Treatment of primary breast cancer at the surgical unit of the Charité 1984-1998.

BACKGROUND: We have analyzed the patient population of one clinic (Charité) over a period of 15 years. Besides the changes in the technical facilities and therapeutical guidelines during these years, this period also reflects the changes in the health system attributable to the reunification of East and West Germany. Until now only few analyses for breast cancer patients from the German speaking area have been reported. PATIENTS AND METHODS: All 2,062 patients undergoing surgical treatment for breast cancer between 1984 and 1998 were documented and followed up until 2007. The analysis included 1,560 patients with a primary breast cancer who fulfilled certain inclusion criteria. The treatment strategies applied to this population are presented in 3 time periods (1984-1990, 1991-1993, and 1994-1998). The effects of prognostic factors on overall survival were investigated using univariate analyses. RESULTS: The percentage of pT1 tumors changed from 50.7% in the first period to 63.1% in the third period. The percentage of node-negative patients hardly changed with time (on average 61.6%). However, the percentage of patients with less than 10 assessed nodes decreased from 48.4% to 6.7% and 2.5% for the 3 periods, respectively. Therapeutic strategies changed drastically. Survival rate increased substantially, most likely due to improved therapeutic strategies, but also for other reasons not considered in the analysis.

Characterization of atherosclerotic plaques in human coronary arteries with 16-slice multidetector row computed tomography by analysis of attenuation profiles.

RATIONALE AND OBJECTIVES: We investigated if 16-slice multidetector row computed tomography (MDCT) allows correct classification of coronary plaques into calcified or noncalcified and further subclassification of noncalcified plaques into either lipid-rich with a necrotic core or fibrous. MATERIALS AND METHODS: Coronary arteries of 30 isolated hearts were filled postmortem with a contrast medium and scanned with a 16-slice MDCT imager (Light Speed 16 pro, GEMS, Milwaukee, WI). Imaging parameters: collimation 16 x 0.625 mm, pitch 0.325, tube voltage 120 kV, tube current 250 mA, and gantry rotation time 500 milliseconds. The images were reformatted perpendicular to the axis of the coronary arteries (AW 4.2 software, GEMS) and analyzed by establishing attenuation profiles of the coronary cross sections (ImageJ 1.33n software, NIH, Bethesda, MD). Results were compared with the correlating histopathologic sections of the arteries. RESULTS: Analysis of 195 CT cross-sections showed a sensitivity and specificity for the correct classification of calcified plaques of 100% and 97.3% and for noncalcified plaques of 80.8% and 95.1%, respectively. The attenuation of epicardial fat ranged from -119 Hounsfield units (HU) to 23 HU (median -71 HU), and from 93 HU to 625 HU (308 HU) for the contrast medium. Calcified plaques showed an attenuation between 333 HU and 1944 HU (1,089 HU), noncalcified plaques between 26 HU and 124 HU (52 HU). Further subclassification of noncalcified plaques showed attenuation values between 26 HU and 67 HU (median 44 HU) for lipid-rich plaques with a necrotic core and from 37 HU to 124 HU (median 67 HU) for fibrous plaques. CONCLUSIONS: Coronary atherosclerotic plaques can be reliably identified and classified as either calcified or noncalcified by 16-slice MDCT in postmortem studies. Further differentiation of noncalcified plaques in either lipid-rich or fibrous is not reliably feasible because of substantial overlap of the attenuation.

Expression of the ELAV-like protein HuR is associated with higher tumor grade and increased cyclooxygenase-2 expression in human breast carcinoma.

PURPOSE: The human ELAV (embryonic lethal abnormal vision)-like protein HuR stabilizes a certain group of cellular mRNAs that contain AU-rich elements in their 3'-untranslated region. Cell culture studies have shown that the mRNA of cyclooxygenase (COX)-2 can be stabilized by HuR. EXPERIMENTAL DESIGN: To investigate a possible contribution of dysregulation of mRNA stability to the progression of cancer and to overexpression of COX-2, we studied expression of HuR in 208 primary breast carcinomas by immunohistochemistry. RESULTS: There were two different staining patterns of HuR in tumor tissue of breast carcinomas: nuclear expression was seen in 61% of cases; and an additional cytoplasmic expression was seen in 30% of cases. Expression of HuR was significantly associated with increased COX-2 expression; this association was particularly significant for cytoplasmic HuR expression (P < 0.0005). We further observed a significant association of cytoplasmic (P = 0.002) or nuclear HuR (P = 0.027) expression with increased tumor grade. Only 13% of the grade 1 carcinomas showed cytoplasmic expression of HuR, compared with 46% of the grade 3 carcinomas. There was no significant correlation between HuR expression and other clinicopathological parameters such as histological type, tumor size, or nodal status as well as patient survival. CONCLUSIONS: Our results suggest that overexpression of HuR in tumor tissue may be part of a regulatory pathway that controls the mRNA stability of several important targets in tumor biology, such as COX-2. Based on our results, additional studies are necessary to investigate whether HuR might be a potential target for molecular tumor therapy.

CD24 expression is a new prognostic marker in breast cancer.

PURPOSE: CD24 is expressed in hematological malignancies as well as in a large variety of solid tumors including breast cancer. We aimed to evaluate CD24 protein expression in breast cancer and to correlate to clinicopathological data including patient survival. EXPERIMENTAL DESIGN: Primary breast carcinomas (201) with a mean clinical follow-up time of 53 months were immunostained using a monoclonal CD24 antibody (Ab-2, clone 24C02). The staining was evaluated as negative versus positive for statistical analysis. RESULTS: In invasive breast carcinomas, CD24 expression was observed in 84.6% of cases. In univariate survival analyses, a significant association of CD24 expression with shortened patient overall survival (5-year survival rate 91.9% versus 83.8%; P = 0.031; log rank test) and disease-free survival (5-year progression rate 88.3% versus 57.0%; P = 0.0008) was demonstrated. In multivariate analyses CD24, tumor grading and nodal status were significant prognostic parameters for shortened disease-free survival. CONCLUSIONS: Our data suggest that CD24 expression in primary breast cancer as detected by immunohistochemistry might be a new marker for a more aggressive breast cancer biology.

Quantification of atherosclerotic coronary plaque components by submillimeter computed tomography.

BACKGROUND: Although several investigations have shown that multi-detecor row computed tomography (MDCT) of the coronary arteries can detect noncalcified atherosclerotic plaque, it has remained unresolved if the method also determines features of a rupture-prone plaque. We set out to correlate the size of atherosclerotic plaque components with cardiac MDCT with histology. METHODS AND RESULTS: In 30 autopsy cases, hearts were isolated, coronary arteries filled with contrast agent, and depicted with a clinical 16-row detector CT with a slice thickness of 0.63 mm. Transections of the three main coronary arteries were reconstructed and compared with histopathologic sections using light microscopy. MDCT measurements of total plaque area (r = 0.73, P < 0.0001) and calcified plaque area (r = 0.83, P < 0.0001) correlated well with histopathology, while measurements of non-calcified plaque area (r = 0.53, P < 0.0001) and lipid core size (r = 0.43; P < 0.0001) correlated less well. MDCT overestimated all plaque areas except lipid core size, which was underestimated. CONCLUSIONS: Coronary CT provides an accurate and reproducible method for the quantitative assessment of total plaque and calcified plaque areas. However, the method is less accurate for the quantification of non-calcified plaque area and lipid core size, which is ascribed to limited spatial and contrast resolution. With the present technique, the detection of vulnerable plaques by MDCT remains uncertain.

Effects of octreotide in acute hemorrhagic necrotizing pancreatitis in rats.

BACKGROUND AND AIM: Octreotide is considered to reduce exocrine pancreatic secretion in acute hemorrhagic necrotizing pancreatitis decreasing pancreatic autodigestion. The aim of this study was to determine whether octreotide also has antioxidative effects in acute pancreatitis. Additionally time and dose of application were of interest. METHOD: Ninety male Sprague-Dawley rats were randomized into six groups (n = 15). Group 1 underwent a laparotomy, and animals in groups 2-6 received intraductal glycodeoxycholic acid followed by intravenous cerulein. Groups 3 and 4 were injected with 0.5 mg octreotide, while groups 5 and 6 received continuous intravenous infusion of 0.05 mg octreotide/h for 10 h. Treatment was initiated 6 hours after induction of pancreatitis (IP) in groups 3 and 5, and 14 h after IP in groups 4 and 6. At 24 h after IP all animals were killed and each pancreas was analyzed histopathologically. In addition, levels of pancreatic lipid peroxidation protective enzymes glutathione-peroxidase (GSH-Px) and superoxide dismutase (SOD) as well as lipid peroxidation via thiobarbituric acid reactive substances (TBARS) were determined. RESULTS: Early bolus application of octreotide reduced severity of histopathological changes in acute pancreatitis and decreased lipid peroxidation in pancreatic tissue samples; however, late bolus application and continuous intravenous infusion did not influence pancreatitis or lipid peroxidation. CONCLUSION: Octreotide seems to have a dose- and time-dependent effect on histopathology and lipid peroxidation in a model of pancreatitis in rats.

Impact of taurolidin and octreotide on liver metastasis and lipid peroxidation after laparoscopy in chemical induced ductal pancreatic cancer.

BACKGROUND: There is controversial discussion whether metastasis initiated by laparoscopy with carbon dioxide might be prevented by instillation of taurolidin or radical scavengers like the somatostatin analogue Octreotide. Therefore we evaluated the effects of laparoscopic lavage with taurolidin and Octreotide on liver metastasis after staging laparoscopy in ductal pancreatic cancer. METHODS: In 60 Syrian hamsters pancreatic adenocarcinoma was induced by weekly subcutanous injection of 10 mg N-nitrosobis-2-oxopropylamin/kg body weight for 10 weeks. In the 16th week laparoscopic staging biopsy by use of carbon dioxide was performed. Finally animals underwent abdominal irrigation with saline (gr.1, n = 20), taurolidin (0.5%) (gr.2, n = 20) or Octreotide (gr.3, n = 20). In week 25 animals were sacrificed, pancreas and liver were analysed. RESULTS: Size of pancreatic carcinomas was decreased in the taurolidin gr. compared to the other two groups. Furthermore the number of liver metastasis per animal was reduced after lavage with taurolidin (2 +/- 2) and Octreotide (2.5 +/- 2) compared to saline irrigation (4 +/- 4) (p < 0.05). Additionally the incidence of port site metastases was significantly reduced in the taurolidin group. Activity of antioxidative enzyme superoxide dismutase (SOD) was increased while concentration of products of lipidperoxidation was decreased in non-metastatic liver after taurolidin irrigation compared to saline or Octreotide irrigation. CONCLUSIONS: Taurolidin irrigation during laparoscopy might be a new concept to reduce the number of liver metastasis and port site metastases in pancreatic cancer.

Peritumoural versus subareolar administration of technetium-99m nanocolloid for sentinel lymph node detection in breast cancer: preliminary results of a prospective intra-individual comparative study.

The scintigraphic detection of sentinel lymph nodes (SNs) in early-stage breast cancer is a widely accepted diagnostic method. However, which radiotracer administration mode should be used is still controversial. This prospective study aimed to intra-individually compare the detection rates obtained after peritumoural versus subareolar injection with regard to SN number and localisation. Fifty-one women (age, 32-76 years) with breast cancer were investigated on two consecutive days. On day 1, 140-400 MBq technetium-99m nanocolloid was injected along the peripheral tumour margins. Static lymphoscintigrams of the axilla, thorax and neck were taken in various views 1 and 19 h p.i. On day 2, 10 MBq (99m)Tc-nanocolloid was injected subareolarly in the clock position of the tumour and dynamic and static scans were performed immediately. Thereafter, 30 MBq (99m)Tc-nanocolloid was administered peri-subareolarly and lymphoscintigrams were acquired in a dynamic and static manner. In 49/51 women, the different injection techniques disclosed the identical number and location of SNs in the axilla. In seven patients, the peritumoural injection detected additional SNs in the parasternal group. Axillary SNs were detected as early as 2-15 min following subareolar injection, both in the clock position and peri-subareolarly, as compared with about 1 h after peritumoural administration. Sixteen patients showed at least one tumour-positive SN, and nine also had tumour-positive non-SNs. One patient with a tumour-negative SN, visualised concordantly by both subareolar and peritumoural administration, demonstrated two metastatic non-SNs, yielding a false-negative rate of 5.9%. In conclusion, a simple subareolar injection in the clock position is sufficient for SN detection in breast cancer, if it is accepted that parasternal lymph node detection has no therapeutic consequences.

Effects of octreotide on lipid peroxidation in pancreas and plasma in acute hemorrhagic necrotizing pancreatitis in rats.

BACKGROUND: The therapeutic effects of octreotide in acute hemorrhagic necrotizing pancreatitis (ANP) have always been considered to be due to the inhibition of the exocrine pancreatic secretion in order to reduce pancreatic autodigestion. In this experimental study we analyzed whether octreotide has also antioxidative effects on acute pancreatitis. METHODS: 40 male Wistar rats were randomized into four groups (n = 10). Group 1 underwent a laparotomy. Groups 2-4 received an injection of natrium taurocholate into the pancreatic duct to induce acute pancreatitis. One hour later group 2 was injected 1 ml NaCl solution intraperitoneally, while groups 3 and 4 received 0.1 or 0.2 mg octreotide, respectively. The severity of ANP was examined histologically. The lipid peroxide level as well as the activity of glutathione peroxidase and superoxide dismutase were measured in plasma and pancreatic tissue samples. RESULTS: High-dose octreotide decreased the lipid peroxide level in plasma (2.1 +/- 0.53 vs. 4.69 +/- 1.35 nmol/l; p < 0.05) and pancreatic tissue samples 4.67 +/- 1.37 vs. 13.20 +/- 2.93 nmol/ml; p < 0.05) compared to the pancreatitis control group. Low-dose octreotide, however, did not reduce lipid peroxidation. CONCLUSION: Octreotide seems to have a dose-dependent antioxidative effect in natrium taurocholate-induced pancreatitis in rats.

Elevated expression of cyclooxygenase-2 is a negative prognostic factor for disease free survival and overall survival in patients with breast carcinoma.

BACKGROUND: Cyclooxygenases regulate the production of prostaglandins and play a role in tumor development and progression. The authors investigated the prognostic impact of expression of the cyclooxygenase (COX) isoforms, COX-1 and COX-2, on disease-free survival and progression-free survival in patients with primary breast carcinoma as well as the association between COX expression and other clinicopathologic parameters. METHODS: In this study COX isoform expression was determined by immunohistochemistry in a cohort of 221 patients with primary breast carcinoma. RESULTS: Expression of COX-2 was detected in 36% of breast carcinoma samples and was associated significantly with several clinicopathologic parameters, including positive lymph node status (P < 0.0005), larger tumor size (P < 0.0005), poor differentiation (P < 0.0005), vascular invasion (P = 0.03), and negative estrogen receptor status (P = 0.04). In contrast, COX-1 was expressed in 45% of tumors and was associated with smaller tumor size (P = 0.02) and with negative lymph node status (P = 0.01). In a univariate survival analysis, a significant association was observed between elevated COX-2 expression and decreases in disease-free survival (P = 0.0007) and overall survival (P = 0.02). In a multivariate analysis, expression of COX-2 was of borderline significance for disease-free survival (relative risk, 1.90; 95% confidence interval, 1.00-3.59), adjusting for tumor size, histologic grade, number of positive lymph nodes, and patient age. Elevated expression of COX-1 in tumor tissue had no statistically significant influence on patient prognosis. CONCLUSIONS: The current data suggest that increased expression of COX-2 may play a role in the progression of primary breast carcinoma. It remains to be investigated whether treatment with selective inhibitors of COX-2 may be an additional therapeutic option for patients with breast carcinoma.

Subareolar injection of technetium-99m nanocolloid yields reliable data on the axillary lymph node tumour status in breast cancer patients with previous manipulations on the primary tumour: a prospective study of 117 patients.

According to recently published guidelines, histological clarification by interventional techniques should be undertaken before planning the surgical management of patients with breast carcinoma. In patients with previous manipulations on the primary tumour, peritumoural injection in the context of preoperative scintigraphic detection of the sentinel lymph nodes is not possible. The aim of this prospective study was to clarify whether subareolar injection of nanocolloid can yield reliable data on the axillary lymph node tumour status in breast cancer patients with previous manipulations on the primary tumour. To date, 117 women (age 31-80 years) with breast carcinoma have been enrolled. All of these patients had undergone a biopsy (n=88) or surgery on the primary tumour (n=29) and were without clinical suspicion of lymph node metastases. Subareolar injection of 40 MBq technetium-99m nanocolloid was carried out in at least eight deposits around the areolar margin [one deposit in the middle of each quadrant and one deposit at each quadrant intersection (0.05 ml/deposit)]. Immediately after injection, dynamic and static lymphoscintigraphy of the axillary, thoracic and cervical areas was performed in various views with a gamma camera (LEAP collimator, 256x256 matrix). Lymphatic drainage was directed exclusively to the ipsilateral axilla. Sentinel lymph node biopsy and elective dissection of axillary lymph nodes were performed in all patients. All lymph nodes removed were examined by histology and immunohistochemistry. In 26 patients, lymph node metastases were found in the sentinel lymph nodes. In six of them, non-sentinel lymph nodes also showed tumour involvement. In the remaining 91 patients, lymph node metastases could be found neither in sentinel lymph nodes nor in non-sentinel lymph nodes. In conclusion, subareolar nanocolloid injection can yield reliable information on the axillary lymph node tumour status in patients with previous manipulations on the primary tumour in the breast.

Métodos de segmentación de imagen aplicados a las lesiones arteriales. I comparación / Image segmentation methods applied to arterial lesions. I. Comparison

Se presenta una comparación de los resultados obtenidos al usar 2 métodos de segmentación de imagen en lesiones ateroscleróticas de la aorta torácica; uno supervisado y el otro no supervisado. La segmentación se empleó con preprocesamiento y sin preprocesamiento en la discriminación de las diferentes lesiones, a saber: estrías adiposas, placas fibrosas, placas complicadas y placas calcificadas. Se consta que en todos los casos los algoritmos no supervisados fueron superiores a los supervisados

Aterosclerosis de las carótidas: estudio patomorfológico y morfométrico utilizando el Sistema Aterométrico

Se analizan las arterias carótidas primitivas derecha e izquierda y los 3 cm proximales de sus bifurcaciones interna y externa de un total de 201 necropsias que reunieron las condiciones para ser consideradas como una serie consecutiva. Se incluyen en los análisis la edad, el sexo, la enfermedad básica causante de la muerte así como la causa directa de ésta. Las arterias, para su estudio patomorfológico y morfométrico se procesan siguiendo criterios internacionales establecidos por la Organización Mundial de la Salud (OMS). Se realizan análisis cualitativos y cuantitativos de las arterias y se aplica el sistema aterométrico (SA), metodología considerada idónea por la OMS para investigar y caracterizar la lesión aterosclerótica. Para su análisis se crearon 4 grupos de edades: menores de 40 años, de 40 a 59; de 60 a 79 y mayores de 79 años. También se consideró el sexo en los análisis. Los resultados más relevantes fueron los siguientes: La aterosclerosis progresa con la edad en todos los tipos de lesiones y en todas las variables del SA. La carótida derecha resultó la arteria más afectada en los 2 sexos. La edad de mayor progreso de las placas fibrosas fue entre los 40 y 50 años y a partir de los 60 años la placa grave progresó notablemente. Los mayores de 80 años exhibieron menos placas graves y fibrosas que los del grupo de 60 a 79 años. Como resultado de esta investigación se plantea la hipótesis de que la geometría vascular de las carótidas es la responsable de la mayor afectación en el lado derecho.

The right and left primordial carotid arteries and the 3 proximal cms of their internal and external bifurcations in 201 necropsies that met the requirementes to be considered a consecutive series were analyzed. Age, sex, basic disease causing death and the direct cause of death were included in the analyses. For the pathomorphological and morphometric study, the arteries processed according to the international standards set by the World Health Organization (WHO). The arteries were qualitatively and quantitatively examined by applying the atherometric system (AS), which is regarded by WHO as the best methodology to study and characterize the atherosclerotic lesion. To this end, 4 age groups were formed: under 40, 40 to 59, 60 to 79 and over 79 years. The most outstanding results were the following: the atherosclerosis increases with rising age in all types of lesions and for all AS variables. The right carotid artery was the most affected in both male and female, the age at which fibrous plaques develop most was 40 to 50 years whereas the progression of the severe plaque was remarkably at 60 and over. Over 80 years-old people showed less severe and fibrous plaques than 60-79 age group. This research work resulted in the hypothesis that vascular geometry of carotid arteries may be responsible for a higher impact on the right side.

Aterosclerosis en edades tempranas de la vida: Estudio patomorfológico y morfométrico aplicando el sistema aterométrico

Se realizó un estudio de las lesiones ateroscleróticas en 50 aortas de fallecidos menores de 35 años, cuyas causas de muerte no estaban relacionadas con la enfermedad aterosclerótica, separados en 3 grupos de edades y sexo. La aorta se analizó dividida en sus segmentos torácico y abdominal, utilizando los procedimientos patomorfológicos clásicos. El análisis morfométrico se realizó aplicando el sistema aterométrico (SA). Las operaciones estadísticas se efectuaron con el paquete comercial Number Cruncher Statistical System (NCSS). Los resultados más destacados fueron los siguientes: 1) las lesiones ateroscleróticas en ambos segmentos de la aorta aumentan con el progreso de la edad y son más intensas en el segmento abdominal; 2) las estrías adiposas (X) se observaron en el segmento torácico de la aorta desde los 5 años de edad, mientras que las placas fibrosas (Y) aparecen a partir de los 16 años, pero en el segmento abdominal. El test estadístico de comparación entre los grupos de edad, mostró significación entre los grupos I - II y I - III, lo que sugiere que a partir de la segunda década de la vida se estabiliza el desarrollo y evolución de las lesiones ateroscleróticas. El SA resultó una herramienta idónea para el estudio de las lesiones ateroscleróticas en etapas tempranas de la vida.

A study was made on the atherosclerotic lesions of 50 aortas from dead people under 35 years whose causes of death were not related to atherosclerosis. The deceased were divided into 3 groups by age and sex. The aortas were divided into thoracic and abdominal segments to be analyzed by the classical pathomorphological method. The morphometric analysis was carried ot using the atherometric system. The statistical operations were performed assisted by the commercial Number Cruncher Statistical System software. The most important results were the following: 1) the atherosclerotic lesions in both segments increase with rising age level and they are more intense in the abdominal segment; 2) the fatty streak (X) were observed in the aorta thoracic segment since 5 years of age whereas fibrous plaques (Y) occured at 16 years of age or over but in the abdominal segment. The statistical comparison test applied to age groups was significant in I-III groups and I-II groups, which suggest that during the second decade of life the development and progression of atherosclerotic lesions are stabilized. The atherometric system was the best tool for the study of atherosclerotic lesions in early stages of life.