The molecular pathology of ovarian serous borderline tumors.

Molecular studies in ovarian serous borderline tumors (OSBTs) have been used to understand different aspects of this neoplasm. (i) Pathogenesis, Kras and Braf mutations represent very early events in the tumorigenesis of OSBT as both are detected in serous cystadenomas associated with OSBTs. In contrast, serous cystadenomas without OSBTs do not show Kras or Braf mutations. In OSBTs, Kras mutations range from 17% to 39.5%, while Braf mutations range from 23% to 48%. The former is comparable with the range of Kras mutations in ovarian low-grade serous carcinomas (OLGSCa), 19%-54.5%. In contrast, Braf mutations in OLGSCa range from 0% to 33%. Serous cystadenomas appear to progress to OSBT due to a Braf mutation, but this mutation is rarely involved in the progression to OLGSCa. OSBTs with Braf mutation are associated with cellular senescence and up-regulation of tumor suppressor genes. In contrast, OSBTs without a Braf mutation may progress to OLGSCa due to Kras mutation or some other genetic alterations. (ii) The relationship between OSBTs and the extraovarian disease, a monoclonal versus mutifocal origin? This is still matter of debate as studies using different techniques have failed to settle this controversy. (iii) Biological behavior, Braf mutations appear to have a protective role against the progression of OSBT to OLGSCa, while Kras mutations are commonly seen in cases of OSBT that recurred as LGSCa. Nevertheless, LGSCa as a recurrence of an OSBT can originate from OSBTs with or without detectable Kras mutations. Also, it appears to be an association between Kras G12v mutation and a more aggressive phenotype of OSBT that recurred as LGSCa. (iv) Actionable targets, currently there are limited data. It has been reported that cancer cell lines with Kras G12v mutation are more sensitive to selumetinib than cell lines with wild-type Kras.

[NEMS: a new predictor of mortality in the critical patient?]. / NEMS: ¿nuevo predictor de mortalidad en el paciente crítico?

Numerical scales are commonly used in intensive care units to predict hospital mortality and to assess the therapeutic effort and care that critically ill patients require. The aim of this work was to study whether the NEMS value can be used as a predictor of mortality, comparing it with the APACHE II. A prospective study in a 24 intensive care unit beds was conducted. The APACHE II and NEMS values were stratified into three levels. Demographic data and the first 24 hours values of APACHE II and NEMS scales were collected. A total of 1257 patients were included, 16.4% of whom died. 69.6% were surgical; median stay was 2 days (1-4). Median age was 66 years (50-77), 59.3% were men. The median APACHE II and NEMS for the living and the dead in the subsequent course was 10 (6-20) versus 22.5 (17.25 to 29) (p <0.001) and 24 (18-29) versus 34 (25 to 39.7) (p<0.001) respectively. The correlation between both scales was rho=0.457 (p<0.01). Logistic regression controlled for age, sex and APACHE II showed an OR of 3.1 (95% CI: 1.5-6.6) only for high NEMS, compared to the lowest level. According to the results NEMS should not be used as a predictor of mortality, although the risk of death increases by three times with high NEMS.

[Blood glucose levels in the first 24 hours of admission is not a risk factor for mortality in critical care patients]. / La glucemia de las primeras 24 horas no es un factor pronóstico de mortalidad en pacientes críticos.

INTRODUCTION: Glycemic alterations are known as a risk condition of death in several diseases, such as ischemic cardiovascular and neurological disorders. The fact that its tight control under narrow normality levels decreases mortality and morbidity have led to further studies seeking to confirm the results and expand them to other disease areas. OBJECTIVES: To determine whether glycemic changes by themselves are a mortality risk factor in a sample of patients within an Intensive Care Unit (ICU), among which predominates traumatic-surgical patients. METHODS: Demographic and analytical characteristics were revised, as well as common monitoring variables in an ICU, among a sample of 2,554 patients from admissions between 1st January 2004 and 31 December 2008. Data were obtained from a database which endorsed records compiled with the monitoring ICU patients program "Carevue". They were processed with dynamics sheets included in the Excel software with the following variables: initial glycemia, mean glycemia during the first 24 hours and number of determinations performed. We used the mean value in the admission day of the remaining analytical and monitoring variables and the number of test performed on this first day. The sample was stratified in two groups for the statistical analysis: a) General Sample (MG) and b) sample excluding patients admitted after a programmed surgery (EQP). In both cases the effect of initial and averaged glycemia was checked. Group b was divided in two, according to the number of determinations b1) a single blood glucose determination group (EQP1) and b2) a multiple determination group (EQPM). From this group of non-programmed surgical patients the study was repeated in those patients who stayed at the ICU 3 or more days (EQP3D). Chi-square and Mantel-Haenzel test for the ODD ratio determination were performed for qualitative variables; quantitative variables were examined with the Mann-Whitney test. At each analysis level, logistic regression was performed using mortality as the dependent variable, including those variables with p-values < 0.05 which represented more than 60% of the data. An initially saturated model with backward till the final equation was used. A p-value of 0.05 (i.e. p < 0.05) was set as the significant threshold for all statistical analysis. They were performed with SPSS and GSTAT 2 statistical software. RESULTS AND DISCUSSION: A total of 2,165 of the 2,554 admitted patients during the study period were included (96.5%). Exclusion criteria were absence of plasma glucose determinations. In the bivariate analysis, first and mean glucose blood levels showed significant differences in mortality rates in absolute figures and also when data were classified stratified in three levels (< 60 mg/dl; 60-110 mg/dl or > 110 mg/dl) or in two (normal values 60 to 110 mg/dl and unusual figures < 60 mg/dl or > 110 mg/dl). These significant differences were lost when a logistic model was applied. From the remaining variables, renal function and NEMS showed to be mortality risks factors in this sample. CONCLUSIONS: Hyperglycemia is a predominant phenomenon in critically ill patients. Hypoglycemia is less frequent and is associated with higher mortality rates. Initial glucose blood level, by itself, was not a mortality risk factor in the multivariate study and at none of the studied levels. Average glycemia did not add any prediction power. The changes in glucose blood levels seemed to be an adaptation process, which determined by itself a risk for the patient's discharge, at least in the first 24 hours period after ICU admission.

Guidelines for specialized nutritional and metabolic support in the critically-ill patient: update. Consensus SEMICYUC-SENPE: multiple trauma patient.

Patients with polytrauma can be viewed as paradigmatic of the critically-ill patient. These previously healthy patients undergo a life-threatening aggression leading to an organic response that is no different from that in other types of patients. The profile of trauma patients has changed and currently corresponds to patients who are somewhat older, with a higher body mass index and greater comorbidity. Severe injuries lead to intense metabolic stress, posing a risk of malnutrition. Therefore, early nutritional support, preferentially through the enteral route, with appropriate protein intake and glutamine supplementation, provides advantages over other routes and types of nutritional formula. To avoid overnutrition, reduced daily calorie intake can be considered in obese patients and in those with medullary lesions. However, little information on this topic is available in patients with medullary lesions.

Guidelines for specialized nutritional and metabolic support in the critically-ill patient: update. Consensus SEMICYUC-SENPE: cardiac patient.

Patients with cardiac disease can develop two types of malnutrition: cardiac cachexia, which appears in chronic congestive heart failure, and malnutrition due to the complications of cardiac surgery or any other type of surgery in patients with heart disease. Early enteral nutrition should be attempted if the oral route cannot be used. When cardiac function is severely compromised, enteral nutrition is feasible, but supplementation with parenteral nutrition is sometimes required. Sustained hyperglycemia in the first 24 hours in patients admitted for acute coronary syndrome, whether diabetic or not, is a poor prognostic factor for 30-day mortality. In critically-ill cardiac patients with stable hemodynamic failure, nutritional support of 20-25 kcal/kg/day is effective in maintaining adequate nutritional status. Protein intake should be 1.2-1.5 g/kg/day. Routine polymeric or high protein formulae should be used, according to the patient's prior nutritional status, with sodium and volume restriction according to the patient's clinical situation. The major energy source for myocytes is glutamine, through conversion to glutamate, which also protects the myocardial cell from ischemia in critical situations. Administration of 1 g/day of omega-3 (EPA+DHA) in the form of fish oil can prevent sudden death in the treatment of acute coronary syndrome and can also help to reduce hospital admission for cardiovascular events in patients with chronic heart failure.

[Guidelines for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus of the Spanish Society of Intensive Care Medicine and Coronary Units-Spanish Society of Parenteral and Enteral Nutrition (SEMICYUC-SENPE): patient with polytrauma]. / Recomendaciones para el soporte nutricional y metabólico especializado del paciente crítico. Actualización. Consenso SEMICYUC-SENPE: paciente politraumatizado.

Patients with polytrauma can be viewed as paradigmatic of the critically-ill patient. These previously healthy patients undergo a life-threatening aggression leading to an organic response that is no different from that in other types of patients. The profile of trauma patients has changed and currently corresponds to patients who are somewhat older, with a higher body mass index and greater comorbidity. Severe injuries lead to intense metabolic stress, posing a risk of malnutrition. Therefore, early nutritional support, preferentially through the enteral route, with appropriate protein intake and glutamine supplementation, provides advantages over other routes and types of nutritional formula. To avoid overnutrition, reduced daily calorie intake can be considered in obese patients and in those with medullary lesions. However, little information on this topic is available in patients with medullary lesions.

[Guidelines for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus of the Spanish Society of Intensive Care Medicine and Coronary Units-Spanish Society of Parenteral and Enteral Nutrition (SEMICYUC-SENPE): cardiac patient]. / Recomendaciones para el soporte nutricional y metabólico especializado del paciente crítico. Actualización. Consenso SEMICYUC-SENPE: paciente cardíaco.

Patients with cardiac disease can develop two types of malnutrition: cardiac cachexia, which appears in chronic congestive heart failure, and malnutrition due to the complications of cardiac surgery or any other type of surgery in patients with heart disease. Early enteral nutrition should be attempted if the oral route cannot be used. When cardiac function is severely compromised, enteral nutrition is feasible, but supplementation with parenteral nutrition is sometimes required. Sustained hyperglycemia in the first 24 hours in patients admitted for acute coronary syndrome, whether diabetic or not, is a poor prognostic factor for 30-day mortality. In critically-ill cardiac patients with stable hemodynamic failure, nutritional support of 20-25 kcal/kg/day is effective in maintaining adequate nutritional status. Protein intake should be 1.2*-1.5 g/kg/day. Routine polymeric or high protein formulae should be used, according to the patient's prior nutritional status, with sodium and volume restriction according to the patient's clinical situation. The major energy source for myocytes is glutamine, through conversion to glutamate, which also protects the myocardial cell from ischemia in critical situations. Administration of 1 g/ day of omega-3 (EPA+DHA) in the form of fish oil can prevent sudden death in the treatment of acute coronary syndrome and can also help to reduce hospital admission for cardiovascular events in patients with chronic heart failure.

Polypoid or non-polypoid? A novel dichotomous approach to uterine carcinosarcoma.

OBJECTIVE: To examine the impact of the polypoid morphology of uterine carcinosarcoma on clinical outcome, as well as its relationship to well-established prognostic factors. METHODS: In a retrospective study of fifty eight patients with uterine carcinosarcoma treated with hysterectomy, we correlated the polypoid status of tumors with stage, lymphatic vascular invasion, myometrial invasion, size, carcinoma to sarcoma ratio, type of carcinomatous and sarcomatous components, disease free survival and overall survival. RESULTS: By multivariate analysis, the polypoid status had no impact on disease free survival (p=0.8958), but approached significance as a positive predictor for overall survival (p=0.0569); patients in the polypoid group lived on average 14.9 months longer than those with non-polypoid tumors. Polypoid neoplasms had a smaller average size and grew to a smaller maximum size than the non-polypoid tumors. While non-polypoid tumors were either carcinoma or sarcoma predominant, polypoid tumors were mostly sarcoma predominant (p=0.0348). Polypoid carcinosarcomas also demonstrated an appreciably lesser extent of myometrial invasion (p=0.0019), a markedly lower rate of lymphatic vascular invasion (p=0.0002), and tended to present as early stage tumors (p=0.0265). Carcinomatous component in polypoid tumors tended to have pure or nearly pure (>or=90%) endometrioid histology (p=0.1608). There was no relationship between polypoid status and type of sarcomatous component (p=0.5299). CONCLUSIONS: Polypoid carcinosarcomas differ from their non-polypoid counterparts in key histological parameters such as the carcinoma to sarcoma ratio, myometrial and lymphatic vascular invasion, stage and type of carcinomatous component. Patients with polypoid tumors may have a better survival outcome than those with non-polypoid tumors.

High-grade ovarian serous carcinoma exhibits significantly higher p16 expression than low-grade serous carcinoma and serous borderline tumour.

AIMS: A dualistic pathway of ovarian serous carcinogenesis is now well established whereby high-grade serous carcinoma and low-grade serous carcinoma represent two distinct tumour types with a different underlying pathogenesis. The aim of this study was to compare expression of p16 INK4A (p16) in these two tumour types. We also included cases of serous borderline tumour, since these are considered to represent a precursor lesion of low-grade serous carcinoma. METHODS AND RESULTS: Cases of serous borderline tumour (n = 18), low-grade ovarian serous carcinoma (n = 22) and high-grade ovarian serous carcinoma (n = 24) were stained with a monoclonal antibody against p16. Cases were scored both with respect to intensity of immunoreactivity (weak, 1+; moderate, 2+; or strong, 3+) and distribution (0, negative or occasional positive cells; 1+, < 10% cells positive; 2+, 10-25% cells positive; 3+, 26-50% cells positive; 4+, 51-75% cells positive; or 5+, 76-100% cells positive). An immunohistochemical composite score was also calculated (0-15) by multiplying the intensity and distribution scores. There was a statistically significant difference in p16 immunoreactivity with respect to intensity, distribution and composite score between high-grade serous carcinoma and each of the other two groups, with the high-grade neoplasms exhibiting stronger and more diffuse positivity. Most high-grade serous carcinomas exhibited positivity of close to 100% of tumour cells. There was no significant difference in p16 expression between the borderline tumours and low-grade serous carcinomas. CONCLUSIONS: The increased expression of p16 in high-grade serous carcinoma compared with low-grade serous carcinoma and serous borderline tumour is in keeping with a different underlying pathogenesis. p16 may be implicated in the development of high-grade serous neoplasia within the ovary and elsewhere within the female genital tract.

Discordant genetic changes in ovarian and endometrial endometrioid carcinomas: a potential pitfall in molecular diagnosis.

Endometrioid carcinoma simultaneously involving ovaries as well as the uterine corpus may present a diagnostic dilemma because of the difficulty in determining whether the lesions are separate primary tumors or metastases. It has been reported that the detection of clonality using microsatellite markers may be useful in solving this dilemma. To determine the usefulness of this technique, we compared the genetic alterations in microsatellite markers present in matched pairs of ovarian tumors from 12 patients. The study includes four ovarian cancer FIGO stage I and eight stage III/IV patients, and four patients also with independent endometrial carcinoma of the uterus. DNA from paraffin-embedded tissue was extracted and amplified using a multiplex polymerase chain reaction, after which the status of microsatellite instability and loss of heterozygosity in four microsatellite loci (BAT25, BAT26, D17S250, and D5S346) were determined. In the four patients with stage I ovarian cancer, four microsatellite markers were identical in one patient and three were identical in the remaining three patients. In high-stage patients, three markers were identical in at least 4/8 cases. In three of four patients with uterine involvement, three of the four markers were identical in the uterine tumor and one of the corresponding ovarian tumors. These results suggest that genetic discordance does not indicate independent origin or metastasis of the tumor but instead a progression of genetic changes at separate sites probably due to the marked genetic instability existing in these tumors. Because of these discordant genetic changes, great caution should be taken when distinguishing between primary and metastatic tumors on the basis of microsatellite markers.

Benign multicystic peritoneal mesothelioma: cases reports in the family with diverticulosis and literature review.

We report on benign multicystic peritoneal mesothelioma in two siblings whose family had a history of multiple familial diseases including diverticulosis. After a genetic evaluation and a chromosomal analysis, we were not able to identify a specific genetic cause of the family's pattern of disease. We assumed that previous surgical procedures and the chronic inflammatory process from diverticulitis were the underlying etiology. Both patients had multiple recurrences with indolent courses similar to those reported in other cases. After the recurrences, one patient was treated with cystic aspiration and the other with hormones. The cysts in both cases regressed partially but the patients were relieved of their clinical symptoms, for 2 years after cystic drainage in one case and for 5 years after hormonal treatment in the other.

[Recommendations for nutritional assessment and specialized nutritional support of critically ill patients]. / Recomendaciones para la valoración nutricional y el soporte nutricional especializado de los pacientes críticos.

Due to the characteristics of critically ill patients, elaborating recommendations on nutritional support for these patients is difficult. Usually the time of onset of nutritional support or its features are not well established, so that its application is based on experts' opinion. In the present document, recommendations formulated by the Metabolism and Nutrition Working Group of the Spanish Society of Intensive and Critical Medicine and Coronary Units (SEMICYUC) are presented. Recommendations are based on the literature analysis and further discussion by the working group members in order to define, consensually, the more relevant issues of metabolic and nutritional support of patients in a critical condition. Several clinical situations have been considered which are developed in the following articles of this publication. The present recommendations aim at providing a guideline for the less experienced clinicians when considering the metabolic and nutritional issues of critically ill patients.

[Nutritional support in the critically ill patient: to whom, how, and when?]. / Soporte nutricional del paciente crítico: a quién, cómo y cuándo?

Existing data about indication and time of onset of nutritional support are not homogeneous. However, the presence of a deterioration of the nutritional status is accompanied by harmful effects so that, broadly speaking, specialized nutritional support onset would be advisable if a fasting period longer than 5-7 days is foreseen. Parenteral nutrition routinely administered to critically ill patients may increase their morbidity and mortality. Whenever possible, enteral nutrition should be the preferred route of nutrients intake since it has been shown to have a favorable effect on infectious complications rates. Enteral nutrition should be started early on (within the first 36 hours of admission). Although transpyloric nutrients administration may however reduce bronchoaspiration and increase the diet effective volume received by patients, there are no data for recommending routinary usage of the transpyloric route for nutritional support in the critically ill patients.

[Nutritional support in sepsis]. / Nutrición artificial en la sepsis.

Although it is considered that metabolic and nutritional support must be part of the management of septic patients, it has not been conclusively shown that nutritional support will improve survival or complications from sepsis. Specific data on this issue are scarce since there are few studies that have investigated specialized nutritional support in septic patients. Thus, most of the recommendations are based on outcomes obtained in severely ill patients with different pathologies. It is assumed that nutritional support should be carried out through the enteral route whenever possible, as in other critically ill patients. The energetic waste in these patients is highly variable, although in general terms the hypermetabolic situation may be classified as moderate. An adjustment factor of 1.25-1.30 is recommended for the Harris-Benedict's equation to calculate the caloric intake. Septic patients should receive a hyperproteic intake. The amount of glucose administered should not exceed 70% of non-protein calories, and lipids intake should not exceed 40%. With regards to micronutrients, it is recommended to increase the supply of those with antioxidant properties (vitamin E, carotenes, vitamin C, selenium). There are data to consider that the use of diets enriched with pharmaco-nutrients (both with parenteral and enteral routes) may be beneficial in septic patients, although there is some controversy when interpreting the outcomes.

Immunohistochemistry in gynecological pathology.

Although the majority of diagnoses in gynecological pathology are established on examination of routine hematoxylin and eosin stained sections, additional tests are occasionally required. Immunohistochemistry is widely used to provide additional diagnostic information in problematic cases. This review touches on some of the basics of the procedure, presents an example immunohistochemical panel, and discusses some of the most common immunohistochemical markers used in diagnostic gynecological pathology. Differential diagnostic problems and relevant immunohistochemical stains for the vulva, vagina, cervix, uterus, and ovary are also addressed.

Langerhans cell histiocytosis of the female genital tract: a literature review.

Langerhans cell histiocytosis (LCH) is a rare malignant disease involving the accumulation of a monoclonal proliferation of cells in various organs, that phenotypically resemble Langerhans cells (LC). LCH is not merely a hyperplasia of LC, as it typically affects organs that are outside of their normal physiologic distribution. Normal Langerhans cells are bone marrow-derived dendritic cells that populate the epidermis and are distinguished by the presence of Birbeck granules and cell surface protein CD1a. LC act as sentinels; they recognize, internalize, and process antigens encountered in the skin. Upon encountering an antigen, LC become activated with subsequent maturation and induction of their migratory capacity. Langerhans cells in patients with LCH are aberrant and profoundly differ from normal LC. The clinical spectrum of LCH is quite diverse; multiple organs can be affected. "Pure" genital Langerhans cell histiocytosis is a rare presentation, with only 12 previously reported cases. Due to the rarity of this disease, treatment of genital LCH is still very diverse. No modality is proven to be superior in improving patient outcome, and relapses frequently occur after surgery. Dramatic responses of cutaneous and ano-genital lesions to thalidomide and interferons have been reported. We advocate the use of immuno-modulating agents in LCH of the female genital tract first, rather than surgery.

Near real time in vivo fibre optic confocal microscopy: sub-cellular structure resolved.

We have built a fibre optic confocal reflectance microscope capable of imaging biological tissue in near real time. The measured lateral resolution is 3 micro m and axial resolution is 6 micro m. Images of epithelial cells, excised tissue biopsies, and the human lip in vivo have been obtained at 15 frames s-1. Both cell morphology and tissue architecture can be appreciated from images obtained with this microscope. This device has the potential to enable reflected light confocal imaging of internal organs for in situ detection of pathology.

Desmoplastic small round cell tumor: report of a case presenting as a primary ovarian neoplasm.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is an intra-abdominal malignancy that typically has extensive peritoneal spread at the time of diagnosis. We report a case of DSRCT with involvement of the ovary and omentum as well as an elevated CA-125 level at presentation. CASE: A 23-year-old female presented to another institution with a pelvic mass and a CA-125 level of 140 U/ml. During tumor reductive surgery the right ovary, omentum, and liver were found to be involved. Initial histologic examination favored an undifferentiated small cell carcinoma of the ovary. The patient received two cycles of Taxol and cisplatin chemotherapy and was referred to the University of Texas M. D. Anderson Cancer Center. Upon review of the pathology material at the time of the referral, a diagnosis of DSRCT was made. Despite two additional cycles of chemotherapy, the tumor progressed, and the patient returned home. CONCLUSION: DSRCT may mimic an ovarian primary tumor by presenting with involvement of the ovary and an elevated CA-125 level, and should be included in the differential diagnosis of ovarian neoplasms in young patients.

Vessels within vessels in the myometrium.

We have encountered a peculiar vascular architecture in the myometrium wherein arteries are found free-floating within cleft-like spaces. Using different colored dye injections in the uterine arteries and veins, we demonstrated that these spaces are venous channels. This was confirmed by immunoperoxidase staining for CD34, which enhanced the cells lining these spaces. A review of 81 hysterectomy specimens showed that this vascular architecture was present in 42 cases (52%), while it was identified in the parenchyma of only two mastectomy specimens among the 45 specimens from different organs studied. A strong association existed between the presence of this architecture and history of menorrhagia (p = 0.0116). This peculiar vascular architecture might be important in the pathogenesis of menorrhagia and the development of intravenous leiomyomatosis. Pathologists should also be able to recognize these spaces as vascular channels in the event that malignant cells are identified within them.