Peritoneal cytology: impact on disease-free survival in clinical stage I endometrioid adenocarcinoma of the uterus

The prognostic significance of positive peritoneal cytology in endometrial carcinoma has led to the incorporation of peritoneal cytology into the current FIGO staging system, While cytology was shown to be prognostically relevant in patients with stage II and III disease, conflicting data exists about its significance in patients who would have been stage I but were classified as stage III solely and exclusively on the basis of positive peritoneal cytology (clinical stage I). Analysis was based on the data of 369 consecutive patients with clinical stage I endometrioid adenocarcinoma of the endometrium. Standard treatment consisted of an abdominal total hysterectomy, bilateral salpingo-oophorectomy with or without pelvic lymph node dissection. Peritoneal cytology was obtained at laparotomy by peritoneal washing of the pouch of Douglas and was considered positive if malignant cells could be detected regardless of the number of malignant cells present. Disease-free survival (DFS) was considered the primary statistical endpoint. In 13/369 (3.5%) patients, positive peritoneal cytology was found. The median follow-up was 29 months and 15 recurrences occurred. Peritoneal cytology was independent of the depth of myometrial invasion and the grade of tumour differentiation, Patients with negative washings had a DFS of 96'7e at 36 months compared with 67% for patients with positive washings (log-rank P < 0.001). The presence of positive peritoneal cytology in patients with clinically stage I endometrioid adenocarcinoma of the endometrium is considered an adverse prognostic factor. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

Melanoma in adolescents: A case-control study of risk factors in Queensland, Australia

The incidence of melanoma increases markedly in the second decade of life but almost nothing is known of the causes of melanoma in this age group. We report on the first population-based case-control study of risk factors for melanoma in adolescents (15-19 years). Data were collected through personal interviews with cases, controls and parents. A single examiner conducted full-body nevus counts and blood samples were collected from cases for analysis of the CDKN2A melanoma predisposition gene. A total of 201 (80%) of the 250 adolescents with melanoma diagnosed between 1987 and 1994 and registered with the Queensland Cancer Registry and 205 (79%) of 258 age-, gender- and location-matched controls who were contacted agreed to participate. The strongest risk factor associated with melanoma in adolescents in a multivariate model was the presence of more than 100 nevi 2 mm or more in diameter (odds ratio [OR] = 46.5, 95% confidence interval [Cl] = 11.4-190.8). Other risk factors were red hair (OR = 5.4, 95%Cl = 1.0-28.4); blue eyes (OR = 4.5, 95%Cl = 1.5- 13.6); inability to tan after prolonged sun exposure (OR = 4.7, 95%Cl = 0.9-24.6); heavy facial freckling (OR = 3.2, 95% Cl = 0.9-12.3); and family history of melanoma (OR = 4.0, 95%Cl = 0.8-18.9). Only 2 of 147 cases tested had germline variants or mutations in CDKN2A. There was no association with sunscreen use overall, however, never/rare use of sunscreen at home under the age of 5 years was associated with increased risk (OR = 2.2, 95%Cl = 0.7-7.1). There was no difference between cases and controls in cumulative sun exposure in this high-exposure environment. Factors indicating genetic susceptibility to melanoma, in particular, the propensity to develop nevi and freckles, red hair, blue eyes, inability to tan and a family history of the disease are the primary determinants of melanoma among adolescents in this high solar radiation environment. Lack of association with reported sun exposure is consistent with the high genetic susceptibility in this group. (C) 2002 Wiley-Liss, Inc.

Occult Axillary Lymph Node Metastases in Breast Cancer Do Matter: Results of 10-Year Survival Analysis

Axillary lymph node status is one of the most powerful prognostic factors for patients with breast cancer and is often critical in stratifying patients into adjuvant treatment regimens. In 203 apparently node-negative cases of breast cancer, a combination of immunohistochemical staining and step-sectioning identified occult metastases in 25% of cases. Ten-year follow-up information is available for these patients. Histologic features of the primary tumor and immunohistochemical staining for estrogen receptor, progesterone receptor, Her-2, and p53 were also evaluated. With multivariate analysis, both occult metastases and higher histologic grade of the primary tumor were independent predictors of disease-free survival. Histologic grade was the only significant independent predictor of overall survival. Estrogen receptor, progesterone receptor, Her-2, and p53 status did not predict the presence of metastases or survival when all tumor types were considered together. Metastases >0.5 mm significantly predicted a poorer disease-free survival when invasive ductal carcinomas were considered alone. Histologic grade was significantly associated with disease-free survival in the premenopausal and perimenopausal patients but not in the postmenopausal patients. The presence of occult metastases approached significance for overall survival in the premenopausal and perimenopausal patients but not in the postmenopausal patients.

Survival following mechanical ventilation of recipients of bone marrow transplants and peripheral blood stem cell transplants

Survival of bone marrow transplant recipients requiting mechanical ventilation is poor but improving. This study reports a retrospective audit of all haematopoietic stem cell transplant (HSCT) recipients requiring mechanical ventilation at an Australian institution over a period spanning 11 years from 1988 to 1998. Recipients of autologous transplants are significantly less likely to require mechanical ventilation than recipients of allogeneic transplants. Of 50 patients requiring mechanical ventilation, 28% survived to discharge from the intensive care unit, 20% to 30 days post-ventilation, 18% to discharge from hospital and 12% to six months post-ventilation. Risk factors for mortality in the HSCT recipient requiting mechanical ventilation include renal, hepatic and cardiovascular insufficiency and greater severity of illness. Mechanical ventilation of HSCT recipients should not be regarded as futile therapy.

The impact of positive peritoneal washings and serosal and adnexal involvement on survival in patients with stage IIIA uterine cancer

Objective. The aim of this study was to determine the prognostic significance of serosal involvement (SER), adnexal involvement (ADN), and positive peritoneal washings (PPW) in patients with Stage IIIA uterine cancer. We also sought to determine patterns of recurrence in patients with this disease. Methods. The records of 136 patients with Stage IIIA uterine cancer treated at the Queensland Centre for Gynecological Cancer between March 1983 and August 2001 were reviewed. One hundred thirty-six patients underwent surgery and 58 (42.6%) had full surgical staging. Seventy-five patients (55.2%) had external beam radiotherapy and/or brachytherapy postoperatively. Overall survival was the primary statistical endpoint. Statistical analysis included univariate and multivariate Cox models. Results. Forty-six patients (33.8%) had adnexal involvement, 23 (16.9%) had serosal involvement, and 40 (29.4%) had positive peritoneal washings. Median follow-up was 55.1 months (95% confidence interval, 36.9 to 73.4 months) after which time 71 patients (52.2%) remained alive. For patients with endometrioid adenocarcinoma, ADN and SER were associated with impaired survival on multivariate analysis (odds ratio 2.8 and 3.2, respectively). In the subgroup of patients with high-risk tumors (including papillary serous carcinomas, clear cell carcinomas, and uterine sarcomas), neither ADN, nor SER, nor PPW influenced survival. Conclusion. Patients with Stage IIIA uterine cancer constitute a heterogeneous group. For patients with endometrioid adenocarcinoma, both ADN and SER, but not PPW, were associated with impaired prognosis. For patients with high-risk histological types, prognosis is poor for all three factors. (C) 2002 Elsevier Science (USA).

Neuronal calcium-binding proteins and schizophrenia

Calcium-binding proteins (CBPs) such as calbindin, parvalbumin and calretinin are used as immunohistochemical markers for discrete neuronal subpopulations. They are particularly useful in identifying the various subpopulations of GABAergic interneurons that control output from prefrontal and cingulate cortices as well as from the hippocampus. The strategic role these interneurons play in regulating output from these three crucial brain regions has made them a focus for neuropathological investigation in schizophrenia. The number of pathological reports detailing subtle changes in these CBP-containing interneurons in patients with schizophrenia is rapidly growing. These proteins however are more than convenient neuronal markers. They confer survival advantages to neurons and can increase the neuron's ability to sustain firing. These properties may be important in the subtle pathophysiology of nondegenerative phenomena such as schizophrenia. The aim of this review is to introduce the reader to the functional properties of CBPs and to examine the emerging literature reporting alterations in these proteins in schizophrenia as well as draw some conclusions about the significance of these findings. (C) 2002 Elsevier Science B.V. All rights reserved.

Suppressor of cytokine signaling 2 regulates neuronal differentiation by inhibiting growth hormone signaling

The intracellular mechanisms that determine the response of neural progenitor cells to growth factors and regulate their differentiation into either neurons or astrocytes remain unclear. We found that expression of SOCS2, an intracellular regulator of cytokine signaling, was restricted to mouse progenitor cells and neurons in response to leukemia inhibitory factor (LIF)-like cytokines. Progenitors lacking SOCS2 produced fewer neurons and more astrocytes in vitro, and Socs2(-/-) mice had fewer neurons and neurogenin-1 (Ngn1)-expressing cells in the developing cortex, whereas overexpression of SOCS2 increased neuronal differentiation. We also report that growth hormone inhibited Ngn1 expression and neuronal production, and this action was blocked by SOCS2 overexpression. These findings indicate that SOCS2 promotes neuronal differentiation by blocking growth hormone-mediated downregulation of Ngn1.

Genetic disruption of the growth hormone receptor does not influence motoneuron survival in the developing mouse

In the rodent central nervous system (CNS) during the five days prior to birth, both growth hormone (GH) and its receptor (GHR) undergo transient increases in expression to levels considerably higher than those found postnatally. This increase in expression coincides with the period of neuronal programmed cell death (PCD) in the developing CNS. To evaluate the involvement of growth hormone in the process of PCD, we have quantified the number of motoneurons in the spinal cord and brain stem of wild type and littermate GHR-deficient mice at the beginning and end of the neuronal PCD period. We found no change in motoneuron survival in either the brachial or lumbar lateral motor columns of the spinal cord or in the trochlear, trigeminal, facial or hypoglossal nuclei in the brain stem. We also found no significant differences in spinal cord volume, muscle fiber diameter, or body weight of GHR-deficient fetal mice when compared to their littermate controls. Therefore, despite considerable in vitro evidence for GH action on neurons and glia, genetic disruption of GHR signalling has no effect on prenatal motoneuron number in the mouse, under normal physiological conditions. This may be a result of compensation by the signalling of other neurotrophic cytokines.

Dietary influences on survival after ovarian cancer

We evaluated the effects of various food groups and micronutrients in the diet on survival among women who originally participated in a population-based case-control study of ovarian cancer conducted across 3 Australian states between 1990 and 1993. This analysis included 609 women with invasive epithelial ovarian cancer, primarily because there was negligible mortality in women with borderline tumors. The women's usual diet was assessed using a validated food frequency questionnaire. Deaths in the cohort were identified using state-based cancer registries and the Australian National Death Index (NDI). Crude 5-year survival probabilities were estimated using the Kaplan-Meier technique, and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were obtained from Cox regression models. After adjusting for important confounding factors, a survival advantage was observed for those who reported higher intake of vegetables in general (HR = 0.75, 95% CI = 0.57-0.99, p-value trend 0.01 for the highest third, compared to the lowest third), and cruciferous vegetables in particular (HR = 0.75, 95% CI = 0.57-0.98, p-value trend 0.03), and among women in the upper third of intake of vitamin E (HR = 0.76, 95% CI = 0.58-1.01, p-value trend 0.04). Inverse associations were also seen with protein (p-value trend 0.09), red meat (p-value trend 0.06) and white meat (p-value trend 0.07), and modest positive trends (maximum 30% excess) with lactose (p-value trend 0.04), calcium and dairy products. Although much remains to be learned about the influence of nutritional factors after a diagnosis of ovarian cancer, our study suggests the possibility that a diet high in vegetable intake may help improve survival. (C) 2003 Wiley-Liss, Inc.

Survival of adult AIDS patients in a reference hospital of a metropolitan area in Brazil

OBJECTIVE: To evaluate the influence of sociodemographic, clinical, and epidemiological factors in AIDS patients survival in a reference hospital. METHODS: A sample of 502 adult AIDS patients out of 1,494 AIDS cases registered in a hospital in Fortaleza, Brazil, was investigated between 1986 and 1998. Sixteen cases were excluded due to death at the moment of the AIDS diagnosis and 486 were analyzed in the study. Socioeconomic and clinical epidemiological were the variables studied. Statistical analysis was conducted using the Kaplan-Meier survival analysis and the Cox proportional hazards model. RESULTS: Three hundred and sixty two out of the 486 patients studied took at least one antiretroviral drug and their survival was ten times longer than those who did not take any drug (746 and 79 days, respectively, p <0.001). Patients who took two nucleoside reverse transcriptase inhibitors (NRTI) plus protease inhibitor were found to have higher survival rates (p <0.001). The risk of dying in the first year was significantly lower for patients who took NRTI and a protease inhibitor compared to those who took only NRTI. In addition, this risk was much lower from the second year on (0.10; 95%CI: 0.42-0.23). The risk of dying in the first year was significantly higher for less educated patients (15.58; 95%CI: 6.64-36.58) and those who had two or more systemic diseases (3.03; 95%CI: 1.74-5.25). After the first year post-diagnosis, there was no risk difference for these factors. CONCLUSIONS: Higher education revealed to exert a significant influence in the first-year survival. Antiretroviral drugs had a greater impact in the survival from the second year on. A more aggressive antiretroviral therapy started earlier could benefit those patients.

Survival of a cohort of women with cervical cancer diagnosed in a Brazilian cancer center

OBJECTIVE: To assess overall survival of women with cervical cancer and describe prognostic factors associated. METHODS: A total of 3,341 cases of invasive cervical cancer diagnosed at the Brazilian Cancer Institute, Rio de Janeiro, southeastern Brazil, between 1999 and 2004 were selected. Clinical and pathological characteristics and follow-up data were collected. There were performed a survival analysis using Kaplan-Meier curves and a multivariate analysis through Cox model. RESULTS: Of all cases analyzed, 68.3% had locally advanced disease at the time of diagnosis. The 5-year overall survival was 48%. After multivariate analysis, tumor staging at diagnosis was the single variable significantly associated with prognosis (p<0.001). There was seen a dose-response relationship between mortality and clinical staging, ranging from 27.8 to 749.6 per 1,000 cases-year in women stage I and IV, respectively. CONCLUSIONS: The study showed that early detection through prevention programs is crucial to increase cervical cancer survival.

Estrogen receptor dependent genetic and epigenetic factors of tamoxifen resistance

Resumo: A decisão da terapêutica hormonal no tratamento do cancro da mama baseiase na determinação do receptor de estrogénio alfa por imunohistoquímica (IHC). Contudo, a presença deste receptor não prediz a resposta em todas as situações, em parte devido a limitações do método IHC. Investigámos se a expressão dos genes ESR1 e ESR2, bem como a metilação dos respectivos promotores, pode estar relacionada com a evolução desfavorável de uma proporção de doentes tratados com tamoxifeno assim como com a perda dos receptores de estrogénio alfa (ERα) e beta (ERß). Amostras de 211 doentes com cancro da mama diagnosticado entre 1988 e 2004, fixadas em formalina e preservadas em parafina, foram utilizadas para a determinação por IHC da presença dos receptores ERα e ERß. O mRNA total do gene ESR1 e os níveis específicos do transcrito derivado do promotor C (ESR1_C), bem como dos transcritos ESR2_ß1, ESR2_ß2/cx, and ESR2_ß5 foram avaliados por Real-time PCR. Os promotores A e C do gene ESR1 e os promotores 0K e 0N do gene ESR2 foram investigados por análise de metilação dos dinucleotidos CpG usando bisulfite-PCR para análise com enzimas de restrição, ou para methylation specific PCR. Atendendo aos resultados promissores relacionados com a metilação do promotor do gene ESR1, complementamos o estudo com um método quantitativo por matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) suportado pelo software Epityper para a medição da metilação nos promotores A e C. Fez-se a avaliação da estabilidade do mRNA nas linhas celulares de cancro da mama MCF-7 e MDA-MB-231 tratadas com actinomicina D. Baixos níveis do transcrito ESR1_C associaram-se a uma melhor sobrevivência global (p = 0.017). Níveis elevados do transcrito ESR1_C associaram-se a uma resposta inferior ao tamoxifeno (HR = 2.48; CI 95% 1.24-4.99), um efeito mais pronunciado em doentes com tumores de fenótipo ERα/PgR duplamente positivo (HR = 3.41; CI 95% 1.45-8.04). A isoforma ESR1_C mostrou ter uma semi-vida prolongada, bem como uma estrutura secundária da região 5’UTR muito mais relaxada em comparação com a isoforma ESR1_A. A análise por Western-blot mostrou que ao nível da 21 proteína, a selectividade de promotores é indistinguivel. Não se detectou qualquer correlação entre os níveis das isoformas do gene ESR2 ou entre a metilação dos promotores do gene ESR2, e a detecção da proteína ERß. A metilação do promotor C do gene ESR1, e não do promotor A, foi responsável pela perda do receptor ERα. Estes resultados sugerem que os níveis do transcrito ESR1_C sejam usados como um novo potencial marcador para o prognóstico e predição de resposta ao tratamento com tamoxifeno em doentes com cancro da mama. Abstract: The decision of endocrine breast cancer treatment relies on ERα IHC-based assessment. However, ER positivity does not predict response in all cases in part due to IHC methodological limitations. We investigated whether ESR1 and ESR2 gene expression and respective promoter methylation may be related to non-favorable outcome of a proportion of tamoxifen treated patients as well as to ERα and ERß loss. Formalin-fixed paraffin-embedded breast cancer samples from 211 patients diagnosed between 1988 and 2004 were submitted to IHC-based ERα and ERß protein determination. ESR1 whole mRNA and promoter C specific transcript levels, as well as ESR2_ß1, ESR2_ß2/cx, and ESR2_ß5 transcripts were assessed by real-time PCR. ESR1 promoters A and C, and ESR2 promoters 0N and 0K were investigated by CpG methylation analysis using bisulfite-PCR for restriction analysis, or methylation specific PCR. Due to the promising results related to ESR1 promoter methylation, we have used a quantification method by matrixassisted laser desorption/ionization time-of-flight mass spectrometry (MALDITOF MS) together with Epityper software to measure methylation at promoters A and C. mRNA stability was assessed in actinomycin D treated MCF-7 and MDA-MB-231 cells. ERα protein was quantified using transiently transfected breast cancer cells. Low ESR1_C transcript levels were associated with better overall survival (p = 0.017). High levels of ESR1_C transcript were associated with non-favorable response in tamoxifen treated patients (HR = 2.48; CI 95% 1.24-4.99), an effect that was more pronounced in patients with ERα/PgR double-positive tumors (HR = 3.41; CI 95% 1.45-8.04). The ESR1_C isoform had a prolonged mRNA half-life and a more relaxed 5’UTR structure compared to ESR1_A isoform. Western-blot analysis showed that at protein level, the promoter selectivity is undistinguishable. There was no correlation between levels of ESR2 isoforms or ESR2 promoter methylation and ERß protein staining. ESR1 promoter C CpG methylation and not promoter A was responsible for ERα loss. We propose ESR1_C levels as a putative novel marker for breast cancer prognosis and prediction of tamoxifen response.

Predictive factors of mortality in burn patients

Burn mortality statistics may be misleading unless they account properly for the many factors that can influence outcome. Such estimates are useful for patients and others making medical and financial decisions concerning their care. This study aimed to define the clinical, microbiological and laboratorial predictors of mortality with a view to focus on better burn care. Data were collected using independent variables, which were analyzed sequentially and cumulatively, employing univariate statistics and a pooled, cross-sectional, multivariate logistic regression to establish which variables better predict the probability of mortality. Survivors and non-survivors among burn patients were compared to define the predictive factors of mortality. Mortality rate was 5.0%. Higher age, larger burn area, presence of fungi in the wound, shorter length of stay and the presence of multi-resistant bacteria in the wound significantly predicted increased mortality. The authors conclude that those patients who are most apt to die are those with age > 50 years, with limited skin donor sites and those with multi-resistant bacteria and fungi in the wound.

Prognostic Factors in Adult Patients with Idiopathic IgA Nephropathy

Introduction. IgA nephropathy is the dominant primary glomerular disease found throughout the majority of the world’s developed countries. Accurately identifying patients who are at risk of progressive disease is challenging. We aimed to characterise clinical and histological features that predict poor prognosis in adults. Patients and Methods. We performed a single-centre retrospective observational study of biopsy-proven IgA nephropathy. The primary outcome was renal survival and death from any cause, and the secondary outcome was proteinuria remission. Results. Data from 49 cases were available for analysis with a median follow-up of 4 years. There were no deaths. Univariable analyses identified acute renal failure, low estimated glomerular filtration rate for ≥3 months (low eGFR), arterial hypertension, baseline proteinuria, glomerular sclerosis >50% and interstitial fibrosis >50% as poor prognostic markers. Low eGFR persisted significant by multivariable model that used only clinical parameters. Multivariable models with histopathologic parameters observed that tubular atrophy/interstitial fibrosis >50% was independently associated with the primary outcome. Proteinuria remission throughout follow-up had no prognostic value in our revision. Conclusions. Two independent predictors of poor renal survival at time of biopsy were found: low eGFR and tubular atrophy/interstitial fibrosis >50%.