND: To determine whether the combination of nab-paclitaxel with gemcitabine has activity in patients with pretreated soft tissue sarcoma (STS). PATIENTS AND METHODS: NAPAGE is a phase Ib/II clinical trial investigating the combination of nab-paclitaxel (nab-pc) with gemcitabine employing two cohorts. One of a dose-de-escalation phase and one of expansion. In phase I, nab-pc was given at 150 mg/m2 in combination with gemcitabine 1000 mg/m2 every two weeks, until disease progression or unacceptable toxicity. This dose was recommended for phase II (RP2D), as there was no dose limiting toxicity (DLT) or discontinuations due to adverse events (AEs). The primary endpoint of the phase II was progression-free rate (PFR) at 3 months (H0: 20%, H1:40%). The secondary endpoints included progression free survival (PFS), overall survival (OS), AEs, objective response and patient-reported outcomes (PRO). Efficacy analysis was by intention to treat. RESULTS: The 3-month PFR was 56.4% (95% confidence interval CI: 39.6-72.2%). The 3-month and 6-month PFS were 58.4% (95% CI: 41.3-72.1%) and 44.6% (95% CI: 28.4-59.5%), respectively. Median PFS was 5.3 months (95% CI: 1.4-8.2) and median OS was 12.8 months (95% CI: 10.5-39.2). The most common treatment-related grade ≥ 3 AE were neutropenia (18%), followed by anemia (2.6%), hypertension (2.6%) and alanine aminotransferase increase (2.6%). Grade 1 and grade 2 peripheral sensory neuropathy (PNP) occurred in 15.4% and 20.5%, respectively. No grade 3-4 PNP was reported. CONCLUSIONS: Combining nab-pc and gemcitabine is safe. Promising activity is observed in pretreated STS patients with manageable toxicity. This regimen should be considered for further exploration.

The Role of Surgical Expertise and Surgical Access in Retroperitoneal Sarcoma Resection - A Retrospective Study.

Background: Retroperitoneal sarcoma (RPS) is a rare disease often requiring multi-visceral and wide margin resections for which a resection in a sarcoma center is advised. Midline incision seems to be the access of choice. However, up to now there is no evidence for the best surgical access. This study aimed to analyze the oncological outcome according to the surgical expertise and also the incision used for the resection. Methods: All patients treated for RPS between 2007 and 2018 at the Department of Visceral Surgery and Medicine of the University Hospital Bern and receiving a RPS resection in curative intent were included. Patient- and treatment specific factors as well as local recurrence-free, disease-free and overall survival were analyzed in correlation to the hospital type where the resection occurred. Results: Thirty-five patients were treated for RPS at our center. The majority received their primary RPS resection at a sarcoma center (SC = 23) the rest of the resection were performed in a non-sarcoma center (non-SC = 12). Median tumor size was 24 cm. Resections were performed via a midline laparotomy (ML = 31) or flank incision (FI = 4). All patients with a primary FI (n = 4) were operated in a non-SC (p = 0.003). No patient operated at a non-SC received a multivisceral resection (p = 0.004). Incomplete resection (R2) was observed more often when resection was done in a non-SC (p = 0.013). Resection at a non-SC was significantly associated with worse recurrence-free survival and disease-free survival after R0/1 resection (2 vs 17 months; Log Rank p-value = 0.02 respectively 2 vs 15 months; Log Rank p-value < 0.001). Conclusions: Resection at a non-SC is associated with more incomplete resection and worse outcome in RPS surgery. Inadequate access, such as FI, may prevent complete resection and multivisceral resection if indicated and demonstrates the importance of surgical expertise in the outcome of RPS resection.

Echocardiographic characterisation of cardiac dilatation induced by volume overload in a canine experimental model.

The aim of this study was to characterise the development of cardiac dilatation induced by chronic volume overload in 12 dogs. Bilateral arteriovenous fistulas were created between the common femoral arteries and the femoral veins, and the animals were serially studied with transthoracic echocardiography for a period of 12 weeks after the operation. Compared to the measurements obtained before the operation (week 0), the data obtained at the end of the experimental period showed significantly increased left ventricular volume measured by 2D-echocardiography (from 25.1 cm3 to 43.8 cm3, p < 0.0001 in diastole and from 8.6 cm3 to 16.8 cm3, p < 0.001 in systole), and left ventricular diameter measured by M-mode echocardiography (from 26.2 mm to 32.6 mm, p < 0.0001 in diastole and from 17.1 mm to 20.6 mm, p < 0.001 in systole). The size of the left atrium also increased in transversal (from 29.2 mm to 33.6 mm, p < 0.01) but not in longitudinal diameter. In spite of a significant cardiac chamber dilatation over the 12-week period, left ventricular systolic functional variables (fractional shortening, FS % and ejection fraction, EF %), and also the left ventricular systolic and diastolic free wall thickness remained unchanged. In this study we demonstrated that chronic progressive volume overload resulted in gradual dilatation of the canine heart, and that the pathological process can be monitored successfully by serial echocardiography. We found that left atrial dilatation occurred without the development of mitral regurgitation and/or detectable left ventricular dysfunction.

Bilateral axillobrachial and external carotid artery manifestation of giant cell arteritis: important role of color duplex ultrasonography in the diagnosis.

A 76-year-old man was admitted to our hospital with vertigo. Previously he had been extensively examined because of an increased erythrocyte sedimentation rate without any clinical symptoms. Physical examination revealed 60 mmHg blood pressure difference between the two arms. Color duplex ultrasound examination revealed bilateral extreme narrowing of the external carotid and axillobrachial artery with a dark, hypo-echoic halo around the lumen. This condition was recognized as a specific sign for giant cell arteritis (GCA), described originally in cases of temporal arteritis. The diagnosis was confirmed by biopsy of the temporal artery. In contrast to the typical cranial form of GCA -- our patient showed an unusual, bilateral large-vessel manifestation. The diagnosis was based on ultrasound images rather than on symptoms that characterize the well-known temporal form. This observation emphasizes the role of color duplex ultrasonography in the diagnosis and follow-up of GCA.

Efficient pathogen-derived resistance induced by integrated potato virus Y coat protein gene in tobacco.

The coat protein (CP) gene from potato virus Y (Hungarian isolate, PVY-H) was engineered into Agrobacterium tumefaciens binary vector for expression in different tobacco lines. Three different Nicotiana tabacum breeding lines were transformed and the integration of the CP gene was confirmed by PCR technique using genomic DNA preparations. The transcription and expression of the integrated CP gene was detected by Northern and Western blots. Pathogen-derived resistance was demonstrated by inoculation of the R1 progeny of the transformed lines with purified PVY-H. The efficiency of protection varied between different transgenic plants ranging from almost complete to no protection. Five CP expressing tobacco lines were resistant to challenge infection with PVY-H as indicated by attenuation or absence of symptom development associated with reduction or lack of detectable virus accumulation. Data from Western blots showed that there is no correlation between the level of the expressed CP and the extent of protection. This suggests that the mechanism of the observed resistance is independent of the level of CP accumulation in the transgenic tobacco plants.

Intratumoral microvessel density predicts local treatment failure of radically irradiated squamous cell cancer of the oropharynx.

PURPOSE: To determine the predictive value of intratumoral microvessel density (IMD), and of the expression of p53, vascular endothelial growth factor (VEGF) and thrombospondin-1 (TSP-1) for the radiocurability of patients with squamous cell cancer of the oropharynx. MATERIALS AND METHODS: 139 patients with squamous cell cancer of the oropharynx were radically irradiated (median dose, 74 Gy) between 1991 and 1997. Biopsies from 100 patients were processed for immunohistochemistry. IMD was determined in hot spot areas of tissue stained with anti-CD31 at a magnification of x200. Staining for p53 was considered positive if more than 10% of the cell nuclei overexpressed the protein. Immunostaining of VEGF and TSP-1 was assessed semiquantitatively. RESULTS: Increasing IMD (range, 54-282) was strongly correlated with incomplete remission of both the primary tumors (p = 0.01) and lymph node metastases (p = 0.02). Moreover, multivariate Cox regression analysis revealed local failure-free survival to decline with increasing IMD (IMD continuous: risk ratio = 1.01 per increase of 1 microvessel, p = 0. 0001; IMD categorical: 130: risk ratio = 13.01). Neither the expression of p53, nor that of VEGF or TSP-1 was associated with the treatment outcome or IMD, but VEGF and TSP-1 expression were positively correlated (p = 0.02). CONCLUSION: IMD represents a powerful and independent predictive factor for local treatment failure in radically irradiated patients with squamous cell cancer of the oropharynx.

A new model of endovascularly induced renal artery stenosis in normocholesterolemic versus hypercholesterolemic rabbits.

RATIONALE AND OBJECTIVES: The authors determine the feasibility of creating renal artery stenosis by overdilatation and deendothelialization and compare the model in normocholesterolemic versus hypercholesterolemic rabbits. METHODS: Thirty male New Zealand White rabbits were randomized into two groups: group A (n = 15) was fed a normal diet and group B (n = 15) was fed a cholesterol-rich diet 4 weeks before stenosis induction. An aortogram was performed, then the right renal artery was overdilated with an angioplasty balloon-catheter, and deendothelialized. After 6 weeks, groups A and B were compared by angiographic and pathologic study. RESULTS: Comparison of group A versus group B showed that 12 arteries (80%) versus 6 (40%) were angiographically stenotic (P < 0.05); 14 (93%) versus 12 (80%) contained neointima (NS), 12 (80%) versus 3 (20%) showed medial disorganization (P < 0.01), and 9 (60%) versus 2 (13%) presented adventitial fibrosis (P < 0.01). CONCLUSIONS: A new model of endovascularly induced renal artery stenosis has been developed in rabbits. Medial proliferation and adventitial fibrosis are more frequent in normocholesterolemic rabbits.

Mitral valve replacement and endocavitary patch repair for a giant left ventricular pseudoaneurysm.

We present a case of a giant inferior left ventricular (LV) wall pseudoaneurysm. The patient had New York Heart Association class IV heart failure due to severe mitral valve regurgitation and poor LV function. Our operative approach included right thoracotomy, excision of the mitral valve, and patch repair of the pseudoaneurysm neck from inside of the dilated LV cavity followed by mitral valve replacement. Surgery was performed without aortic cross-clamping on a normothermic perfused beating heart. The patient had an uncomplicated cardiac recovery and is doing well 15 months after surgery.

Patent foramen ovale and pulmonary embolism. An underestimated co-morbidity following cardiac surgery.

When pulmonary embolism occurs in the presence of a patent foramen ovale the sudden increase in the right heart pressure can open the defect and could cause right to left atrial shunting. This may further aggravate the already existing hypoxemia, and the direct communication between the venous and the arterial circulation increases the risk of paradoxical embolization. In this paper we present a case of postoperative pulmonary embolization in a patient with patent foramen ovale, and the effects of these co-existing conditions are reviewed. In the cardiac surgical literature such a complication has not yet been described.

Alternative technique to cannulate the descending aorta for abdominal organ procurement in a hemodynamically unstable patient.

During organ procurement, maintaining adequate organ perfusion is crucial. Hemodynamic instability may compromise organ viability and demand quick intervention, sometimes rapid, early cannulation of vessels, so that organs may be salvaged. In this case report of an unstable donor with large retroperitoneal hematoma, a surgical approach is presented that has previously not been described. The technique facilitated hemodynamic stability while allowing rapid cannulation of the retrocardiac descending aorta.

Left internal mammary artery graft retransplantation from the recipient to the donor heart: a case report.

A case of heart transplantation with concomitant coronary artery bypass graft is reported. The patient was an alternate transplant list candidate with a history of bilateral below-knee amputation and 2 previous myocardial revascularization procedures. The previously used and patent left internal mammary artery graft was successfully removed and retransplanted from the recipient to the donor heart.

3,3',5-Triiodothyronine (T3) uptake and expression of thyroid hormone receptors during the adaptation to hypothyroidism of the brain of chicken.

Thyroid hormone action in the brain is strictly regulated, since these hormones play a crucial role in the development and physiological functioning of the central nervous system. Hormone kinetics and molecular events at the nuclear receptor level during the adaptation of the brain of chicken to hypothyroidism were simultaneously investigated. Data obtained by Oldendorff's 'single-pass' technique showed a significantly higher labelled 3,3'5-triiodothyronine (125I-T3) uptake into the brain of surgically thyroidectomized (TX) 2-week-old broilers after 1 week of surgery in comparison to sham-operated (SH) and t3 supplemented (TX + T3) controls in the 10th second after the bolus injection. Telencephalons showed the highest, while cerebellum the lowest uptake intensity in all groups. In a similar arrangement of experiments the expression of the TR alpha- and TR beta nuclear thyroid receptors in the telencephalon of TX and control chickens was investigated by a semiquantitative RT-PCR-based approach for beta-actin, then amplified for thyroid receptors. The level of both the TR alpha and TR beta coding mRNA was elevated in hypothyroidism. In conclusion, the presented hormone kinetics and TR expression data provide further details of the cellular and molecular events occurring during the adaptation to hypothyroidism of the brain of chicken.

[The place and role of coronary endarterectomy in the management of ischemic heart disease]. / A coronaria endarteriectomia helye és szerepe az ischaemiás szívbetegség mütéti kezelésében.

Coronary endarterectomy is one of the oldest operation performed on the coronary arteries. In the case of multivessel coronary artery disease it is an alternative method to achieve complete myocardial revascularisation however it increases both perioperative infarction rate and mortality. Sometimes it is undoubtedly the only chance of the patient apart from heart transplantation. Since 1983 when the first coronary endarterectomy was performed in the Cardiovascular Surgical Clinic of Semmelweis Medical University of Budapest, until the end of 1990 the procedure has been used in 97 patients on 119 coronary artery segments. A new surgical technique of coronary endarterectomy is described, a detailed analysis of the cases is presented and the results are discussed.

[Combined coronary artery and heart valve surgery at the Clinic for Cardiovascular Surgery (1979-1990)]. / Coronariamütéttel kombinált szívbillentyü-sebészet az Er- és Szívsebészeti Klinikán (1979-1990).

As a result of increasing mean age of patient undergoing open heart surgery more and more combined valve and coronary surgery cases are performed. The operative risk of combined procedure is higher than that of valve replacement or coronary bypass grafting alone. In case of aortic valve disease the operation reduces the workload of the left ventricle thus decreasing the oxygen demand of the myocardium. In pure mitral valve stenosis as a consequence of valve replacement the left ventricular preload increases and coexisting coronary artery disease is of greater importance than in the other case. Since 1979 until the end of 1990 there were 146 combined operations performed in the Cardiovascular Surgical Clinic of Semmelweis Medical University of Budapest. The operative results and theoretical considerations are discussed.

[Development of Hungarian heart surgery, its results and current state in the light of the 40-year activity of the "Városmajor Clinic". Review of 40 years of surgery in Hungary, analysis of mortality data]. / A magyar szívsebészet fejlödése, eredményessége és helyzete a "Városmajori Klinika" 40 éves szívsebészetének tükrében Szívsebészetünk 40 évének szakmatörténeti áttekintése, mtéti és halálozási mutatóinak elemzése.

Forty years have passed since the first heart surgical department was founded in Hungary. In the University Hospital (present name: Cardiovascular Surgical Clinic of Semmelweis Medical University of Budapest) the Hungarian "pioneers" had produced internationally respected results in the mid-fiftieth with the operation of closed mitral commissurotomy. However the technique of cardiopulmonary bypass was first introduced into the clinical practice quite early, it has not become a routine everyday procedure until the late seventies. Over the last 15 years period the number of open heart surgical cases has increased permanently, and the operative mortality decreased at the same time. The analysis of 4743 cases performed between 1976 and 1990 showed improving results both in the field of valve replacement and coronary artery surgery and the recent operative mortality figures (3-5% in different groups) are comparable to other European centers.

[Pathogenic role of a pacemaker in occult infection]. / Pacemaker kóroki szerepe rejtett infectio létrejöttében.

A case of seronegative pacemaker lead infection is presented. The diagnosis based on patient history and echocardiography was proved by removing the infected leads from the beating heart through surgery.

[Development and results of valve replacement surgery at the Városmajor Clinic 1976-1990 (retorospective clinical analysis)]. / A szívbillentyü-sebészet fejlödése és eredményei a Városmajori Klinikán 1976-1990 (retrospektív klinikai analízis).

In Hungary valve replacement is still a major indication for heart surgery in adults. In the Cardiovascular Surgical Clinic of Semmelweis Medical University of Budapest from 1976 to 1990 2435 patients were operated for valve disease. Majority of the cases had single (aortic n = 856, mitral n = 912) or double (aortic + mitral n = 513) valve replacement. Over this 15 years period there have been many alterations in patients characteristics and surgical technique as well. In spite of the increasing mean age of patients the operative mortality has decreased (in the last 5 years period it was 2.7%, 5.5% and 7.9% in the three groups respectively). At the same time the number of patients requiring valve re-replacement or combined valve + coronary procedure has increased. The use of bioprosthetic valves has fallen below 10 percent from the 60--80 percent observed between 1976--1980. The analysis showes excellent surgical results in the field of valve replacement in Hungary.