Electron and High-Dose-Rate Brachytherapy Boost in the Conservative Treatment of Stage I-II Breast Cancer First Results of the Randomized Budapest Boost Trial

Background and Aims: To evaluate the effect of electron and high-dose-rate brachytherapy (HDR BT) boost on local tumor control (LTC), side effects and cosmesis after breast-conserving surgery (BCS) in a prospective randomized study. Patients and Methods: 207 women with stage I-II breast cancer who underwent BCS were treated by 50 Gy irradiation to the whole breast and then randomly assigned to receive either a boost to the tumor bed (n = 104) or no further radiotherapy (n = 103). Boost treatments consisted of either 16 Gy electron irradiation (n = 52) or 12-14,25 Gy HDR BT (n = 52). Breast cancer-related events, side effects, and cosmetic results were assessed. Results: At a median follow-up of 5.3 years, the crude rate of local recurrences was 6.7% (7/104) with and 15.5% (16/103) without boost. The 5-year probability of LTC, relapse-free survival (RFS), and cancer-specific survival (CSS) was 92.7% vs. 84.9% (p = 0.049), 76.6% vs. 66.2% (p = 0.044), and 90.4% vs. 82.1% (p = 0.053), respectively. There was no significant difference in LTC between patients treated with electron or HDR BT boost (94.2% vs. 91.4%; p = 0.74). On multivariate analysis, patient age < 40 years (RR: 4.53), positive margin status (RR: 4.17), and high mitotic activity index (RR: 3.60) were found to be significant risk factors for local recurrence. The incidence of grade 2-3 side effects was higher in the boost arm (17.3% vs. 7.8%; p = 0.03). However, the rate of excellent/good cosmetic results was similar for the two arms (85.6% vs 91.3%; p = 0.14). Cosmesis was rated as excellent/good in 88.5% of patients treated with HDR BT and 82.7% of patients with electron boost (p = 0.29). Conclusions: Boost dose significantly improves LTC and RFS in patients treated with BCS and radiotherapy. In spite of the higher incidence of late side effects in the boost arm, boost dose is strongly recommended for patients at high risk for local recurrence. Positive or close margin status, high mitotic activity index, and young patient age should be viewed as absolute indications for tumor bed boost. LTC and cosmesis are excellent and similar to patients boosted with either HDR BT or electrons. Hintergrund und Ziel: In einer prospektiv randomisierten Studie werden die Effekte eines Elektronenboosts und eines High-Dose-Rate-Brachytherapie-(HDR-BT-)Boosts bezüglich lokaler Tumorkontrolle (LTC), Nebenwirkungen und kosmetischer Ergebnisse nach brusterhaltender Operation (BCS) evaluiert. Patienten und Methodik: 207 Patientinnen mit Brustkarzinomen im Stadium I-II wurden einer BCS zugeführt. Postoperativ erfolgte eine perkutane Radiatio der gesamten Brust bis 50 Gy. Daran schloss sich willkürlich entweder eine Boostbestrahlung des Tumorbetts (n = 104) oder keine weitere Radiatio (n = 103) an. Die Boostbestrahlung erfolgte perkutan mit 16 Gy Elektronen (n = 52) oder in Form einer HDR-BT mit 12-14,25 By (n = 52). Untersucht wurden LTC, Nebenwirkungen und kosmetische Ergebnisse. Ergebnisse: Die mediane Nachbeobachtungszeit betrug 5,3 Jahre. Die Lokalrezidivrate lag mit Boostbestrahlung bei 6,7% (7/104), ohne Boost bei 15,5% (16/103). Die 5-Jahres-Überlebensrate für LTC, für die rezidivfreie Überlebenszeit (RFS) und für die krebsspezifische Überlebenszeit (CSS) betrugen 92,7% vs. 84,9% (p = 0,049), 76,6% vs. 66,2% (p = 0,044) und 90,4% vs. 82,1% (p = 0,053). Bezüglich der LTC bestand kein signifikanter Unterschied zwischen Patienten, die mit einem Elektronen- oder HDR-BT-Boost behandelt wurden (94,2% vs. 91,4$; p = 0,74). Die multivariate Analyse zeigte, dass Faktoren wie Patientenalter > 40 Jahre (RR: 4,53), positive Resektionsränder (RR: 4,17) und ein hoher Mitoseaktivitätsindex (RR: 3.60) das Risiko eines lokalen Rezidivs signifikant erhöhen. Die Inzidenz von Nebenwirkungen Grad 2-3 war im Boost-Arm höher (17,3% vs. 7,8%; p = 0,03). Allerdings waren die sehr guten kosmetischen Ergebnisse in beiden Armen gleich (85,6% bs. 91,3%, p = 0,14). Sehr gute kosmetische Ergebnisse wurden bei 88,5% der Patientinnen mit HDR-BT-Boost und 82,7% der Patientinnen mit Elektronenboost erreicht (p = 0,29). Schlussfolgerungen: Die Boost-Dosis verbessert signifikant LTC und RFS bei Patientinnen, die einer BCS und anschließender Radiatio zugeführt wurden. Obwohl eine höhere Inzidenz an Spätnebenwirkungen im Boost-Arm gefunden wurde, wird eine Boost-Dosis für Patientinnen mit hohem Risiko für die Entwicklung eines Lokalrezidivs empfohlen. Unserer Meinung nach ist bei Faktoren wie positive Schnittränder, schmaler Sicherheitssaum, hoher Mitoseaktivitätsindex und niedriges Patientenalter, die absolute Indikation zur Boost-Bestrahlung des Tumorbetts gegeben. LTC und die kosmetischen Ergebnisse sind sehr gut und unterscheiden sich nicht in Bezug auf Elektronenboost oder HDR-BT-Boost.     

Plasma levels of IL-6 correlate with hemodynamic abnormalities in acute pancreatitis in rabbits

OBJECTIVE: To examine the relationship between plasma cytokine levels and cardiac and hemodynamic function. DESIGN: Measurement of cytokines and the systolic (left ventricular dimensions, heart rate, and cardiac output) and diastolic (early and late transmitral peak flow velocity: E and A-waves and their ratio) functions of the left ventricle (assessed by echocardiography) in rabbits. SETTING AND INTERVENTIONS: Laboratory and echocardiographic analyses were performed at baseline and at 1, 3, 6, 12, and 24 h after acute necrotizing pancreatitis induction (Group ANP), in rabbits after somatostatin pretreatment (Group S-ANP) and in sham-operated controls (Group C). MEASUREMENTS AND RESULTS: Left ventricular dilatation occurred at 6 h and cardiac output was increased 3 h after induction of acute necrotizing pancreatitis. Somatostatin pretreatment mitigated the left ventricular enlargement and filling abnormalities. Plasma level of IL-6 was increased significantly 3 h after pancreatitis induction, but to a lesser extent in Group S-ANP, while somatostatin prevented TNFalpha release (IL-6: Group ANP: 0, 0, 518+/-139, 956+/-125, 373+/-48, and 122+/-37 pg/ml; Group S-ANP: 0, 0, 191+/-68, 261+/-49, 23+/-13, and 0 pg/ml; TNFalpha: Group ANP: 88+/-42, 371+/-40, 2963+/-291, 276+/-30, 197+/-106, and 23+/-14 U/l; Group S-ANP: 91+/-34, 41+/-25, 68+/-42, 25+/-9, 0, and 0 U/ml). The increase in plasma level of IL-6 correlated significantly with left ventricular end-diastolic diameter and volume, cardiac output, and diastolic dysfunction. CONCLUSIONS: Plasma levels of IL-6, but not TNFalpha correlate with cardiac output and left ventricular filling characteristics in acute pancreatitis. Somatostatin pretreatment improves the cardiac and hemodynamic changes, probably through the decrease in cytokine release.     

Evaluation of intraosseous sampling for measurements of alanine aminotransferase,alkaline phosphatase,aspartate aminotransferase,creatinine kinase,gamma-glutamyl transferase and lactate dehydrogenase

Background: Intraosseous (IO) access can be established faster than a venous or arterial access when there is an urgent need for rapid initiation of treatment. The access can also be used to draw marrow samples. The aim of the present study was to evaluate the potential use of IO samples for enzyme determinations using a porcine model.

Materials and methods: Bilateral tibial intraosseous cannulae and an arterial catheter were used for blood sampling from five healthy anesthetized pigs. Samples were collected at baseline and thereafter hourly for 6?h and analyzed for alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, creatinine kinase, gamma-glutamyl transferase and lactate dehydrogenase.

Results: Creatinine kinase, lactate dehydrogenase and alkaline phosphatase levels decreased over time. The differences between IO and arterial sampling were limited for all studied markers.

Conclusion: The correlation between marrow and blood analysis for liver function tests and CK is sufficiently accurate in an emergency situation.     

In vitro and in vivo complement activation and related anaphylactic effects associated with polyethylenimine and polyethylenimine-graft-poly(ethylene glycol) block copolymers

Complement activation by polymeric gene and drug delivery systems has been overlooked in the past. As more reports appear in the literature concerning immunogenicity of polymers and their impact on gene expression patterns, it is important to address possible immune side effects of polymers, namely complement activation. Therefore, in this study the activity of low and high molecular weight poly(ethylene imine) and two PEGylated derivatives to induce complement activation were investigated in human serum. These in vitro results revealed that PEI 25 kDa caused significant and concentration dependent complement activation, whereas none of the other polymers induced such effects at their IC(50) concentrations determined by MTT-assays. To verify these in vitro results, additionally, studies were carried out in a swine model after intravenous administration, showing complement activation-related pseudoallergy (CARPA), reflected in symptoms of transient cardiopulmonary distress. Injections of PEI 25 kDa or PEI(25k)-PEG(2k)(10) at a dose of 0.05 and 0.1 mg/kg caused strong reactivity, while PEI 5 kDa and with PEI(25k)-PEG(20k)(1) were also reactogenic at 0.1 mg/kg. It was found that PEI 25 kDa caused both self- and cross-tolerance, whereas the PEG-PEIs were neither self- nor cross-reactively tachyphylactic. As a result of this study, it was shown that PEGylation of polycations with PEG of 20 kDa or higher molecular weight may be favorable. However, potential safety concerns in the development of PEI-based polymeric carriers for drugs and nucleic acids and their translation from bench to bedside need to be taken into consideration for human application.     

Breast cancer multifocality, disease extent, and survival

The prognostic information implied in subgross morphologic parameters such as lesion distribution (unifocal, multifocal, or diffuse) and disease extent in breast cancer has remained largely unexplored in the literature. We aimed to test whether these parameters influence survival in breast carcinoma. The parameters were assessed in a series of 574 cases, all documented in large-format histology sections. We used Cox proportional hazards regression accompanied by Kaplan-Meyer survival curves, with P < .05 regarded as significant. The invasive component was unifocal in 62% (311/499), multifocal in 24% (122/499), and diffuse in 5% (26/499) of the cases. Combining the in situ and invasive tumor components resulted in 48% (274/574) unifocal, 25% (141/574) multifocal, and 20% (117/574) diffuse tumors. Sixty percent (347/574) of the tumors were categorized as having limited extent (occupying an area <40 mm in largest dimension) and 29% (164/574) as extensive. Highly significant (P < .0001) differences were observed in 10-year disease-specific cumulative survival among the cases with unifocal, multifocal, and diffuse invasive (89.6%, 76.0%, and 63.6%, respectively) and combined (92.3%, 82.3%, and 75.7%, respectively) lesion distribution. Patients with extensive tumors exhibited a significantly lower cumulative survival (P < .0001) compared with those with limited extent (91.6% and 75.5%) and a statistically significantly 1.89-fold (95% confidence interval, 1.07-3.37; P = .03) risk for breast cancer death after controlling for tumor attributes, type of surgery, and adjuvant therapy. The hazard ratio for breast cancer death for mutifocal and/or diffuse tumors versus unifocal ones was 1.96 (95%; 1.11-3.48; P = .02) after controlling for the same factors. Lesion distribution and disease extent represent important independent survival-related prognostic parameters in breast carcinoma.     

Intracranial landmarks and other techniques to further improve the precision of stereotaxic tracer injections

This study is meant to combine traditional aspects of tracer microinjections using bone landmarks like bregma and lambda with novel procedures in which specific parts of the brain can serve as reference points. For telencephalic and diencephalic injections, the brain surface, the interhemispheric groove and the straight sinus can be used as absolute zero points for dorso-ventral, medio-lateral and rostro-caudal coordinates, respectively. In case of brainstem targets, the surface of the rhomboid fossa, the posterior spinal artery and the obex could serve as reference points along the above-mentioned coordinates. The application of high-precision stereotaxic measurements based on intracranial landmarks and sophisticated surgical procedures can yield well-targeted, small and well circumscribed injection sites that make possible the mapping of discrete nuclear subdivisions or delicate nuclei in the brain.     

Gray matter morphology and the level of functioning in one-year follow-up of first-episode schizophrenia patients

Schizophrenia is a condition with a highly variable course that is hard to predict. The aim of the present study was to investigate if local gray matter volume (GMV) can differentiate poor (PF) and good (GF) functioning patients using voxel-wise analysis in a group of first-episode schizophrenia subjects (FES).     

Prefrontal but not temporal grey matter changes in males with first-episode schizophrenia

INTRODUCTION: Changes of brain morphology are now considered as a part of the pathology of schizophrenia. Voxel-based morphometry may be used to study regional changes of the grey matter in the whole brain. It is advantageous to study first-episode patients to prevent the influence of many possible biasing factors when trying to identify primary pathological processes underlying the manifestation of the illness. OBJECTIVE: To investigate regional grey matter changes in the first-episode schizophrenia patients. METHODS: Optimized voxel-based morphometry was used to detect changes in grey matter volume in 22 patients with first-episode schizophrenia compared with 18 healthy volunteers of comparable age, gender and handedness. RESULTS: The first-episode schizophrenia group had significantly reduced grey matter volume in the prefrontal cortex (inferior and middle prefrontal gyrus, cingulate gyrus). We identified no differences in the temporal cortex. CONCLUSION: Our data support the theoretical assumption that prefrontal dysfunction underlines the primary pathology and clinical manifestation of schizophrenia. We are inclined to explain the differences in the pattern of morphological changes reported in other first-episode studies--especially the lack of changes in the temporal cortex--by heterogeneity of schizophrenia, potential progression and antipsychotic medication effect.