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.

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.

Hydrodynamics of raindrop impact stimulate ascospore discharge of Venturia inaequalis.

Ascospores of Venturia inaequalis are released from leaves following the impact of raindrops during rain events. Atmospheric humidity or moisture from dew does not have an inductive effect on ascospore release. The hydrodynamics of raindrop impact on leaf surfaces was investigated. Raindrops induced dampened periodic vibrations on leaf surfaces. Vibrations, linear, and/or oscillatory flows of water applied to the leaves all induced spore releases at low energy thresholds. The fungal perceptibility of kinetic energy enables selective discharge of spores when environmental conditions are most conducive to survival. Identification of kinetic effects of rain which reveal start, thresholds, and proportional distribution is not only important for disease prognosis research, but may also serve as a model for a common fungal sensing mechanism.

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.

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.

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.

Involvement of the hepatocyte growth factor/scatter factor receptor c-met and of Bcl-xL in the resistance of oropharyngeal cancer to ionizing radiation.

The activation of cytoplasmic signal transduction pathways by a number of growth factors and their tyrosine-kinase receptors, including hepatocyte growth factor/scatter factor (HGF/SF) and its receptor c-met, exerts an inhibitory influence on apoptosis induced by ionizing radiation in vitro. The clinical relevance of the aforementioned ligand-receptor pair, of Bcl-xL, which is targeted by HGF/SF/c-met signaling, and of Bcl-2, was assessed by evaluating their predictive and prognostic impact in a cohort of 97 patients with radically irradiated squamous cell cancers of the oropharynx. Immunohistochemical expression of c-met and Bcl-xL was correlated with decreased rates of complete remission of the primary tumor in both the univariate (c-met: P = 0.01; Bcl-xL: P = 0.001) and multivariate analyses. Expression of c-met was, moreover, a significant and independent predictor of impaired local failure-free survival (P = 0.003), disease-free survival (P = 0.003) and overall survival (p = 0.001). Bcl-2 expression was, on the other hand, associated with a favorable outcome, in terms of both local failure-free survival (P = 0.01) and overall survival (P = 0.001). In accordance with in vitro data, c-met and Bcl-xL appear to be involved in the resistance of oropharyngeal cancers to ionizing radiation, and may therefore represent attractive targets for radiosensitization.

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.

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.

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.

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.

Balloon angioplasty of the internal mammary artery trunk for early postoperative ischemia: a case report.

In this case report kinking of the internal mammary artery graft with possible superimposed spasm is described. Angiographic diagnosis was made 72 hrs following coronary artery bypass surgery and the lesion was successfully dilated with balloon angioplasty.

Surgical management of instrumentation-induced coronary artery dissection.

The mechanism of instrument-induced coronary artery dissections (IICDs) is briefly presented. Depending on the coronary anatomy, three different situations that may occur are distinguished: (1) major coronary branches between the site of dissection and planned anastomosis; (2) no important collaterals at the same location; and (3) perforation of the coronary artery. Surgical methods applicable to each for the correction of these situations is presented.