Bedside hyperspectral imaging indicates a microcirculatory sepsis pattern - an observational study.

INTRODUCTION: Microcirculatory alterations are key mechanisms in sepsis pathophysiology leading to tissue hypoxia, edema formation, and organ dysfunction. Hyperspectral imaging (HSI) is an emerging imaging technology that uses tissue-light interactions to evaluate biochemical tissue characteristics including tissue oxygenation, hemoglobin content and water content. Currently, clinical data for HSI technologies in critical ill patients are still limited. METHODS AND ANALYSIS: TIVITA® Tissue System was used to measure Tissue oxygenation (StO2), Tissue Hemoglobin Index (THI), Near Infrared Perfusion Index (NPI) and Tissue Water Index (TWI) in 25 healthy volunteers and 25 septic patients. HSI measurement sites were the palm, the fingertip, and a suprapatellar knee area. Septic patients were evaluated on admission to the ICU (E), 6 h afterwards (E+6) and three times a day (t3-t9) within a total observation period of 72 h. Primary outcome was the correlation of HSI results with daily SOFA-scores. RESULTS: Serial HSI at the three measurement sites in healthy volunteers showed a low mean variance expressing high retest reliability. HSI at E demonstrated significantly lower StO2 and NPI as well as higher TWI at the palm and fingertip in septic patients compared to healthy volunteers. StO2 and TWI showed corresponding results at the suprapatellar knee area. In septic patients, palm and fingertip THI identified survivors (E-t4) and revealed predictivity for 28-day mortality (E). Fingertip StO2 and THI correlated to SOFA-score on day 2. TWI was consistently increased in relation to the TWI range of healthy controls during the observation time. Palm TWI correlated positively with SOFA scores on day 3. DISCUSSION: HSI results in septic patients point to a distinctive microcirculatory pattern indicative of reduced skin oxygenation and perfusion quality combined with increased blood pooling and tissue water content. THI might possess risk-stratification properties and TWI could allow tissue edema evaluation in critically ill patients. CONCLUSION: HSI technologies could open new perspectives in microcirculatory monitoring by visualizing oxygenation and perfusion quality combined with tissue water content in critically ill patients - a prerequisite for future tissue perfusion guided therapy concepts in intensive care medicine.

[Morel-Lavallée lesion : Severely injured 13 year old after being run over]. / Morel-Lavallée-Läsion : Schwerstverletzte 13-Jährige nach Überrolltrauma.

Accidents in which a person is run over are often associated with multiple serious injuries. Immediate bleeding control is crucial. Pressure and shear stress at the borders of subcutaneous tissue to the muscle fascia can cause hypoperfusion and the emergence of blood-filled cavities that are associated with a high risk of infection and necrosis, a so-called Morel-Lavallée lesion. Insufficient therapy can lead to local complications and furthermore to live-threatening sepsis.

Crystalloid volume versus catecholamines for management of hemorrhagic shock during esophagectomy - assessment of microcirculatory tissue oxygenation of the gastric conduit in a porcine model using hyperspectral imaging - an experimental study.

INTRODUCTION: Oncologic esophagectomy is a two-cavity procedure with considerable morbidity and mortality. Complex anatomy and the proximity to major vessels constitute a risk for massive intraoperative hemorrhage. Currently, there is no conclusive consensus on the ideal anesthesiologic countermeasure in case of such immense blood loss. The objective of this work was to identify the most promising anesthesiologic management in case of intraoperative hemorrhage with regards to tissue perfusion of the gastric conduit during esophagectomy using hyperspectral imaging (HSI). MATERIAL AND METHODS: An established live porcine model (n=32) for esophagectomy was used with gastric conduit formation and simulation of a linear stapled side-to-side esophagogastrostomy. After a standardized procedure of controlled blood loss of about 1 L per pig, the four experimental groups (n=8 each) differed in anesthesiologic intervention i.e. (I) permissive hypotension, (II) catecholamine therapy using noradrenaline, (III) crystalloid volume supplementation and (IV) combined crystalloid volume supplementation with noradrenaline therapy. HSI tissue oxygenation (StO2) of the gastric conduit was evaluated and correlated with systemic perfusion parameters. Measurements were conducted before (T0) and after (T1) laparotomy, after hemorrhage (T2) and 60 minutes (T3) and 120 minutes (T4) after anesthesiologic intervention. RESULTS: StO2 values of the gastric conduit showed significantly different results between the four experimental groups with 63.3% (±7.6%) after permissive hypotension (I), 45.9% (±6.4%) after catecholamine therapy (II), 70.5% (±6.1%) after crystalloid volume supplementation (III) and 69.0% (±3.7%) after combined therapy (IV). StO2 values correlated strongly with systemic lactate values (r=-0.67; CI -0.77 to -0.54), which is an established prognostic factor. CONCLUSION: Crystalloid volume supplementation (III) yields the highest StO2 values and lowest systemic lactate values and therefore appears to be the superior primary treatment strategy after hemorrhage during esophagectomy with regards to microcirculatory tissue oxygenation of the gastric conduit.

The Bethesda terminology for reporting thyroid cytopathology: from theory to practice in Europe.

OBJECTIVES: A 2007 conference held at the National Cancer Institute, Bethesda, Md., USA, proposed a new terminology for classifying the results of thyroid fine-needle aspiration (FNA) - The Bethesda System for Reporting Thyroid Cytology (TBSRTC). The need to standardize thyroid FNA terminology was emphasized during the 35th European Congress of Cytology in 2009. An interobserver review study to assess the new terminology for analyzing the results of thyroid FNA was organized by the scientific committee of the European Federation of Cytology Societies. STUDY DESIGN: Four experts in thyroid FNA examined and classified 116 FNAs according to the 6 levels of TBSRTC which are: nondiagnostic (ND); benign; atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS); follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN), with those of Hürthle cell type reported as follicular neoplasm, Hürthle cell type/suspicious for a follicular neoplasm, Hürthle cell type (FNHCT/SFNHCT); suspicious (SUS), and malignant. RESULTS: The total consensus was 62.1%; the cytopathologists disagreed on 44 cases, including 8 cases of AUS/FLUS and 18 of FN/SFN; 59% of the cases had no consensus. They agreed on 73 and 80% of the cases classified as benign and malignant, respectively, and on 58.3% of the SUS cases. The percentage of no consensus for each expert was between 32 and 39%. CONCLUSIONS: Disagreement regarding the use of TBSRTC terminology for classifying the results of thyroid FNA mainly occurred in the most-often criticized categories of AUS/FLUS and FN/SFN.

Cervical cancer screening in Mediterranean countries: implications for the future.

Prompted by feedback from the 34th European Congress of Cytology (ECC), the practice of including a special symposium in the programme was continued in the 35th ECC in Lisbon (2009) by arranging a satellite symposium entitled 'Cervical Cancer Screening in the Mediterranean Countries'. Because of the importance to the future of this discipline, it was felt appropriate to summarize the highlights of this symposium here. Cervical cancer prevention strategies in the countries participating in the symposium (Portugal, Spain, Italy, Croatia, Greece and Turkey) appear to be highly variable. As yet, none of these countries can demonstrate a fully implemented national screening programme, but all are in different phases of designing and/or setting up such a programme, which is important. At present, the time-honoured concept of cervical cancer prevention by Pap smear screening is under review, because prophylactic human papillomavirus (HPV) vaccines demonstrate a potential to prevent the vast majority (albeit not all) of cases of cervical cancer in the foreseeable future. Cervical cancer screening is still needed in this emerging era of HPV vaccination, but clearly the existing screening strategies must be modified to provide a cost-effective combination of vaccination and screening. If the currently evaluated new screening strategies, such as HPV testing followed by cytology triage, become a reality, there is the likelihood that the Pap test will have only a secondary role, subordinate to HPV testing. Supporters of this scenario claim that Pap test performance will deteriorate in vaccinated populations. Reduced positive predictive value (PPV), due to lower disease prevalence, is inevitable, however, and this would also affect HPV tests. Any decline in sensitivity and specificity depends on human performance, and as such is avoidable by taking appropriate preventive measures. As clinical cytologists, we should focus attention on minimizing the risk to the Pap test of falling sensitivity because of unfamiliarity with abnormal cells, and also of reduced specificity if the fear of missing significant disease leads to overcalling of benign abnormalities.

BRCA1 dysfunction in sporadic basal-like breast cancer.

Basal-like breast cancers form a distinct subtype of breast cancer characterized by the expression of markers expressed in normal basal/myoepithelial cells. Breast cancers arising in carriers of germline BRCA1 mutations are predominately of basal-like type, suggesting that BRCA1 dysfunction may play a role in the pathogenesis of sporadic basal-like cancers. We analysed 37 sporadic breast cancers expressing the basal marker cytokeratin 5/6, and age- and grade-matched controls, for downregulation of BRCA1. Although BRCA1 promoter methylation was no more common in basal-like cancers (basal 14% vs controls 11%, P=0.72), BRCA1 messenger RNA expression was twofold lower in basal-like breast cancers compared to matched controls (P=0.008). ID4, a negative regulator of BRCA1, was expressed at 9.1-fold higher levels in basal-like breast cancer (P<0.0001), suggesting a potential mechanism of BRCA1 downregulation. BRCA1 downregulation correlated with the presence of multiple basal markers, revealing heterogeneity in the basal-like phenotype. Finally, we found that 63% of metaplastic breast cancers, a rare type of basal-like cancers, had BRCA1 methylation, in comparison to 12% of controls (P<0.0001). The high prevalence of BRCA1 dysfunction identified in this study could be exploited in the development of novel approaches to targeted treatment of basal-like breast cancer.

Epileptogenicity and pathology - Under consideration of ablative approaches.

Besides resective epilepsy surgery, minimally invasive ablation using new diagnostic and therapeutic techniques recently became available. Optimal diagnostic approaches for these treatment options are discussed. The pathophysiology of epileptogenic networks differs depending on the lesion-types and location, requiring a differential use of non-invasive or invasive functional studies. In addition to the definition of epileptogenic zones, a challenge for pre-surgical investigation is the determination of three-dimensional epileptic networks to be removed.

Radiofrequency-thermoablation: General principle, historical overview and modern applications for epilepsy.

Stereotactically guided radiofrequency thermoablation (RFTA) for epilepsy has been frequently applied over the last 40 years. Radiofrequency electrodes with temperature control function generate a coagulation lesion with clearly defined borders. In combination with high-resolution MRI imaging, this technique allows minimally-invasive ablation of periventricular nodular heterotopias, small focal type II dysplasias, and hypothalamic hamartomas. This review summarises the literature addressing this topic mainly regarding technical aspects. In essence, RFTA is a safe treatment option for patients suffering from epileptogenic pathologies visible on MRI-images.

Mutations in gastrointestinal stromal tumors diagnosed by endoscopic ultrasound-guided fine needle aspiration.

Gastrointestinal stromal tumors (GISTs) are characterized by overexpression and mutations of c-Kit. Approximately 80% of c-Kit mutations occur in exon 11, being a response factor to imatinib (Gleevec) therapy. We aimed to assess whether c-Kit and PDGFRA mutation analysis of GISTs obtained by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) could be routinely performed. Mutation analysis of c-Kit hotspot exons (9, 11, 13 and 17) and PDGFRA hotspot exons (12 and 18) was performed in aspirates 51 mesenchymal tumors. We identified c-Kit mutations in 61% of GIST cases, in accordance with previously published ranges (30-90%). Nearly 95% (19/20) of c-kit-mutant tumors carried exon 11 mutations. Mutation analysis is possible in FNA cell blocks and can assist in the diagnosis and therapeutic decisions in GIST cases.

Multistep progression from an oestrogen-dependent growth towards an autonomous growth in breast carcinogenesis.

We investigated the relationship between hormone receptor status and cellular proliferation in a series of proliferative epithelial breast lesions in an attempt to clarify the putative role of this interaction in the process of breast carcinogenesis. The separation of oestrogen receptor (ER) positive and ER negative cases revealed that in hyperplastic breast epithelium (with and without atypia) the ER positive cases had a higher proliferation rate than that of ER negative cases. Conversely, in ductal carcinomas (both in situ and invasive), ER negative cases had rates of proliferation higher than those observed among the ER positive cases. The observation of higher proliferation in ER positive benign proliferative breast lesions fits with the concept of an initial hormone-dependent status in breast carcinogenesis. According to this assumption, activation of ER by hormone increases the possibility that cells may undergo malignant transformation. Although we are limited by our static view of the process, our results point to the existence of successive steps of progression from a hormone-dependent towards an autonomous growth. The demonstration of higher proliferation in ER-negative carcinomas, from the in situ phase onwards, reinforces the hypothesis that breast cancer progression is paralleled by a progressive hormone independence.

Adenoid cystic carcinoma of trachea metastatic to the placenta.

This is the first case described of an adenoid cystic carcinoma of trachea metastatic to the placenta. An immunohistochemical study is reported as well as a brief review of the literature.

Spectrum of carcinoembryonic antigen immunoreactivity from isolated ductal hyperplasias to atypical hyperplasias associated with infiltrating ductal breast cancer.

AIMS: To study the immunohistochemical expression of carcinoembryonic antigen (CEA) in ductal hyperplasia of the breast and to investigate its putative relation with atypia and co-existing infiltrating ductal carcinoma. METHODS: Paraffin wax embedded tissue from 37 cases of isolated ductal hyperplasia (five with atypia and 32 without atypia) and 25 cases of ductal hyperplasia associated infiltrating ductal carcinoma (IDC) (seven with atypia and 18 without atypia) was stained with a monoclonal anti-CEA antibody using a standard avidin biotin immunoperoxidase method. RESULTS: CEA immunoreactivity was observed in eight (12.8%) ductal hyperplasia cases. The percentage of CEA positivity in ductal hyperplasia cases with atypia (33.3%) was substantially higher than that observed in cases of ductal hyperplasia without atypia (8.0%). Six cases of ductal hyperplasia associated IDC reacted with CEA; in these six cases the neoplastic cells of the co-existing carcinoma were also CEA positive. The percentage of CEA immunoreactivity in ductal hyperplasia associated IDC was higher than that observed in isolated ductal hyperplasia (24.0 v 5.4%). The percentage of CEA immunoreactivity in atypical ductal hyperplasia associated IDC was similar to that observed in IDC alone (42.9 v 40.0%). CONCLUSIONS: The presence of CEA immunoreactivity has been confirmed in benign proliferative breast lesions. The prevalence of such immunoreactivity increases from 3.1% in isolated, nonatypical ductal hyperplasia to 42.9% in atypical ductal hyperplasia associated IDC. This finding and the similarity of the frequency of CEA positivity in atypical ductal hyperplasia associated IDC and in IDC alone suggests that there is a pathogenetic link between ductal hyperplasia and some types of breast cancer.

Simple mucin-type carbohydrate antigens (T, sialosyl-T, Tn and sialosyl-Tn) in breast carcinogenesis.

Immunohistochemical analysis of the expression of simple mucin-type carbohydrate antigens (Tn, sialyl-Tn and T) was performed in a series of 43 cases of intraductal hyperplasia without atypia, 9 cases of intraductal hyperplasia with atypia, 54 cases of ductal carcinoma in situ (DCIS) and 26 cases of invasive breast carcinoma. We also studied 36 cases of isolated breast normal epithelium, 20 cases of "normal" breast epithelium adjacent to neoplasms and 14 cases of apocrine metaplasia. All antigens were detected in different frequencies in normal, hyperplastic, metaplastic and neoplastic breast epithelium. Tn and sialyl-Tn are expressed more frequently in malignant than in benign breast epithelium; while Tn expression increases from normal to invasive carcinomas, sialyl-Tn increases until DCIS and drops in invasive carcinomas, suggesting that either there is a failure of a proportion of DCIS to progress to invasive carcinoma or loss of expression of sialyl-Tn when some carcinomas become invasive. The high frequency of Tn and sialyl-Tn expression in breast intraductal proliferations probably reflects incomplete glycosylation in these lesions, which is a well-known tumour-associated phenomenon and supports the assumption that such lesions are putative precursors of breast cancer. T antigen was expressed in all groups studied, but its prevalence differed significantly between normal and neoplastic epithelium. The expression of these antigens in epithelium adjacent to carcinomas is similar to that found in isolated normal breast epithelium, whereas apocrine metaplasia has a pattern of simple mucin-type glycosylation that is specific and distinct from that of the normal breast epithelium, with a high frequency of marked expression of Tn and sialyl-Tn. The similarity of the pattern of expression of simple mucin-type antigens in metaplasia and malignant neoplasia reduces the usefulness of these markers from a diagnostic standpoint.

Bilateral apocrine carcinoma of the breast. Molecular and immunocytochemical evidence for two independent primary tumours.

Apocrine carcinoma is an uncommon variant of breast cancer. The frequency of bilaterality in patients who have apocrine carcinoma in one breast is not significantly different from that for bilateral mammary carcinomas in general, but bilateral apocrine carcinomas are very uncommon. We report on a bilateral apocrine carcinoma of the breast in a 74-year-old woman. The apocrine differentiation in both tumours was confirmed by the positivity of the cytoplasmic granules for PAS after diastase digestion and immunoreactivity for GCDFP-15 and sialyl-Tn. The tumour in the right breast showed immunohistochemical expression of p53, and a mutation was demonstrated by PCR-SSCP; the tumour in the left breast was negative for p53 on immunohistochemistry, and no mutation was found at the molecular level. c-erbB2 expression was not detected in the right tumour but there was overexpression (at the cell membrane) in the left tumour. Both tumours were aneuploid: the right tumour displayed multiple stemlines, whereas the left tumour had a triploid profile. Using the fluorescence in situ hybridization technique we demonstrated that both tumours displayed chromosome 17 polysomy and numerical abnormalities of chromosome 1, polysomy in the right and monosomy in the left tumour. We conclude that the two tumours are probably independent, as are most bilateral carcinomas of the breast.

p63 Staining of myoepithelial cells in breast fine needle aspirates: a study of its role in differentiating in situ from invasive ductal carcinomas of the breast.

AIMS: One of the limitations of fine needle aspiration biopsy (FNAB) of the breast is in distinguishing invasive carcinoma (IDC) from ductal carcinoma in situ (DCIS). It has been proposed that the presence of myoepithelial cells overlying epithelial malignant cell clusters suggests DCIS. However, the recognition of myoepithelial cells in aspirates may be difficult. The aim of this study was to investigate a new nuclear myoepithelial cell marker, p63, a p53 homologue nuclear transcription factor, in a series of breast FNABs in an attempt to distinguish IDC from DCIS. METHODS: Papanicolaou stained smears from eight cases of pure DCIS and 15 cases of pure IDC with a histologically confirmed diagnosis were submitted to immunocytochemical analysis using the antibody 4A4 against p63. Two pathologists evaluated the presence of p63 positive cells overlying malignant cell clusters and admixed with malignant cells. The frequency of p63 positive cells in DCIS and IDC was compared using Fisher's exact test. RESULTS: p63 consistently stained the nuclei of myoepithelial cells, either overlying malignant cell clusters and/or admixed with malignant cells. p63 positive myoepithelial cells were seen in all DCIS cases and in nine of the 15 cases of IDC (p = 0.0375). In eight cases (three DCIS and five IDC), scattered p63+ epithelial malignant cells were seen. CONCLUSIONS: Although p63 positive myoepithelial cells are found more frequently in DCIS cases, their presence cannot be used as a criterion to rule out invasion in breast FNABs because they are present in up to 60% of invasive cases.

Cyclo-oxygenase 2 expression is associated with angiogenesis and lymph node metastasis in human breast cancer.

AIMS: Cyclo-oxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin biosynthesis. COX-2 is induced by a wide variety of stimuli, and present during inflammation. COX-2 overexpression has been observed in colon, head and neck, lung, prostate, stomach, and breast cancer. In colon and gastric cancer, COX-2 expression was associated with angiogenesis. The aim of this study was to determine the relation between COX-2 expression and angiogenesis in breast cancer, and to correlate the expression of this enzyme with classic clinicopathological parameters. METHODS: COX-2 expression was investigated by immunohistochemistry and western blotting analysis. The expression of COX-2 was then related to age, histological grade, nodal status, oestrogen receptor status, p53 expression,c-erb-B2 overexpression, mitotic counts, MIB-1 labelling index, apoptotic index, sialyl-Tn expression, transforming growth factor alpha expression, microvessel density, and disease free survival in 46 patients with invasive ductal breast carcinoma. RESULTS: By means of immunohistochemistry, COX-2 expression was detected in eight of the 46 carcinomas studied. Western blotting showed COX-2 protein expression in the same breast tumours, but not in normal adjacent tissues. The density of microvessels immunostained with anti-F-VIII related antigen was significantly higher in patients with COX-2 expression than in those without expression (p = 0.03). In addition, COX-2 was significantly associated with the presence of sialyl-Tn expression (p = 0.02), lymph node metastasis (p = 0.03), a high apoptotic index (p = 0.03), and a short disease free survival (p = 0.03) in univariate analyses. CONCLUSIONS: These data suggest that COX-2 expression is associated with angiogenesis, lymph node metastasis, and apoptosis in human breast cancer. Moreover, these results warrant further studies with larger series of patients to confirm the association with short disease free survival in patients with breast cancer.