Unfavorable Prognostic Sign Research Articles

Role of multidetector CT in the recognition of hyperdense middle cerebral artery sign (HMCAS) in patients with acute cerebral ischaemia: correlation with DWI-MRI sequences and clinical data.

The aim of this study was to verify the sensitivity and specificity of the hyperdense middle cerebral artery sign (HMCAS) obtained by multidetector computed tomography (CT) in predicting acute stroke, using diffusion-weighted (DW) magnetic resonance imaging (MRI) as a reference. The location of the HMCAS, the extension of the ischaemic lesion and its prognostic value were also assessed. The CT examinations of 654 patients with symptoms related to acute cerebral stroke were retrospectively reviewed. DW-MRI confirmed recent stroke in 175 patients. Two expert neuroradiologists analysed the CT examinations of these patients in four phases. Sensitivity, specificity and interobserver reliability was evaluated. Patients were divided into three groups according to the HMCAS site (M1-M2-M3) and the Alberta Stroke Program Early CT Score (ASPECTS) on DW-MRI was calculated. The ASPECTS average score was correlated with the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS) at 3 months. In 41 patients, the presence of HMCAS was confirmed (71 % sensitivity; 100 % specificity; Interobserver reliability k, 84 %). An inverse correlation was found by comparing the ASPECTS and NIHSS scores (Rsq = -0.206). After logistic regression analysis, HMCAS was found to be independently associated with a poor outcome (mRS >2) at 3 months after adjusting for age, NIHSS on admission, risk factors and aetiology of stroke. Our study demonstrated that HMCAS obtained with multidetector CT can be detected in more than 70 % of patients with large acute ischaemic lesion and it is an unfavourable prognostic sign.

Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA

Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell type-specific gene expression programs1-4, but how those enhancers are exploited to institute alternative, signal-dependent transcriptional responses remains poorly understood. Here we present evidence that cell lineage-specific factors, such as FoxA1, can simultaneously facilitate and restrict key regulated transcription factors, exemplified by the androgen receptor (AR), to act on structurally- and functionally-distinct classes of enhancers. Consequently, FoxA1 down-regulation, an unfavorable prognostic sign in certain advanced prostate tumors, triggers dramatic reprogramming of the hormonal response by causing a massive switch in AR binding to a distinct cohort of pre-established enhancers. These enhancers are functional, as evidenced by the production of enhancer-templated non-coding RNA (eRNA5) based on global nuclear-on (GRO-seq) analysis6, with a unique class apparently requiring no nucleosome remodeling to induce specific enhancer-promoter looping and gene activation. GRO-seq data also suggest that liganded AR induces both transcription initiation and elongation. Together, these findings reveal a large repository of active enhancers that can be dynamically tuned to elicit alternative gene expression programs, which may underlie many sequential gene expression events in development, cell differentiation and disease progression.

Abstract 930: Reprogramming the transcriptional response to hormone through functionally-distinct classes of gene enhancers in prostate cancer cells

Abstract Mammalian genomes are populated with thousands of transcriptional enhancers that orchestrate cell type-specific gene expression programs; however, the potential that there are pre-established enhancers that permit alternative signal-dependent transcriptional responses has remained unexplored. Here we present evidence that cell lineage-specific factors, such as FoxA1, which contribute to the activation of cell-type specific enhancers by selectively favoring the recruitment of key regulated transcription factors such as the androgen receptor (AR) in prostate cancer cells, can simultaneously restrict these same factors from activating additional (alternative) pre-established but yet inactive enhancers, thus licensing specific signal-activated responses and restricting others. Importantly, these alternative hormonal responses are linked to distinct structural and functional classes of enhancers. Consequently, FoxA1 down-regulation, an unfavorable prognostic sign in some sets of advanced prostate tumors, causes a massive switch in AR binding from one functional enhancer class to another, which massively reprograms the hormonal response. The molecular basis for this switch lies in the release of FoxA1-mediated “restriction” of AR binding to the new enhancer class that requires no apparent nucleosome remodeling for their activation. Multiple global analyses of enhancer formation, structure, looping, and activation were combined to support these conclusions, including: H3K4me1/me3, H3K27ac, and H4K4ac mapping (ChIP-seq); nucleosomal H3K4me2 mapping (nucleosomal ChIP-seq); FoxA1, AR, p300, and MED12 mapping (ChIP-seq), also supported by the 3C assay; enhancer ncRNA or eRNAs generation analysis (GRO-seq); and gene expression analysis (microarray and GRO-seq). Together, these findings reveal a large repository of pre-determined enhancers in the human genome that can be dynamically tuned to induce alternative gene expression programs, which -we speculate- may underlie many sequential gene expression events in development or during cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 930. doi:10.1158/1538-7445.AM2011-930

Échographie et Doppler fœtaux dans le bloc auriculoventriculaire congénital d’origine immunologique

Isolated congenital heart block is linked to transplacental passage of maternal anti-SSA/Ro and/or anti-SSB/La antibodies that may be related to a connective tissue disease. Ultrasonography and Doppler are essential to screen fetus at risk. They allow the diagnosis of first- and second-degree blocks which are probably preliminary stages in conducting tissue's injury. In these situations, a maternal treatment by fluorinated steroids can be proposed because of its possible effect on partial blocks. However, these early signs of nodal injury can be lacking: some fetus present a complete heart block without previously detected less advanced block. Moreover, the significance of first-degree block is unclear since it could reverse spontaneously. Other markers of nodal injury would be valuable. In case of complete congenital heart block, ultrasonography is useful to detect congestive heart failure and help the obstetrical management when unfavorable prognostic signs occur.

Balance of cytokines in patients with severe head injury

Dynamic study of the blood levels of cytokines (interleukins IL-1β, IL-6, IL-1O and TNFalfa) was carried out in 40 patients with different outcomes of acute severe head injury. It was shown that severe head trauma resulted in the disbalance of pro- and antiinflammatory cytokines. During the first 24 hours, the direction of pathologic shifts did not differ between different patient groups and was characterized by the increase in IL-1β, IL-6 and IL-10 concentrations. By week 3, the decrease in concentrations of both pro- and anti-inflammatory cytokines was found in patients who had been discharged from the hospital for ambulant therapy. In cases of fatal outcome, deterioration of general condition of patients was combined with the decrease in IL-1β concentration and the considerable increase in IL-6 and IL-10 concentrations, which may be regarded as one of unfavorable prognostic signs of head injury.

Nail Changes in Langerhans Cell Histiocytosis: A Possible Marker of Multisystem Disease

We describe a child with a 6-month history of onycholysis, subungual hyperkeratosis, and hemorrhages in most of her fingernails and toenails. Nail involvement preceded the identification of osteolytic lesions at the mastoid on a cranial computed tomography scan, which was performed because of repeated episodes of acute otitis media. Some weeks later, a small number of erythematous papules developed over the trunk and face. The diagnosis of Langerhans cell histiocytosis was made by histopathologic examination of bone, skin, and bed and matrix nail biopsies. Response to treatment with vinblastine and prednisone was excellent. Nail changes in Langerhans cell histiocytosis are extremely uncommon, particularly as the presenting manifestation of the disease. The role of nail involvement as an unfavorable prognostic sign is unclear.

Role and mechanism of vasculogenic mimicry in gastrointestinal stromal tumors

Vasculogenic mimicry (VM) is the formation of fluid-conducting channels by highly invasive and genetically dysregulated tumor cells. In this study, we collected specimens of 84 human gastrointestinal stromal tumors (GISTs) along with clinicopathologic data and another 42 GISTs with fresh tissue that was used for gelatin zymography. VM was found in 21 of the 84 GISTs using CD31/periodic acid-Schiff double staining and CD117 and CD31 immunohistochemical staining. There was a significant difference in the VM-positive rate between the lesions with a mitotic rate > or =5/50 high-power fields and those with a lower mitotic rate (P = .000) and between the cases with and without liver metastasis (P = .008). There was a significant difference in the VM-positive rate between the high-risk group (5.9%) and the very low/low-risk group (12.5%) (P = .010) or the intermediate-risk group (39.5%) (P = .020). Kaplan-Meier survival analysis showed VM indicated a poor prognosis (P = .0000). Cox proportional hazards model indicated that the presence of VM, tumor size 10 cm or greater, and hemorrhage were independent predictors of a poor prognosis (P = .000, .005, .032, respectively). The staining indexes of matrix metalloproteinase (MMP)-2 and MMP-9 were higher in the VM-positive than in the VM-negative group (P = .024 and .037, respectively). Gelatin zymography showed that the activity of MMP-2 and MMP-9 was significantly higher in the VM-positive lesions (P = .013 and .033, respectively). We conclude that VM in GISTs is an unfavorable prognostic sign and that patients with VM-positive tumors are prone to suffer liver metastasis. Both MMP-2 and MMP-9 play an important role in VM formation in GISTs.

Retrospective analysis of seizures associated with feline infectious peritonitis in cats

Seizures have been reported frequently in feline infectious peritonitis (FIP) but have not been studied in detail in association with this disease. The purpose of this study was to perform a retrospective analysis of neurological signs in a population of 55 cats with a histopathologically confirmed neurological form of FIP. Seizure patterns were determined and it was attempted to relate occurrence of seizures with age, breed, sex and neuropathological features. Fourteen cats had seizure(s), while 41 cats had no history of seizure(s). Generalised tonic–clonic seizures were seen in nine cats; and complex focal seizures were observed in four patients. The exact type of seizure could not be determined in one cat. Status epilepticus was observed in one patient but seizure clusters were not encountered. Occurrence of seizures was not related to age, sex, breed or intensity of the inflammation in the central nervous system. However, seizures were significantly more frequent in animals with marked extension of the inflammatory lesions to the forebrain (P = 0.038). Thus, the occurrence of seizures in FIP indicates extensive brain damage and can, therefore, be considered to be an unfavourable prognostic sign.

Preoperative computed tomography and selection of patients with colorectal peritoneal carcinomatosis for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Aim A survival benefit has been observed for colorectal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC). However, this treatment modality is associated with a considerable morbidity and mortality and in a significant number of patients survival is not improved. We studied whether poor survivors could be identified on preoperative computed tomography (CT), in order to avoid unnecessary surgery. Patients and methods Films of abdominopelvic CT scans from 25 such patients treated by cytoreductive surgery and HIPEC were retrospectively analysed by two radiologists separately. A simplified peritoneal cancer index (SPCI) was used to determine the extent of peritoneal involvement. Correlation between the on preoperative CT based SPCI-scores as well as number of involved abdominopelvic areas ( N) and survival was examined with the log-rank test. The relation between each affected region and survival was evaluated with Cox regression analysis. Results The preoperative SPCI- and N-scores of one of the radiologists had no statistically significant prognostic value, while for the second radiologist SPCI≥7 and N≥4 were associated with particularly poor outcome. Additionally, the presence of ileocaecal region involvement and, depending on the radiologist, the occurrence of tumour deposits in the left subdiaphragmatic area on CT appeared to be unfavourable prognostic signs. Conclusions The prognostic value of preoperative conventional CT appeared to be radiologist dependent and may, therefore, be of limited value in selecting colorectal cancer patients with peritoneal carcinomatosis who will not benefit from extensive cytoreductive surgery followed by HIPEC.

Role of matrix metalloproteinases 2 and 9 in determination of invasive potential of pancreatic tumors.

Our findings indicate that expression of matrix metalloproteinase-2 is an important prognostic marker of invasive potential of pancreatic tumors. Expression of this marker in neuroendocrine tumors (particularly in gastrinomas) can be used as a differential diagnostic criterion characterizing more malignant phenotype of tumors with the presence of ductal component. On the contrary, weak expression matrix metalloproteinase-9 is characteristic of less invasive phenotype of tumor cells (neuroendocrine and solid pseudopapillary tumors, mucinous cystadenomas). Co-expression of matrix metalloproteinases 2 and 9 is an unfavorable prognostic sign.

Successful homotransplantation of the human kidney between identical twins

A patient whose illness had begun with edema and hypertension was found to have suffered extreme atrophy of both kidneys. Because of the steady worsening of the condition and the appearance of uremia with other unfavorable prognostic signs, transplantation of one kidney from the patients' healthy identical twin brother was undertaken.

Primary pediatric neuroblastic tumors of the neck

Neuroblastic tumors are the third most common cause of solid tumors in early childhood. Cervical tumors account for only 5% of cases. In this report, we describe a series of four pediatric neuroblastic tumors of the neck. The histological diagnosis was ganglioneuroblastoma in three cases and neuroblastoma in one case. Presenting signs were solitary cervical mass in two cases and respiratory distress in association with Claude-Bernard Horner's syndrome in two cases. Mean age at presentation was 15 months. Cervical computed tomography scan and/or magnetic resonance imaging depicted calcifications within the tumor in 50% of cases and allowed accurate assessment of extension. Increased urine catecholamine levels were observed only in the patient with neuroblastoma. Scintigraphy with [131]iodine-methyliodobenzylguanidine demonstrated selective uptake by the tumor in two cases. Amplification of N-myc oncogene, a documented unfavorable prognostic sign, was not found in any case. Surgical treatment was performed in all patients. Neoadjuvant chemotherapy was performed in one case. All patients underwent regular surveillance. No evidence of recurrence has been observed with a mean follow-up period of 7 years.

Levels of neurotransmitter amino acids in the cerebrospinal fluid of patients with acute ischemic insult.

The dynamics of excitatory (glutamate, aspartate) and inhibitory (GABA, glycine) neurotransmitter amino acid contents in the cerebrospinal fluid were studied in 110 patients with hemispheric ischemic insult. These studies revealed significant increases in the levels of glutamate and aspartate in the first six hours of illness, and the level and duration of these changes correlated with the severity of the insult. Peak GABA and glycine levels were seen at the end of the first day after strokes, reflecting the delayed activation of the mechanisms of protective inhibition. The insufficiency of GABAergic mediation in strokes located in the hemispheres to a significant extent mirrored the severity of clinical features and the potential of restorative processes. Early significant biochemical criteria were identified for objective assessment of the severity of brain ischemia, and these had prognostic value for the course and outcome of strokes. The most unfavorable prognostic signs were the presence of low (or undetectable) GABA levels in the first days after insult and progressive increases in aspartate levels to the third day on the background of sharp reductions in glutamate levels (after initial elevation on the first day).

The relationship of the erythrocyte sedimentation rate to inflammatory cytokines and survival in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitors

OBJECTIVESThe object of the study was to assess the relationship between erythrocyte sedimentation rate (ESR) and inflammatory cytokine production in chronic heart failure (CHF). Our findings lead us to re-evaluate the prognostic value of the ESR in assessing patients with CHF.BACKGROUNDThe search for simple prognostic markers in CHF that can be assessed anywhere at low cost is important. Increases in ESR are related to the acute phase response in states of inflammation and infection.METHODSInitially, we studied ESR in relation to plasma levels of inflammatory cytokines in 58 CHF patients. The findings prompted us to analyze the mortality predictive power of ESR compared with established risk factors in these patients and (retrospectively) in a second group of 101 clinically stable CHF patients who had ESR measured.RESULTSIn all 159 CHF patients (age 62 ± 2 years, New York Heart Association [NYHA] class 2.7 ± 0.1), ESR ranged from 1 to 96 mm/h (median 14 mm/h). The ESR was correlated with tumor necrosis factor (TNF)-alpha (r = 0.31, p < 0.05), soluble TNF receptor-1 (r = 0.48, p < 0.0005), soluble TNF receptor-2 (r = 0.39, p < 0.005) and interleukin 6 (r = 0.45, p < 0.005) levels. High ESR levels indicated a poor prognosis (p < 0.0001), and this was independent of age, NYHA class, ejection fraction and peak oxygen consumption (p < 0.005). Patients with ESR above median (≥15 mm/h) compared with patients with ESR <15 mm/h had an impaired survival (hazard ratio 2.62, 95% confidence interval 1.58–4.36, p < 0.0001).CONCLUSIONSOur study demonstrates that in CHF a high ESR is an unfavorable prognostic sign, independent of patients’ symptomatology and ventricular function. These results are in diametrical contrast to previous results. This may reflect a change in the underlying pathophysiology due to today’s treatment with angiotensin-converting enzyme inhibitors.

Does maximizing programmed cell death necessarily yield an optimum clinical advantage?

Generally it has been believed that a maximum therapeutic induction of programmed cell death in cancer cells is universally desirable. As a corollary, the presence of Bcl-2, a major anti-programmed cell death protein, is considered an unfavorable prognostic sign. The latter is not and the former may not be universally true.

Temporary Drainage of Symptomatic Malignant Ascites by a Catheter Inserted Under Computerized Tomography

The development of malignant ascites is an unfavorable prognostic sign in patients with advanced cancer. Interventions may be justified when discomfort and overall compromise in well-being are due to diaphragmatic spinting and abdominal compression of viscera. A patient with symptomatic ascites was admitted to hospital for temporary drainage using a catheter inserted under computerized tomography. Over 12 liters of fluids were removed in 3 days, without complications. A minimal ascitic leakage occurred after removing the cannula. Dyspnea and gastrointestinal symptoms improved and the patient died with good symptom control 15 days later. This approach should be considered in advanced cancer patients with symptomatic ascites that is not responsive to diuretics. J Pain Symptom Manage 1998;15:374–378.

Overexpression of MDM2 in Acute Childhood Lymphoblastic Leukemia

Mutation of the TP53 gene is one of the most common molecular alterations in a variety of tumors, but it occurs infrequently in childhood and adult hematological malignancies. Protein accumulation often results from mutations that lead to inactivation of the p53 protein. Other causes of functional inactivation of the p53 protein include stabilization of p53 via proteins such as MDM2, an oncoprotein capable of forming specific complexes with p53. In the present study, protein expressions of MDM2 and p53 were investigated by immunohistochemistry from bone marrow samples in 23 patients with acute lymphoblastic leukemia aged 1–13 years at diagnosis. P53 protein overexpression was detected in only one case, while overexpression of MDM2 was detected in samples from five patients. All five patients overexpressing MDM2 belonged to a group with unfavorable prognostic signs at diagnosis and three of them relapsed or died within 6 months after diagnosis.

Predictors of survival in 171 patients with systemic sclerosis (scleroderma).

Predictors of survival were determined in 171 patients with systemic sclerosis by univariate analysis, and the Cox proportional hazards model using both cross sectional data at entry into the follow-up and time-dependent follow-up data. Clinical and laboratory data were evaluated from 1982 to the end of 1993. The presence of diffuse scleroderma, kidney and cardiac involvements were unfavourable prognostic signs in both the univariate analysis, and the Cox proportional hazards models. The Cox model, using the variables detected at study entry, indicated that pericarditis, and anaemia were bad prognostic signs. Analysis with time dependent data has not been reported in systemic sclerosis. The appearance of pigmentation disturbances, anaemia, and respiratory failure during the follow-up also caused a poor prognosis of the disease by the Cox model. In the stepwise selection models, diffuse scleroderma, internal organ manifestations including renal, and cardiac involvements were predominantly selected as the most unfavourable factors for survival. As to the extent of skin involvement and internal organ manifestations, the general behaviour of the disease seems to be similar throughout the world. The early appearance of pericarditis and pigmentation disturbances at study entry are bad prognostic signs.

Natural history of congenital complete atrioventricular block.

An update of studies on the natural history of congenital complete AV block is presented. A risk for heart failure, syncope, and sudden death is present at any age including fetal life. Unfavorable prognostic signs in utero are low and decreasing ventricular rate (VR), hydrops, AV valve regurgitation, and low aortic flow velocity. Indications for pacing in infancy are congestive heart failure, ventricular rate < 55 beats/min in isolated block and < 65 beats/min with associated disease, prolonged OTc, syncope attacks, frequent ventricular ectopic beats, and alternating ventricular pacemakers. Indications for immediate pacing in childhood and adult life are syncope, presyncope, VR rates lower than median for age, periods of junctional exit block, prolongation of QTc and mitral regurgitation, and change of ventricular pacemaker. Pacing is recommended to all patients older than 15 years.

The prognostic value of prostate specific antigen in the follow-up of patients after radical prostatectomy.

The authors compared the PSA levels in 19 patients who had undergone radical prostatectomy between 1986 and 1991. Measurements were done preoperatively, 3-4 weeks postoperatively and at the end of 1993. The increase of the average preoperative level corresponds to the stage of the disease (local, local advanced, metastatic lymph nodes). Patients with high preoperative PSA levels have a higher risk for progression, even if their postoperative PSA values are normal. While the predictive value of low PSA levels measured immediately after prostatectomy is small, high postoperative PSA levels are unfavourable prognostic signs.