Nikolaos Goutas

Breast Angiosarcoma That Is Not Related to Radiation Exposure : A Comprehensive Review of the Literature

Breast angiosarcomas that are not related to previous radiotherapy are very rare. Surgical resection is the primary treatment for these tumors, but there is no general agreement on the extent of surgery. The role of multimodality adjuvant treatment also remains controversial. The aim of this study was to summarize the available data from the largest published series of patients in terms of management and outcome. We also sought to identify prognostic factors influencing patient survival. We have included studies presenting detailed data on multimodality therapy and survival of patients with breast angiosarcoma. Ten studies presenting data on 280 patients were included in the review. Seventyfive percent of patients underwent a total mastectomy and 25% had breast-conserving treatment (BCT). In 42% of patients, an axillary node dissection was combined with mastectomy or BCT. Thirty-six percent of patients received chemotherapy and 35% were treated with radiotherapy in an adjuvant or neoadjuvant setting. Survival varied significantly according to tumor size and grade. Adjuvant multimodality therapy may improve the outcome in selected patients with breast angiosarcoma. Tumor size, grade, and margin status are the most important prognostic factors for survival.

Comparison of Chromogenic In Situ Hybridisation with Fluorescence In Situ Hybridisation and Immunohistochemistry for the Assessment of Her-2/neu Oncogene in Archival Material of Breast Carcinoma

The successful treatment of breast cancer is dependent upon a number of complex factors. Her-2/neu gene amplification is known to be one of the most common genetic alterations associated with breast cancer and its accurate determination has become necessary for the selection of patients for trastuzumab therapy. The aim of this study was to prove the consistency of chromogenic in situ hybridisation (CISH) technique after analyzing the overexpression of the Her-2/neu proto-oncogene in 100 invasive breast carcinomas and by comparing CISH results with immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH). Moreover, it was done to evaluate the possible correlation of estrogen (ERs) and progesterone receptors (PRs), the proliferation marker Ki67 and the tumour suppressor gene p53 with HER-2/neu status of these breast carcinomas. Of the 100 breast carcinomas that were analysed, 22 cases showed HER-2/neu amplification, 66 cases showed no amplification, whereas 12 cases were non-interpretable in both assays (FISH and CISH). Consequently, the overall concordance between FISH and CISH was 100%. Additionally, it was observed that when HER-2/neu gene was overexpressed, there was an association with negative PRs and ERs status, negative p53 protein expression and high Ki67 labelling index. It is concluded that patients with tumours scoring 2+ with the CBE356 antibody (borderline immunohistochemistry-tested cases) would also benefit from CISH as it is shown to be highly accurate, practical and can be easily integrated into routine testing in any histopathology laboratory. Finally, CISH represents an important addition to the HER2 testing algorithm.

Hypoxemic resuscitation from hemorrhagic shock prevents lung injury and attenuates oxidative response and IL-8 overexpression

We investigated whether hypoxemic resuscitation from hemorrhagic shock prevents lung injury and explored the mechanisms involved. We subjected rabbits to hemorrhagic shock for 60 min by exsanguination to a mean arterial pressure of 40 mm Hg. By modifying the fraction of the inspired oxygen, we performed resuscitation under normoxemia (group NormoxRes, P(a)O(2)=95-105 mm Hg) or hypoxemia (group HypoxRes, P(a)O(2)=35-40 mm Hg). Animals not subjected to shock constituted the sham group (P(a)O(2)=95-105 mm Hg). We performed bronchoalveolar lavage (BAL) fluid, lung wet-to-dry weight ratio, and morphological studies. U937 monocyte-like cells were incubated with BAL fluid from each group. Cell peroxides, malondialdehyde, proteins, and cytokines in the BAL fluid were lower in sham than in shocked animals and in HypoxRes than in NormoxRes animals. The inverse was true for ascorbic acid and reduced glutathione. Lung edema, lung neutrophil infiltration, myeloperoxidase, and interleukin (IL)-8 gene expression were reduced in lungs of HypoxRes compared with NormoxRes animals. A colocalized higher expression of IL-8 and nitrotyrosine was found in lungs of NormoxRes animals compared to HypoxRes animals. The BAL fluid of NormoxRes animals compared with HypoxRes animals exerted a greater stimulation of U937 monocyte-like cells for proinflammatory cytokine release, particularly for IL-8. In the presence of p38-MAPK and Syk inhibitors and monosodium urate crystals, IL-8 release was reduced. We conclude that hypoxemic resuscitation from hemorrhagic shock ameliorates lung injury and reduces oxygen radical generation and lung IL-8 expression.

Atypical Kawasaki disease presenting with symptoms from the genitourinary system: an autopsy report.

Symptoms from the genitourinary system are unusual in Kawasaki disease (KD). Renal involvement is even rarer and it is confirmed by biopsy when the person is alive. We describe the case of an 11-year-old boy admitted to the hospital complaining about prolonged fever (5 days) and hematuria. His urinalysis showed also pyuria, proteinuria and urinary renal tubular epithelial cells concentrations. During the next days, the patient presented limb edema. After almost 2 weeks of hospitalization the patient was transferred to the intensive care unit because of melena and intense abdominal pain. Upon admission, the patient collapsed and died. The diagnosis of KD was established during autopsy. The macroscopical and histopathological examination of the heart showed increased dimensions and weight and multiple thrombi in the coronary arteries with intramural dense polymorphonuclear inflammatory infiltration and necrosis. Histological examination of the kidneys revealed normal glomerulus, mild expansion of mesangial matrix, interstitial infiltration with lymphocytes, plasmatocytes and eosinophiles, normal vessels and normal immunofluorescence.

Mucinous tubular and spindle cell carcinoma of the kidney: a case report.

Background: Mucinous tubular and spindle cell carcinoma (MTSC) is a rare and newly described type of renal cell carcinoma (RCC) with relatively indolent behavior. Although there are small series of this clinical entity in the literature, its histogenetic origin or line of differentiation remains unclear. Patients and Methods: A 67-year-old woman was hospitalized for flank pain; imaging studies revealed a 6.5-cm mass in the right kidney. She was referred for fine needle aspiration of the lesion, which showed an epithelial tumor with round to oval nuclei associated with strands of metachromatic stromal tissue. Cytopathologic diagnosis was consistent with RCC. Results: Subsequent right heminephrectomy was performed and the surgical pathology specimen showed an MTSC of the kidney. The patient has done well postoperatively, with 24 months of benign follow-up. Conclusion: A precise differential diagnosis between MTSC and other renal carcinomas (e.g. papillary RCC with sarcomatoid transformation) is important for predicting patient prognosis. Even though MTSC is a rare cause of renal masses, it should be included in the differential diagnosis, especially because its imaging might be misleading, mimicking other benign renal diseases. Heminephrectomy is the preferred treatment in these subjects.

Anatomic Variations of the Right Hepatic Duct: Results and Surgical Implications from a Cadaveric Study

Purpose. Thorough understanding of biliary anatomy is required when performing surgical interventions in the hepatobiliary system. This study describes the anatomical variations of right bile ducts in terms of branching and drainage patterns, and determines their frequency. Methods. We studied 73 samples of cadaveric material, focusing on the relationship of the right anterior and posterior segmental branches, the way they form the right hepatic duct, and the main variations of their drainage pattern. Results. The anatomy of the right hepatic duct was typical in 65.75% of samples. Ectopic drainage of the right anterior duct into the common hepatic duct was found in 15.07% and triple confluence in 9.59%. Ectopic drainage of the right posterior duct into the common hepatic duct was discovered in 2.74% and ectopic drainage of the right posterior duct into the left hepatic duct in 4.11%. Ectopic drainage of the right anterior duct into the left hepatic ductal system and ectopic drainage of the right posterior duct into the cystic duct was found in 1.37%. Conclusion. The branching pattern of the right hepatic duct was atypical in 34.25% of cases. Thus, knowledge of the anatomical variations of the extrahepatic bile ducts is important in many surgical cases.

Does history of childhood maltreatment make a difference in prison? A hierarchical approach on early family events and personality traits

This study attempts to assess childhood maltreatment in prison through a hierarchical approach. The hierarchical approach principally aims to disentangle the independent effects of childhood maltreatment upon psychiatric morbidity/personality traits, if any, from the burden that the adverse family conditions have already imposed to the mental health of the maltreated individual-prisoner. To this direction, a conceptual framework with five hierarchical levels was constructed, namely: immutable demographic factors; family conditions; childhood maltreatment (physical abuse, neglect and sexual abuse); personality traits, habits and psychiatric morbidity; prison-related variables. A self-administered, anonymous set (battery) of questionnaires was administered to 173 male prisoners in the Chalkida prison, Greece; 26% of prisoners disclosed childhood maltreatment. Psychiatric condition in the family, parental alcoholism and parental divorce correlated with childhood maltreatment. After adjustment for immutable demographic factors and family conditions, childhood maltreatment was associated with aggression (both in terms of Lifetime History of Aggression and Buss–Perry Aggression Questionnaire scores), illicit substance use, personal history of psychiatric condition, current smoking, impulsivity and alcohol abuse. In conclusion, childhood maltreatment represents a pivotal, determining factor in the life course of male prisoners. Delinquents seem to suffer from long-term consequences of childhood maltreatment in terms of numerous mental health aspects.

Nitrosative and Oxidative Stresses Contribute to Post-Ischemic Liver Injury Following Severe Hemorrhagic Shock: The Role of Hypoxemic Resuscitation

Purpose Hemorrhagic shock and resuscitation is frequently associated with liver ischemia-reperfusion injury. The aim of the study was to investigate whether hypoxemic resuscitation attenuates liver injury. Methods Anesthetized, mechanically ventilated New Zealand white rabbits were exsanguinated to a mean arterial pressure of 30 mmHg for 60 minutes. Resuscitation under normoxemia (Normox-Res group, n = 16, PaO2 = 95–105 mmHg) or hypoxemia (Hypox-Res group, n = 15, PaO2 = 35–40 mmHg) followed, modifying the FiO2. Animals not subjected to shock constituted the sham group (n = 11, PaO2 = 95–105 mmHg). Indices of the inflammatory, oxidative and nitrosative response were measured and histopathological and immunohistochemical studies of the liver were performed. Results Normox-Res group animals exhibited increased serum alanine aminotransferase, tumor necrosis factor - alpha, interleukin (IL) -1β and IL-6 levels compared with Hypox-Res and sham groups. Reactive oxygen species generation, malondialdehyde formation and myeloperoxidase activity were all elevated in Normox-Res rabbits compared with Hypox-Res and sham groups. Similarly, endothelial NO synthase and inducible NO synthase mRNA expression was up-regulated and nitrotyrosine immunostaining increased in animals resuscitated normoxemically, indicating a more intense nitrosative stress. Hypox-Res animals demonstrated a less prominent histopathologic injury which was similar to sham animals. Conclusions Hypoxemic resuscitation prevents liver reperfusion injury through attenuation of the inflammatory response and oxidative and nitrosative stresses.

Validation of a Real-Time Quantitative Polymerase Chain Reaction Method for the Quantification of 3 Survivin Transcripts and Evaluation in Breast Cancer Tissues

BACKGROUND Survivin is a novel antiapoptotic gene, which is a member of the inhibitor of apoptosis protein (IAP) family. Recently, 3 splice variants of this gene were cloned and characterized. This study aimed to validate a sensitive and specific method for the detection of survivin variants in breast cancer. METHODS Real-time quantitative polymerase chain reaction (qPCR) was performed on the cDNA with a reverse primer specific for each splice variant and a pair of common hybridization probes. RESULTS The expression of wild-type survivin was significantly correlated with survivin-2b, survivin-ΔEx3, and the ratio of survivin-ΔEx3 to wild-type survivin (P < .001). The ratio of survivin-2b to wild-type survivin was strongly associated with the ratio of survivin-ΔEx3 to wild-type survivin (P < .001). There was a strong positive association between the grade of the tumor and survivin-2b mRNA, survivin-ΔEx3 mRNA, and the ratio of survivin-ΔEx3 to wild-type survivin mRNA (P < .05). The ratio of survivin-2b to wild-type survivin was significantly associated with the presence of estrogen receptors (P = .05). CONCLUSION Our validated data suggest that survivin isoforms may be related to clinicopathological features and could be used as molecular prognostic tools or as new therapy targets.

Genetic counseling of medullary breast cancer patients

To the Editor: Germline mutations in the BRCA1 and BRCA2 genes account for approximately 40% of families with evidence of inherited susceptibility to breast cancer but for only 2–3% of all breast cancer cases. However, these genes are highly penetrant, and mutations in either of these genes confer a 60–85% lifetime risk of breast cancer and a 15–40% lifetime risk of ovarian cancer (1). Mutation analysis in the BRCA1 and BRCA2 genes is cumbersome and expensive, because both genes are extremely large, with a total cDNA of 16.7 kb, and mutations are scattered throughout the entire coding region. It is therefore imperative for genetic counselors to be able to efficiently identify those patients in real need of the complete genetic analysis of both genes. An overrepresentation of the rare subtype of medullary breast carcinoma among patients with mutations in the BRCA1 gene has recently been reported, while this is not occurring for the BRCA2 gene (2–4). The inclusion of the histology of medullary breast cancer as an independent selection criterion for referral to BRCA1 mutation analysis, besides family history and age, has been proposed as a possibility for genetic counseling (2–4). However, in a recent investigation of 42 cases of typical and atypical medullary breast cancer, only three BRCA1 mutations (7%) were detected, and these were among young patients with a significant family history (5). It has also been proposed that besides family history, other morphological and biological features of breast cancer could improve the efficacy of BRCA1 mutation screening (6, 7). It is now realized that the tumor phenotype of BRCA1 mutation carriers differs significantly from the phenotype of sporadic breast cancer, while the phenotype of BRCA2 tumors lies somewhere in between. BRCA1 tumors tend to be of a higher grade and higher mitotic index than the sporadic cases (8). They are often negative for both estrogen and progesterone receptors (ER and PgR) and are associated with aneuploidy, high S-phase, and presence of p53 somatic mutations that confer a far more aggressive pattern in the BRCA1 tumor compared with a sporadic one (8). In the most recent and largest of all cohorts of cases with a BRCA1 germline mutation (n1⁄4 165), these observations were substantiated and three immunohistochemical markers emerged as the ones showing significant difference compared to sporadic breast cancer: 90% and 79% of the BRCA1 tumors were negative for the presence of the hormone receptors ER and PgR, respectively, and 97% of them were negative for the overexpression of the c-erbB-2 oncogene (9). Our data agree with the above remarks and we also suggest to include a fourth parameter: an estimate of the tumor proliferation with either the Ki-67 proliferation marker assessed immunohistochemically or the proliferation profile obtained from cytometry which in our BRCA1 tumors is always extensive (10, 11). The goal of our study was to test for the above two proposals and examine their validity alone or in combination in a group of medullary carcinoma patients. Medullary carcinoma of the breast is rather scarce (<3% of breast cancer cases in most populations), but we managed to collect phenotypic and genetic data from 17 Greek patients suffering from this rare subtype. Patients were asked about their family history in counseling sessions. After informed consent, mutation analysis was performed on genomic DNA isolated from blood leukocytes employing a combination of the Protein Truncation Test (PTT) for the large exon 11 of the BRCA1 gene and DNA sequencing on an ABI 310 Genetic Analyzer (Perkin-Elmer, Applied Biosystems, Foster City, CA, USA) of the other small exons and all exon/intron boundaries of the BRCA1 gene (including exon 11) (10). Complex rearrangements constituting about 10% of BRCA1 mutations were not covered by our mutation detection methods. Histological diagnosis and classification in the corresponding tumor specimens on hematoxylin and eosin slides were based on criteria previously described (12, 13). We performed immunohistochemistry (IHC) with the LSAB methodology by using the following monoclonal antibodies for the four phenotypic parameters mentioned above: 1D5 (ER), 10A9 (PgR), MIB-1 (Ki-67), and 3B5 (c-erbB-2), all purchased from Clin Genet 2004: 65: 343–344 Copyright # Blackwell Munksgaard 2004 Printed inDenmark. All rights reserved CLINICALGENETICS doi: 10.1111/j.1399-0004.2003.00231.x