Predictor Of Poor Outcome In Patients Research Articles

Should we reconsider iron administration based on prevailing ferritin and hepcidin concentrations?

The results of recent randomized, controlled trials in patients with chronic kidney disease and anemia have suggested that hyporesponsiveness to erythropoiesis stimulating agents (ESA) is a significant predictor of poor patient outcomes. Functional iron deficiency (FID) is the most common cause of suboptimal ESA response, and intravenous iron administration (IVFe) efficiently raises hemoglobin (Hb) concentrations even under the condition of FID. Consequently, renal anemia correction has conceptually shifted from ‘higher Hb values with high ESA doses’ to ‘prevention of ESA hyporesponsiveness with IVFe’. The discovery of hepcidin has profoundly changed our understanding of the place of FID in renal anemia therapy. Hepcidin reduces the abundance of iron transport proteins which facilitate iron absorption from the gut and iron mobilization from macrophages. Serum hepcidin is mainly modulated by iron stores, as is serum ferritin. High hepcidin or ferritin levels block intestinal iron absorption and iron recycling in macrophages and decrease iron availability for erythropoiesis, leading to FID. Iron administration, especially IVFe, increases hepcidin levels and concomitantly inhibits iron supply to erythroid cells. This in turn could lead to a vicious circle, exacerbating FID and increasing iron demand. Therefore, physicians should be cautious with unrestricted IVFe to chronic kidney disease patients with FID.

Characteristics and prognostic value of acute catecholamine surge in patients with aneurysmal subarachnoid hemorrhage

Objectives: The characteristics of serum catecholamine concentration at the hyper-acute phase of aneurysmal subarachnoid hemorrhage (SAH) and its relationship between patient outcome and delayed vasospasm were investigated.Methods: Patients with aneurysmal SAH (170) were prospectively studied between August 2008 and June 2011. Baseline demographic data and physiological parameters, including plasma concentrations of adrenaline (AD), noradrenaline (NA), and dopamine (DP) were evaluated for all patients.Results: On admission, plasma AD, NA, and DP levels were significantly higher in patients with a poor clinical grade on admission (Hunt and Kosnik grade: IV–V), compared to those with a good clinical grade on admission (Hunt and Kosnik grade: I–III). AD showed a markedly high concentration immediately after the onset of SAH and then rapidly decreased. NA levels peaked within 6 hours after onset, then significantly decreased. The increase of DP with time was not significant, but showed a similar trend to that of NA. The level of each catecholamine showed significant mutual correlation.Our multivariate model demonstrated that age, poor clinical grade at admission, plasma AD and NA levels were good predictors of poor patient outcome [receiver operating characteristic (ROC) area: 0·83]. And that poor clinical grade at admission, Fisher scale, blood sugar level and plasma AD level were good predictors of the development of delayed vasospasm (ROC area: 0·81) (1·3).Conclusions: The present findings suggest that sympathetic activation in patients in the acute phase of SAH reflects the severity of SAH, and is closely related to the development of delayed vasospasm, leading to the subsequent immune response and inflammatory reactions. Strategies for suppressing catecholamine at the hyper-acute phase may contribute to vasospasm prevention and improve patient outcome.

Persistent Leukocytosis: A Persistent Problem for Stroke Patients (P06.229)

Objective: To determine the clinical significance of persistent versus transient leukocytosis in acute ischemic stroke (AIS). Background Transient but significant elevation in white cell counts have been described after status epilepticus, head trauma, and spinal cord injury, independent of steroid administration or infection.Leukocytosis may be secondary to alpha adrenergic stimuli, endogenous corticosteroid increase, or a combination of the two. Design/Methods: Patients who presented with AIS to our center within 48hrs of symptom onset between 7/2008 and 6/2010 were retrospectively identified by chart review. Patients were included if they had leukocytosis on admission (defined as WBC count >11,000/μl based on laboratory reference range). Demographics, NIHSS scores, leukocyte counts, length of stay (LOS), disposition, and good functional outcome (mRS 0-2) were compared in patients with persistent (still elevated 48hrs after admission) vs. transient (resolved Results: Of the 438 patients screened, 49 had leukocytosis on admission; (mean age 61.5, median admission NIHSS 9, mean LOS 8.5 days, and median discharge mRS 3). 24 (49%) had persistent leukocytosis. When compared to patients with transient leukocytosis, baseline NIHSS was significantly higher in the persistent leukocytosis group (p=0.0476), and the mean LOS was significantly longer (p=0.044). More people with transient leukocytosis had a good functional outcome (44% vs 16%, p=0.006). After adjusting for NIHSS, persistent leukocytosis was not an independent predictor of good functional outcome (OR=2.5, 95%CI 0.562-10.7, p=0.2322). NIHSS correlated significantly with persistence of leukocytosis (r=0.306, p=0.0044). Conclusions: Persistent leukocytosis, present in half of patients with AIS, is associated with higher baseline NIHSS scores, longer LOS, and poorer functional outcomes. Persistent leukocytosis is tightly linked with baseline stroke severity and may serve as a predictor of poor patient outcomes the setting of AIS. Disclosure: Dr. Boehme has nothing to disclose. Dr. Kumar has nothing to disclose. Dr. Gillette has received research support from the Infectious Disease Society of America. Dr. Siegler has nothing to disclose. Dr. Albright has nothing to disclose. Dr. Martin-Schild has nothing to disclose.

Impact of operative indication and surgical complexity on outcomes after thoracic endovascular aortic repair at National Surgical Quality Improvement Program Centers

Thoracic endovascular aortic repair (TEVAR) devices are increasingly being utilized to treat aortic pathologies outside of the original Food & Drug Administration (FDA) approval for nonruptured descending thoracic aorta aneurysms (DTAs). The objective of this study was to evaluate the outcomes of patients undergoing TEVAR, elucidating the role of surgical and pathologic variables on morbidity and mortality. National Surgical Quality Improvement Program (NSQIP) data were reviewed for all patients undergoing endovascular thoracic aorta repair from 2005 to 2007. The patients' operative indication and surgical complexity were used to divide them into study and control populations. Comorbid profiles were assessed utilizing a modified Charlson Comorbidity Index (CCI). Thirty-day occurrences of mortality and serious adverse events (SAEs) were used as study endpoints. Univariate and multivariate models were created using demographic and clinical variables to assess for significant differences in endpoints (P ≤ .05). A total of 440 patients undergoing TEVAR were identified. When evaluating patients based on operative indication, the ruptured population had increased mortality and SAE rates compared to the nonruptured DTA population (22.6% vs 6.2%;P < .01 and 35.5% vs 9.1%;P < .01, respectively). Further analysis by surgical complexity revealed increased mortality and SAE rates when comparing the brachiocephalic aortic debranching population to the noncovered left subclavian artery population (23.1% vs 6.5%; P = .02 and 30.8% vs 9.1%; P < .01, respectively). Multivariate analysis demonstrated that operative indication was not a correlate of mortality or SAEs (odds ratio [OR], 0.95; P = .92 and OR, 1.42; P = .39, respectively); however, brachiocephalic aortic debranching exhibited a deleterious effect on mortality (OR, 8.75; P < .01) and SAE rate (OR, 6.67; P = .01). The operative indication for a TEVAR procedure was not found to be a predictor of poor patient outcome. Surgical complexity, specifically the need for brachiocephalic aortic debranching and aortoiliac conduit, was shown to influence the occurrence of SAEs in a multivariate model. Comparative data, such as these, illustrate real-world outcomes of patients undergoing TEVAR outside of the original FDA-approved indications. This information is of paramount importance to various stakeholders, including third-party payers, the device industry, regulatory agencies, surgeons, and their patients.

HER2 codon 655 polymorphism is associated with advanced uterine cervical carcinoma

Objectives: It has been suggested that overexpression of HER2 in advanced cervical tumors can be considered an independent predictor of poor patient outcome. Design and methods: Employing PCR-RFLPs, we examined the distribution of HER2 Ile655Val (rs 1136201) genotypes and alleles in patients with advanced cervical cancer ( n = 109) and controls ( n = 220). Results: Odds ratio (OR) for patients with advanced cervical cancer with the HER2 Val/Val homozygous or Val/Ile heterozygous state was 1.778 (95% CI = 1.117–2.830, p = 0.0176). We also observed an association of the HER2 Val/Val genotype with advanced cervical cancer in the patient group OR = 3.706 (95% CI = 1.061–12.950, p = 0.0459). However, we did not find a significant association between the distribution of genotypes or alleles and cancer characteristics for the HER2 Ile655Val polymorphism. Conclusions: Our results indicate that the HER2 655Val variant may be associated with the incidence of advanced cervical cancer.

The Case Against Heavy PETing

The Case Against Heavy PETing

HSD17B4 overexpression, an independent biomarker of poor patient outcome in prostate cancer

Steroid hormones and their metabolising enzymes have been studied extensively for their potential role in prostate cancer, with more recent interest in the androgen/estrogen inactivating enzyme 17beta-hydroxysteroid dehydrogenase type 4 (HSD17B4). Gene expression profiling showed HSD17B4 to be significantly overexpressed in prostate cancer compared to matched-benign epithelium. We therefore hypothesized that altered HSD17B4 expression may contribute to prostate cancer progression via altered hormone balance. In this study, HSD17B4 mRNA and protein expression were assessed by in situ hybridisation (ISH) and immunohistochemistry (IHC), respectively, in tissue arrays of prostate tissue from 172 patients treated by radical prostatectomy. Overexpression of HSD17B4 mRNA and protein was associated with prostate cancer (P<0.0001) and multivariate Cox proportional hazards analysis, adjusted for known prognostic indicators, demonstrated HSD17B4 mRNA and high protein expression were significant independent predictors of poor patient outcome as measured by time until PSA relapse (mRNA: hazards ratio [HR]=1.90, 95% confidence interval [CI]=1.15-3.12; P<0.0001; and protein: HR=2.09, 95% CI=1.31-3.33; P=0.0026). Here we provide strong evidence that both mRNA and protein overexpression of HSD17B4 is not only associated with the presence of prostate cancer, but is also a significant independent predictor of poor patient outcome.

Severe Streptococcus pyogenes infections, United Kingdom, 2003-2004.

As part of a Europe-wide initiative to explore current epidemiologic patterns of severe disease caused by Streptococcus pyogenes, the United Kingdom undertook enhanced population-based surveillance during 2003-2004. A total of 3,775 confirmed cases of severe S. pyogenes infection were identified over 2 years, 3.33/100,000 population, substantially more than previously estimated. Skin/soft tissue infections were the most common manifestation (42%), followed by respiratory tract infections (17%). Injection drug use was identified as a risk factor for 20% of case-patients. One in 5 infected case-patients died within 7 days of diagnosis; the highest mortality rate was for cases of necrotizing fasciitis (34%). Nonsteroidal antiinflammatory drugs, alcoholism, young age, and infection with emm/M3 types were independently associated with increased risk for streptococcal toxic shock syndrome. Understanding the pattern of these diseases and predictors of poor patient outcome will help with identification and assessment of the potential effect of targeted interventions.

Tumor Necrosis as Prognostic Indicator in Transitional Cell Carcinoma of the Upper Urinary Tract

The clinicopathological features predictive of outcome in patients with upper urinary tract transitional cell carcinoma are not clearly established. We analyzed the prognostic impact of tumor necrosis with respect to metastasis-free survival. The presence of focal (10% or less of the tumor area) and extensive (greater than 10% of the tumor area) coagulative tumor necrosis was retrospectively reevaluated in 268 cases of consecutive upper urinary tract transitional cell carcinoma and correlated with outcome. Overall tumor necrosis was noted in 113 of 268 (42.2%) cases of transitional cell carcinoma with 63 (23.5%) showing focal and 50 (18.7%) showing extensive necrosis, respectively. Tumor necrosis was associated with high tumor stage (p <0.001) and high tumor grade (p <0.001). In addition, tumor necrosis was more common in pelvic tumors compared with ureteral tumors (p <0.001). Actuarial 5-year metastasis-free survival rates for patients with transitional cell carcinoma with extensive, focal and lacking necrosis were 24%, 45% and 78%, respectively (log rank test p <0.001). Multivariate analysis proved pT stage greater than 1 (p <0.001, RR 6.04, 95% CI 2.82-12.93), high tumor grade (p <0.001, RR 3.37, 95% CI 1.65-6.89) and extensive tumor necrosis as independent predictors of poor patient outcome (p = 0.02, RR 1.82, 95% CI 1.09-3.05). The presence of extensive tumor necrosis proved to be an additional histological variable with an independent influence on metastasis-free survival in patients with upper urinary tract transitional cell carcinoma. Its assessment is readily applicable in routine sections and should thus be commented upon separately in the pathology report.

Weak Expression of Focal Adhesion Kinase (pp125FAK) in Patients with Cervical Cancer Is Associated with Poor Disease Outcome

The pp125 focal adhesion kinase (FAK) plays a pivotal role in tumor cell signaling. FAK expression has been linked to tumor cell invasion and metastasis, but data on cervical cancer are inconclusive. Our goal was to investigate FAK expression in cervical cancer and to assess whether its expression correlates with prognosis. FAK expression was examined using immunohistochemistry with sections from 162 resected cervical cancer specimens. Kaplan-Meier survival curves were used to determine the significance of FAK expression in the prognosis of cervical cancer patients. Specific FAK expression was found in the tumor cells, whereas normal cervical epithelium showed barely any FAK expression. Of 162 invasive cervical cancer specimens, 55 (34%) revealed weak expression of FAK, whereas moderate and strong expression was found in 63 (39%) and 44 (27%) tumors, respectively. Patients with tumors expressing weak amounts of FAK were characterized by a significantly poorer overall survival compared with those with moderate and high intratumoral FAK expression (P = 0.002). Weak expression of FAK correlated with pelvic lymph node metastasis (P = 0.026) and recurrent disease (P = 0.013). Multivariate Cox regression analysis revealed decreased FAK expression and pelvic lymph node metastasis to be significant independent factors predictive of poor disease outcome (hazard ratio, 0.36; P = 0.005; hazard ratio, 2.38; P = 0.018, respectively). Weak expression of FAK in invasive cervical cancer is a strong independent predictor of poor patient outcome. Further studies are warranted to elucidate whether FAK expression analysis is a suitable tool identifying patients at high risk even at an early clinical stage.

Targeting the cell cycle for prognosis and therapy of breast cancer

Cyclin E is a G1-cyclin that plays a key role in the G1 to S transition of the cell cycle. Cyclin E is processed in tumor cells by an elastase-like protease into low-molecular-weight (LMW) isoforms that are biochemically hyperactive. The LMW isoforms of cyclin E are unique to cancer cells. In breast cancer, such alteration of cyclin E is a very strong predictor of poor patient outcome. Alterations in the binding properties of these LMW isoforms to CDK2 and the CDK inhibitors (CKIs), p21 and p27, result in their functional hyperactivity. The LMW forms of cyclin E are several-fold more effective at binding to CDK2. Additionally, compared with the full-length cyclin E–CDK2 complexes, the LMW cyclin E–CDK2 complexes are significantly more resistant to inhibition by p21 and p27, despite equal binding of the CKIs to the LMW complexes. When both the full-length and the LMW cyclin E are co-expressed, p27 preferentially binds to the LMW forms yet is unable to inhibit the CDK2 activity. When overexpressed in breast cancer cells, the LMW forms of cyclin E, but not the full-length form, result in their hyperactivity due to increased affinity for cdk2 and resistance to inhibition by the CDK inhibitors p21 and p27, result in resistance to the growth inhibiting effects of anti-estrogens, and result in chromosomal instability. Finally, tumors from breast cancer patients overexpressing the LMW forms of cyclin E are polyploid in nature and are resistant to endocrine therapy. To assess the oncogenic role of cyclin E-LMW as compared with full-length cyclin E, we examined the consequences of overexpressing these isoforms in the mammary glands of transgenic mice using the MMTV promoter. Four constructs were generated: MMTV-M46A coding for the full-length cyclin E (EL1), MMTV-EL1/EL4 coding for EL1 and the isoform translated at methionine 46 (EL4), and MMTV-T1 and MMTV-T2 coding for the isoforms generated by elastase cleavage at the first site (EL2 + EL3) and at the second site (EL5 and EL6), respectively. For each construct at least two transgenic lines were established. Transgene expression was demonstrated by RT-PCR, northern blotting and western blotting. Overexpression of cyclin E was seen in more than 90% of ductal and lobular cells of the mammary glands for each independent line. Mammary-specific LMW cyclin E overexpression induced extensive abnormalities at 2 months, including perturbed architecture, polyploidy, anysocytosis and apoptosis. Whole-mount preparations of mammary glands at different development stages showed that overexpression of EL1/EL4 and cyclin E-T1 induced growth delay, while at 6 months of age an increased proportion of cells in the S phase was found (25.6 ± 5.6% for EL1/EL4, 9.0 ± 2.7% for T1 compared with 3.9 ± 1.9% for non-transgenic animals). We observed a 34% (13/38) incidence of mammary adenocarcinomas in the EL1/EL4 transgenic lines with a mean latency of 18.3 months, and observed a 20% (5/25) incidence in the T1 transgenic lines with a mean latency of 17.1 months. The tumor incidence rate of the other transgenic lines, M46A and T2, are still unknown due to the young age of the mice (all under 7 months of age) and the long latency of cyclin E-mediated tumor generation. Thirty percent (4/13) of the EL1/EL4 and 40% (2/5) of the T1 tumor-bearing animals developed lung metastasis. The tumors induced by the EL1/EL4 and T1 transgenes were mainly solid adenocarcinomas with very little differential to glandular for EL1/EL4 and mostly glandular for T1. Since p53 alterations are common in human breast carcinomas, we bred a T1 line with p53+/- mice. The T1 × p53+/- cross generated tumors that are much more malignant than the T1 tumors; the incidence increased to 100%, with a much shorter latency of 11 months. Biochemical analysis of the tumors revealed that 64% (9/14) retained cyclin E expression and that, on average, the cyclin E-overexpressing tumors had threefold higher cyclin E kinase activity than the non-cyclin E-expressing tumors. Taken together, these data indicate that tumor progression in cyclin E transgenic mice follow sequential steps of dysplasia, mammary intraepithelial neoplasia and invasive/metastatic tumors. Collectively, the biochemical and biological differences between the full-length and the LMW isoforms of cyclin E provide a molecular mechanism for the poor clinical outcome observed in breast cancer patients harboring tumors expressing high levels of the LMW forms of cyclin E. The transgenic mouse model system can serve as a useful system in which to study the mechanisms responsible for LMW cyclin E-induced genetic instability and may help identify those factors that promote tumor progression and metastasis. The properties of the LMW forms of cyclin E suggest that they are not just surrogate markers of poor outcome, but that they are bona fide mediators of aggressive disease and potential therapeutic targets for patients whose tumors overexpress these forms.

The Tumor-specific Hyperactive Forms of Cyclin E Are Resistant to Inhibition by p21 and p27

The low molecular weight (LMW) isoforms of cyclin E are unique to cancer cells. In breast cancer, such alteration of cyclin E is a very strong predictor of poor patient outcome. Here we show that alteration in binding properties of these LMW isoforms to CDK2 and the CDK inhibitors (CKIs), p21 and p27, results in their functional hyperactivity. The LMW forms of cyclin E are severalfold more effective at binding to CDK2. Additionally, compared with the full-length cyclin E-CDK2 complexes, the LMW cyclin E-CDK2 complexes are significantly more resistant to inhibition by p21 and p27, despite equal binding of the CKIs to the LMW complexes. When both the full-length and the LMW cyclin E are co-expressed, p27 preferentially binds to the LMW forms yet is unable to inhibit the CDK2 activity. Thus, the LMW forms of cyclin E may contribute to tumorigenesis through their resistance to the inhibitory activities of p21 and p27 while sequestering these CKIs from the full-length cyclin E.

Treatment-related acute renal failure in the elderly: a hospital-based prospective study.

Elderly individuals need a host of diagnostic procedures and therapeutic interventions to take care of ailments. This prospective study was carried out to determine the magnitude of treatment-related acute renal failure (ARF) in the elderly in a hospital setting, to know about pathogenetic factors and to study the factors that could predict an adverse outcome. All elderly patients (>60 years) admitted over a 12-month period were screened prospectively throughout their hospital stay for the development of ARF. Of 31860 patients admitted, 4176 (13%) were elderly. Of these 59 (1.4%) developed ARF in the hospital. Nephrotoxic drugs contributed towards development of ARF in 39 (66%), sepsis and hypoperfusion in 27 (45.7%) each, contrast medium in 10 (16.9%) and postoperative ARF occurred in 15 (25.4%) patients. These pathogenetic factors were responsible for ARF in different combinations. Amongst these combination of pathogenetic factors, radiocontrast administration (partial chi(2) 28.1, P<0.0001), surgery (partial chi(2) 14.89, P=0.001), and drugs (partial chi(2) 6. 22, P=0.0126) predicted ARF on their own. Nine patients (15.23%) needed dialytic support. Of 59 patients, 15 (25.4%) died, of those who survived, 38 (86.3%) recovered renal function completely and six (13.6%) partially. Mortality in the elderly with ARF was significantly higher than in those without ARF (25.4 vs 12.5%; chi(2) 8.3, P=0.03). Sepsis (odds ratio 43), oliguria (odds ratio 64), and hypotension (odds ratio 15) were independent predictors of poor patient outcome on logistic regression analysis. Incidence of treatment-related ARF in the elderly was 1.4%, with more than one pathogenetic factor playing a role in the development of ARF in the majority. Sepsis, hypotension, and oliguria were the independent predictors of poor patient outcome.

Quantification of midline shift as a predictor of poor outcome following head injury

A retrospective study of patient outcome, based on admission computed tomography, was carried out in 75 consecutive patients with head injury. Computed tomography data collected included the type and extent of intracranial hemorrhage, the extent of midline shift, and the ratio of midline shift compared with the extent of intracranial hemorrhage. Midline shift was considered to be out of proportion to intracranial hemorrhage when the midline shift of the septum pellucidum exceeded the extent of the hemorrhage as measured radially from the inner table of the skull. When computed tomography data were analyzed by logistic regression, significant predictive factors for poor outcome were intracranial hemorrhage (34%), intracranial hemorrhage with midline shift (61%), and midline shift out of proportion to the extent of intracranial hemorrhage (88%). When patient outcome and mortality rates are considered, our study indicates that midline shift out of proportion to the extent of intracranial hemorrhage is a highly useful predictor of poor patient outcome following head injury.