Chronic rhinosinusitis with nasal polyposis and biological agents: the ARIA-ITALY Survey.

Summary: Background. Chronic rhinosinusitis (CRS) is an inflammatory disease that affects the nasal mucosa and the paranasal sinuses. CRS can be associated by nasal polyposis (CRSwNP phenotype) in up to 30% of patients and it is frequently associated with bronchial asthma. CRSwNP shows predominantly an underlying activation of type 2 inflammatory pathways with the involvement of eosinophils, IgE, interleukin (IL)-4, IL-5 and IL-13. Biological drugs that target these inflammatory cytokines are currently a therapeutic option recognized by guidelines for the treatment of uncontrolled form of the disease. Methods. As part of the activity of the "ARIA-Italy" working group, a panel of 255 Italian Ear, Nose and Throat (ENT) specialists, pneumologists and immuno-allergologists actively participated in this national survey and answered a series of questions geared toward understanding the main criteria for patient characterization and therapeutic decision, highlighting multidisciplinarity, and the implementation of the management of CRSwNP patients, as a part of the precision medicine concept and the appropriate use of the biologicals. Results. Two hundred and fifty-five experts and specialists participated in the survey. Conclusions. The results of this survey obtained from an extensive number of active specialists throughout Italy allow some important concluding remarks to be drawn. The main points of agreement were that multidisciplinary care teams provide many benefits but that, once the team is established, meetings and communication between members must be coordinated. Finally, the dissemination of national disease registries and the continuous updating of guidelines and position papers related to CRSwNP and comorbidities should be encouraged.

Severe asthma: follow-up after one year from the Italian Registry on Severe Asthma (IRSA)

Summary: Background. Asthma affects millions of people worldwide, with a subgroup suffering from severe asthma (SA). Biologics have revolutionized SA treatment, but challenges remain in managing different patient traits. This study analyzed data from the Italian Registry on Severe Asthma (IRSA) to investigate changes in SA characteristics and effectiveness of treatments after one year of follow-up, and to identify factors associated with response to treatments in a real-world setting. Methods. Data on SA patients with one year of follow-up were extracted from IRSA. Asthma control, exacerbations, lung function, and treatments, were assessed at follow-up and analyzed against baseline characteristics. Results. After one year of follow-up, notable improvements were observed in all the outcomes of SA of the included patients (n = 570). The effectiveness of biologic therapies was particularly evident, as they contributed significantly to these positive outcomes. Additionally, certain factors were found to be associated with improvement, namely T2 phenotype, baseline eosinophil count (BEC), and area of residence. On the other hand, comorbidities (obesity, gastro-esophageal reflux disease) and poor lung function were risk factors. Notably, poor-responders to biologics exhibited lower level of education, BEC, and exacerbations, and higher frequency of atopy and ACT score ≥ 20. Conclusions. The findings demonstrate the effectiveness of biologics in asthma management, when implemented as part of a planned follow-up strategy aimed at optimizing and fine-tuning the therapy. Moreover, the study highlights the importance of considering key traits such as the T2 phenotype, BEC, education, and comorbidities when tailoring SA treatment. Overall, this study contributes to enhancing our understanding of SA management and guiding the development of personalized treatment approaches for patients with SA.

Severe asthma management in the era of biologics: insights of the Italian Registry on Severe Asthma (IRSA).

Summary: Background. The Italian Registry on Severe Asthma (IRSA) is the most recent and largestregistry in Italy. Objective. To improve the knowledge on the clinical and biological features of severe asthma (SA), and to monitor its treatments. Methods. To analyze clinical,functional, inflammatory, and treatment characteristics of severe asthmatics from the IRSA registry. Results. 851 subjects were enrolled. 31.8% and 64.5% of patients were submitted to oral corticosteroids (OCS), and monoclonal antibodies (MABs), respectively. At least tw ocomorbidities affected 77.4% patients. Asthma was uncontrolled in 62.2% patients. Uncontrolled patients had a higher frequency of exacerbations, and hospitalization, showing a highere osinophilic phenotype, a greater use of OCS, and being treated with MAB less frequently. However, uncontrolled patients treated with MAB had a lower use of OCS and a lower rateof hospitalization. Comparing SA patients with atopy and without atopy, the latter showeda greater use of OCS, and more frequent nasal polyposis and osteoporosis. Among SA patients with atopy treated with MAB, 36% were on a treatment targeting the IL-5 pathway. Conclusions and clinical relevance. This study shows the features of the greatest Italian registryof SA patients, revealing at the time of enrollment a poor disease control, and the use of OCSand MABs in about one third and two thirds of patients, respectively. SA is a complex diseasethat requires a more precise phenotyping and a greater disease control.

Acute disseminated encephalomyelitis in China, Singapore and Japan: a comparison with the USA.

BACKGROUND AND PURPOSE: Ethnicity-related differences in the incidence of acute disseminated encephalomyelitis (ADEM) and other demyelinating diseases including multiple sclerosis and neuromyelitis optica spectrum disorders have been reported. Little is reported on the influence of ethnicity and geographical location in ADEM. METHODS: Medical records of patients who presented with ADEM (ICD-9 323.61 and 323.81) at large referral hospitals in China, Singapore and Japan (years 1992-2015) were retrospectively reviewed and data were collected in a centralized database. Presenting features and outcomes of ADEM were compared between this multi-country Asian cohort and a uniformly collected US cohort using risk differences and risk ratios. Both cohorts were standardized to a 35% pediatric population to facilitate the comparison. RESULTS: There were 83 Asian patients (48 male, 16 pediatric) followed for a median of 2 (25th-75th percentile 1-10) months. Asian patients exhibited a 26% higher prevalence of spinal cord involvement on magnetic resonance imaging [95% confidence interval (CI) 0-52%; P = 0.05; 63% vs. 37%], a 39% lower prevalence of preceding events (95% CI 12-65%; P < 0.01; 33% vs. 72%) and a 23% lower prevalence of corpus callosum involvement (95% CI 7-39%; P < 0.01; 8% vs. 31%). No difference was observed between the two cohorts in the probability of relapse over the first year after disease onset. CONCLUSIONS: It is hypothesized that the high proportion of Asian patients with spinal cord lesions relates to genetic vulnerability or the higher incidence of neuromyelitis optica spectrum disorders in Asia or could be a spurious association. ADEM presentations most probably vary across geographical settings or ethnicities.

Analysis of mitochondrial DNA alteration in new phenotype ACOS.

BACKGROUND: Mitochondria contain their own DNA (MtDNA) that is very sensitive to oxidative stress and as a consequence could be damaged in quantity. Oxidative stress is largely recognized to play a key role in the pathogenesis of asthma and COPD and might have a role in the new intermediate phenotype ACOS (asthma-COPD overlap syndrome). The aim of this study was to investigate MtDNA alterations, as an expression of mitochondrial dysfunction, in ACOS and to verify whether they might help in the identification of this new phenotype and in its differentiation from asthma and COPD. METHODS: Ten (10) ACOS according to Spanish guidelines, 13 ACOS according to GINA guidelines, 13 COPD, 14 asthmatic patients and ten normal subjects were enrolled. They further underwent a blood, induced sputum and exhaled nitric oxide collection. Content of MtDNA and nuclear DNA (nDNA) were measured in the blood cells of patients by Real Time PCR. RESULTS: ACOS patients showed an increase of MtDNA/nDNA ratio. Dividing ACOS according to guidelines, those from the Spanish showed a higher value of MtDNA/nDNA compared to those from GINA/GOLD (92.69 ± 7.31 vs 80.68 ± 4.16). Spanish ACOS presented MtDNA/nDNA ratio closer to COPD than asthma. MtDNA was higher in asthmatic, COPD, GINA and Spanish ACOS patients compared to healthy subjects (73.30 ± 4.47-137.0 ± 19.45-80.68 ± 4.16-92.69 ± 7.31 vs 65.97 ± 20.56). CONCLUSION: We found an increase of MtDNA/nDNA ratio in ACOS subjects that led us to conclude that there is presence of mitochondrial dysfunction in this disease, that makes it closer to COPD than to asthma. Although the MtDNA/nDNA ratio results are a useful marker for differential diagnosis from asthma, COPD and ACOS, further studies are needed to confirm the potentiality of MtDNA/nDNA ratio and to a better characterization of ACOS.

A population-based case-control study of 1250 stroke deaths in rural Bangladesh.

BACKGROUND AND PURPOSE: There are limited population-based studies to determine the risk factors for stroke in Bangladesh. METHODS: A health and demographic surveillance system has been maintained in Matlab, Bangladesh (population 223 886, 142 villages in 2008). All adult stroke and injury deaths (2005-2008) were monitored by verbal autopsy. Risk factors for stroke deaths were calculated using a multivariable logistic regression model with adult injury deaths as controls. RESULTS: A total of 1250 stroke deaths (51% women; mean age 72.3 years, range 20-101) occurred out of 4955 total deaths and were compared with 246 adult injury deaths (47% women, mean age 55.8 years, range 20-100). The population-attributable mortality of stroke was 25.2% based on the verbal autopsy instrument and 17.8% when accounting for the reported sensitivity and specificity of a similar verbal autopsy instrument that has been validated for stroke death. Risk of stroke death was significantly increased with hypertension (OR 7.94, 95% CI 4.44-15.54, P < 0.001), diabetes mellitus (OR 2.54, 1.21-6.21, P = 0.02), and betel consumption (OR 2.36, 1.45-3.80, P < 0.001) when adjusted for age and sex. An increased risk was not observed with heart disease (OR 1.37, 0.45-5.95, P = 0.62), cigarette smoking (OR 1.41, 0.82-2.45, P = 0.22), tobacco powder (OR 1.15, 0.30-7.64, P = 0.86), or cigar/hookah pipe smoking 0.94 (0.45-2.18, P = 0.88) when adjusted for age and sex. There were more strokes in winter (December-March) than summer (June-September) (P < 0.001). CONCLUSIONS: There is a high modifiable burden of risk factors for adult stroke deaths in rural Bangladesh, most notably including hypertension. Betel consumption may be an under-recognized risk factor for stroke death.

[Questionnaires for occupational disability evaluation in patients with chronic respiratory diseases]. / Questionari per la valutazione della disabilità occupazionale in pazienti con malattie respiratorie croniche.

Chronic Obstructive Pulmonary Disease (COPD) represents a model of respiratory degenerative chronic disabling disorder. In Pulmonary Rehabilitation (PR), occupational approach is aimed at restoring patient's abilities at best in the social, familiar and working scenarios, and it is an essential part of a good PR Programme. To evaluate first occupational disability and then the occupational outcome of a PR programme, we need appropriate tools. London Chest Activity of Daily Living (LCADL) ed il Manchester Respiratory Activities of Daily Living (MRADL) are two questionnaires with such characteristics available in the literature. Our aim was to translate into Italian and adapt to the Italian social reality these two questionnaires. This may be a preliminary albeit necessary step to obtain reliable data on the occupational outcome of PR programmes in Italy.

Efficacy of pulmonary rehabilitation in chronic respiratory failure (CRF) due to chronic obstructive pulmonary disease (COPD): The Maugeri Study.

UNLABELLED: While the effectiveness of pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) is well established, its effectiveness in the most severe category of COPD, i.e. patients with chronic respiratory failure (CRF), is less well known. OBJECTIVE: To verify the effects of PR in patients with CRF, and compare the level of improvement with PR in these patients to that of COPDs not affected by CRF. METHODS: A multi-centre study was carried out on COPD patients with versus without CRF. The PR program included educational support, exercise training, and nutritional and psychological counselling. Lung function, arterial gases, walk test (6MWT), dyspnoea (MRC; BDI/TDI), and quality of life (MRF(28); SGRQ) were evaluated. RESULTS: Thousand forty seven consecutive COPD inpatients (327 with CRF) were evaluated. In patients with CRF all parameters improved after PR (0.001). Mean changes: FEV(1), 112 ml; PaO(2), 3.0 mmHg; PaCO(2), 3.3 mmHg; 6MWT, 48 m; MRC, 0.85 units; MRF(28) total score, 11.5 units. These changes were similar to those observed in patients without CRF. CONCLUSIONS: This study, featuring the largest cohort so far reported in the literature, shows that PR is equally effective in the more severe COPD patients, i.e. those with CRF, and supports the prescription of PR also in these patients.

Maugeri Respiratory Failure questionnaire reduced form: a method for improving the questionnaire using the Rasch model.

PURPOSE: The Maugeri Respiratory Failure questionnaire (MRF-28) is the first instrument specifically developed for use with chronic respiratory failure (CRF) patients. The 28 items were selected using classical test theory. The purpose of the current analysis was to further refine the questionnaire using item response theory, specifically, the Rasch model analysis. METHODS: Three hundred and seventeen CRF patients (mean aged 66.7 yrs; Male 219, Female 98) completed the MRF-28 health status measure. Data were collected through the self-report questionnaire and analyzed using 1-parameter logistic models by means of RUMM software. RESULTS: The 28-item questionnaire has good psychometric properties in terms of discriminant power because the Person Separation Index is 0.896. However, the item-trait interaction was not good as shown by the total-item Chi-square (chi(2)(112), p<0.001). Removing two items that did not fit the Rasch model well, produced a minor improvement in Person Separation Index to 0.899 and the item-trait interaction improved (chi(2)(104), p = NS). In the preliminary analysis we identified 21 patients who were outliers; when they were excluded the distribution of the residuals, according to the Kolmogorov-Smirnov statistics, was normal and factor analysis of the item residuals showed that the components had similar eigenvalues and no strong correlation with items. These results suggest that the MRF-26 is a unidimensional measure of health-related quality of life impairment for chronic respiratory failure patients. CONCLUSIONS: A combination of classical psychometric tests and Rasch analysis produced an instrument of moderate size that covers a wide range of effects of CRF and has interval scaling properties.

Degree of control of physician-diagnosed asthma and COPD in Italy.

BACKGROUND: It is important for the Italian National Health Service to obtain data on the degree of control of asthma and chronic obstructive pulmonary disease (COPD) in the general population in Italy in order for balanced planning of future investments in these diseases to be made. Currently, precise estimates of these parameters are not available in literature. OBJECTIVES: In collaboration with the Italian Academy of General Practitioners (SIMG; www.simg.it) we have investigated the degree of control of physician-diagnosed asthma and COPD in Italy. METHODS: A standardised questionnaire on asthma and COPD has been self-administered to a sample of 1937 Italian family physicians (representing around 5% of all the Italian doctors involved in general practice) chosen to cover all the Italian counties. RESULTS: We have collected questionnaire data from 19,917 patients with asthma and COPD followed in their practice and 12,438 (62.4%) were correctly filled in enabling evaluation. We selected the number of emergency room visits, hospitalisations and intensive care unit admissions for asthma and COPD in the last 12 months as objective measures of the degree of asthma and COPD morbidity in these patients. The figures were respectively 12.4% (emergency room visits), 17.3% (hospitalisations) and 1.2% (intensive care unit admissions) of all patients with physician-diagnosed asthma and COPD. CONCLUSIONS: This data suggests that in Italy the morbidity of asthma and COPD remains high; representing a significant burden for the Italian National Health Service. There is a clear necessity for further studies to investigate the causes of this incomplete control.

Doubly robust nonparametric inference on the average treatment effect.

Doubly robust estimators are widely used to draw inference about the average effect of a treatment. Such estimators are consistent for the effect of interest if either one of two nuisance parameters is consistently estimated. However, if flexible, data-adaptive estimators of these nuisance parameters are used, double robustness does not readily extend to inference. We present a general theoretical study of the behaviour of doubly robust estimators of an average treatment effect when one of the nuisance parameters is inconsistently estimated. We contrast different methods for constructing such estimators and investigate the extent to which they may be modified to also allow doubly robust inference. We find that while targeted minimum loss-based estimation can be used to solve this problem very naturally, common alternative frameworks appear to be inappropriate for this purpose. We provide a theoretical study and a numerical evaluation of the alternatives considered. Our simulations highlight the need for and usefulness of these approaches in practice, while our theoretical developments have broad implications for the construction of estimators that permit doubly robust inference in other problems.

A new questionnaire specifically designed for patients affected by chronic obstructive pulmonary disease; The Italian Health Status Questionnaire.

The aim of this study was to develop a specific and valid questionnaire for Italian COPD patients, living on the north or the south of Italy-which are two culturally distinct areas. The project consisted in three steps: (1) initial item set generation to identify items relevant to both genders, all ages and both regions; (2) item reduction including tests of regional specificity; (3) tests of internal validity using item-response theory using Rasch one-parameter modelling. Ninty-six COPD patients (mean aged 69 yr; 78 Male) completed the original set of 124 items of the Italian Health Status Questionnaire (IHSQ). Item reduction was carried out using an established standardised approach employing classical psychometric test theory. The internal construct validity of the 47 items that survived this process were tested to determine whether they constituted a unidimensional construct "impaired health due to COPD" using Rasch analysis. This showed that the questionnaire had very good psychometric properties, with an excellent Person Separation Index of 0.95 and no evidence of bias due to item-trait interaction (chi104(2)=127.1, P=n.s.). The combination of classical test theory and modern item-response methodology has produced a questionnaire with excellent measurement properties suitable for COPD patients whether from the north or south of Italy.

Detection of blood-borne cells in colorectal cancer patients by nested reverse transcription-polymerase chain reaction for carcinoembryonic antigen messenger RNA: longitudinal analyses and demonstration of its potential importance as an adjunct to multiple serum markers.

The use of reverse transcription-PCR (RT-PCR) to analyze cells in the blood of cancer patients for the detection of mRNA expressed in tumor cells has implications for both the prognosis and the monitoring of cancer patients for the efficacy of established or experimental therapies. Carcinoembryonic antigen (CEA) is expressed on approximately 95% of colorectal, gastric, and pancreatic tumors, and on the majority of breast, non-small cell lung, and head and neck carcinomas. CEA shed in serum is useful as a marker in only approximately 50% of colorectal cancer patients and rarely is shed by some other carcinoma types. RT-PCR has been used previously to detect CEA mRNA in cells in the blood and lymph nodes of cancer patients. Under the assay conditions validated in the studies reported here, 34 of 51 (67%) patients with different stages of colorectal cancer had blood cells that were positive by RT-PCR for CEA mRNA, whereas none of 18 patients with colonic polyps were positive; 2 of 60 apparently healthy individuals (who were age and sex matched with the carcinoma patients and were part of a colon cancer screening program as controls) were marginally positive. The results of CEA PCR in the blood of the carcinoma patients and the other groups showed strong statistical correlation with the disease (P2 < 0.0001). Analyses were carried out to detect both serum CEA protein levels and CEA mRNA in blood cells of colorectal carcinoma patients by RT-PCR. For all stages of disease, 18 of 51 patients (35%) were positive for serum CEA, whereas 35 of 51 (69%) were positive by RT-PCR. More importantly, only 5 of 23 (20%) of stage B and C colorectal cancer patients were positive for serum CEA, whereas 16 of 23 (70%) were positive by RT-PCR. The use of two other serum markers (CA19.9 and CA72-4) for colorectal cancer in combination with serum CEA scored two additional patients as positive; both were positive by RT-PCR for CEA mRNA. Pilot long-term longitudinal studies conducted before and after surgery identified some patients with CEA mRNA in blood cells that were negative for all serum markers, who eventually developed clinical metastatic disease. The studies reported here are the first to correlate RT-PCR results for CEA mRNA in blood cells with one or more serum markers for patients with different stages of colorectal cancer, and are the first long-term longitudinal studies to use RT-PCR to detect CEA mRNA in blood cells of cancer patients. Larger cohorts will be required in future studies to define the impact, if any, of this technology on prognosis and/or disease monitoring.

Propensity score estimators for the average treatment effect and the average treatment effect on the treated may yield very different estimates.

OBJECTIVE: Propensity score matching is typically used to estimate the average treatment effect for the treated while inverse probability of treatment weighting aims at estimating the population average treatment effect. We illustrate how different estimands can result in very different conclusions. STUDY DESIGN: We applied the two propensity score methods to assess the effect of continuous positive airway pressure on mortality in patients hospitalized for acute heart failure. We used Monte Carlo simulations to investigate the important differences in the two estimates. RESULTS: Continuous positive airway pressure application increased hospital mortality overall, but no continuous positive airway pressure effect was found on the treated. Potential reasons were (1) violation of the positivity assumption; (2) treatment effect was not uniform across the distribution of the propensity score. From simulations, we concluded that positivity bias was of limited magnitude and did not explain the large differences in the point estimates. However, when treatment effect varies according to the propensity score (E[Y(1)-Y(0)|g(X)] is not constant, Y being the outcome and g(X) the propensity score), propensity score matching ATT estimate could strongly differ from the inverse probability of treatment weighting-average treatment effect estimate. We show that this empirical result is supported by theory. CONCLUSION: Although both approaches are recommended as valid methods for causal inference, propensity score-matching for ATT and inverse probability of treatment weighting for average treatment effect yield substantially different estimates of treatment effect. The choice of the estimand should drive the choice of the method.

Study of mitochondrial DNA alteration in the exhaled breath condensate of patients affected by obstructive lung diseases.

Mitochondrial DNA (MtDNA) has been studied as an expression of oxidative stress in asthma, COPD, lung cancer and obstructive sleep apnea, but it has been mainly investigated systemically, although the pathogenetic mechanisms begin in the airways and only later progress to systemic circulation. The aim of this study was to investigate the MtDNA alterations in the exhaled breath condensate (EBC) of patients with asthma, COPD and asthma-COPD overlap syndrome (ACOS). In order to analyze better what happens to mitochondria, both locally and systemically, we compared MtDNA/nDNA in blood and EBC of paired patients. Thirteen (13) COPD patients, 14 asthmatics, 23 ACOS (10 according to Spanish guidelines, 13 in line with GINA guidelines) and 12 healthy subjects were enrolled. Patients underwent clinical and functional diagnostic tests as foreseen by the guidelines. They underwent blood and EBC collection. Content of MtDNA and nuclear DNA (nDNA) was measured in the blood cells and EBC of patients by Real Time PCR. The ratio between MtDNA/nDNA was calculated. For the first time we were able to detect MtDNA/nDNA in the EBC. We found higher exhaled MtDNA/nDNA in COPD, asthmatic and ACOS patients respectively compared to healthy subjects (21.9 ± 4.9 versus 6.51 ± 0.21, p < 0.05; 7.9 ± 2.5 versus 6.51 ± 0.21, p = 0.06; 18.3 ± 3.4 versus 6.51 ± 0.21, p < 0.05). The level of exhaled MtDNA/nDNA was positively correlated with the plasmatic one. The levels of MtDNA/nDNA in the EBC, as expression of oxidative stress, are increased in COPD, asthmatic and ACOS patients compared to healthy subjects. These are preliminary results in a small number of well characterized patients that requires confirmation on a larger population. We support new studies directed toward the analysis of exhaled MtDNA/nDNA as a new exhaled non-invasive marker in other inflammatory/oxidative airways diseases.

Comparing Preliminary and Final Neuroradiology Reports: What Factors Determine the Differences?

BACKGROUND AND PURPOSE: Trainees' interpretations of neuroradiologic studies are finalized by faculty neuroradiologists. We aimed to identify the factors that determine the degree to which the preliminary reports are modified. MATERIALS AND METHODS: The character length of the preliminary and final reports and the percentage character change between the 2 reports were determined for neuroradiology reports composed during November 2012 to October 2013. Examination time, critical finding flag, missed critical finding flag, trainee level, faculty experience, imaging technique, and native-versus-non-native speaker status of the reader were collected. Multivariable linear regression models were used to evaluate the association between mean percentage character change and the various factors. RESULTS: Of 34,661 reports, 2322 (6.7%) were read by radiology residents year 1; 4429 (12.8%), by radiology residents year 2; 3663 (10.6%), by radiology residents year 3; 2249 (6.5%), by radiology residents year 4; and 21,998 (63.5%), by fellows. The overall mean percentage character change was 14.8% (range, 0%-701.8%; median, 6.6%). Mean percentage character change increased for a missed critical finding (+41.6%, P < .0001), critical finding flag (+1.8%, P < .001), MR imaging studies (+3.6%, P < .001), and non-native trainees (+4.2%, P = .018). Compared with radiology residents year 1, radiology residents year 2 (-5.4%, P = .002), radiology residents year 3 (-5.9%, P = .002), radiology residents year 4 (-8.2%, P < .001), and fellows (-8.7%; P < .001) had a decreased mean percentage character change. Senior faculty had a lower mean percentage character change (-6.88%, P < .001). Examination time and non-native faculty did not affect mean percentage character change. CONCLUSIONS: A missed critical finding, critical finding flag, MR imaging technique, trainee level, faculty experience level, and non-native-trainee status are associated with a higher degree of modification of a preliminary report. Understanding the factors that influence the extent of report revisions could improve the quality of report generation and trainee education.

A re-evaluation of carcinoembryonic antigen (CEA) as a serum marker for breast cancer: a prospective longitudinal study.

PURPOSE: Carcinoembryonic antigen (CEA) is still a widely used test for monitoring breast cancer, although recent reports discourage its routine use because of low sensitivity. This is a prospective study evaluating the efficacy of CEA and CA 15.3 in monitoring breast cancer. EXPERIMENTAL DESIGN: Serum CEA and CA 15.3 were measured in 2191 patients with either benign (n = 738) or malignant (n = 1453) breast diseases. Five hundred and forty-nine patients were monitored during postsurgical follow-up for either a minimum of 5 years or until time of recurrence. Fifty-three patients with metastases were also monitored during chemotherapy. RESULTS: Elevated CEA and CA 15.3 levels were found in 16.7% and 33.0% of patients, respectively. CEA sensitivity rose to 41.3% and CA 15.3 sensitivity rose to 80.8% in metastatic patients. The adjunct of CEA increased the CA 15.3 sensitivity by 6% in the overall population and by only 2.1% for patients with metastases. During postsurgical follow-up, CEA was elevated in 38.0% and CA 15.3 in 70.2% of patients with recurrence. The combination of CEA and CA 15.3 increased the overall sensitivity by only 1.4%. Longitudinal monitoring of 53 metastatic patients undergoing chemotherapy demonstrated that, when positive, both CEA and CA 15.3 paralleled response to treatment, although CA 15.3 was a significantly more powerful marker for determining response to treatment. The cost effectiveness ratio of CEA was clearly less favorable than that of CA 15.3. CONCLUSIONS: CEA monitoring should be considered an expensive and inefficient method of follow-up evaluation for breast cancer patients, and it provides no additional value when used in combination with CA 15.3.

Mesial Temporal Sclerosis: Accuracy of NeuroQuant versus Neuroradiologist.

BACKGROUND AND PURPOSE: We sought to compare the accuracy of a volumetric fully automated computer assessment of hippocampal volume asymmetry versus neuroradiologists' interpretations of the temporal lobes for mesial temporal sclerosis. Detecting mesial temporal sclerosis (MTS) is important for the evaluation of patients with temporal lobe epilepsy as it often guides surgical intervention. One feature of MTS is hippocampal volume loss. MATERIALS AND METHODS: Electronic medical record and researcher reports of scans of patients with proved mesial temporal sclerosis were compared with volumetric assessment with an FDA-approved software package, NeuroQuant, for detection of mesial temporal sclerosis in 63 patients. The degree of volumetric asymmetry was analyzed to determine the neuroradiologists' threshold for detecting right-left asymmetry in temporal lobe volumes. RESULTS: Thirty-six patients had left-lateralized MTS, 25 had right-lateralized MTS, and 2 had bilateral MTS. The estimated accuracy of the neuroradiologist was 72.6% with a κ statistic of 0.512 (95% CI, 0.315-0.710) [moderate agreement, P < 3 × 10(-6)]), whereas the estimated accuracy of NeuroQuant was 79.4% with a κ statistic of 0.588 (95% CI, 0.388-0.787) [moderate agreement, P < 2 × 10(-6)]). This discrepancy in accuracy was not statistically significant. When at least a 5%-10% volume discrepancy between temporal lobes was present, the neuroradiologists detected it 75%-80% of the time. CONCLUSIONS: As a stand-alone fully automated software program that can process temporal lobe volume in 5-10 minutes, NeuroQuant compares favorably with trained neuroradiologists in predicting the side of mesial temporal sclerosis. Neuroradiologists can often detect even small temporal lobe volumetric changes visually.

Renal hemodynamics in renal transplant recipients. The role of reduced kidney mass and cyclosporine administration.

It has been hypothesized that both the cyclosporine (CsA) treatment and the reduction of renal mass may affect the renal hemodynamic regulation in kidney transplant recipients. To address this question, we evaluated the renal hemodynamic response to hyperaminoacidemia (i.v. mixed amino acid infusion 3.3 mg/kg/minute for 150 minutes) in four study groups: (1) 16 renal transplant recipients (Tx), (2) 6 uninephrectomized (Nx) subjects, (3) 7 subjects treated with CsA for chronic uveitis (CsA), and (4) 9 normal controls (NC). In response to amino acid administration (AA), glomerular filtration rate (GFR) rose significantly in NC subjects (80 +/- 6 vs. 91 +/- 6 ml/minute; P<0.01) and Nx patients (57 +/- 3 vs. 68 +/- 7 ml/minute; P<0.01) and failed to increase in Tx recipients (39 +/- 3 vs. 37 +/- 3 ml/minute) and CsA-treated patients (58 +/- 3 vs. 53 +/- 4 ml/minute). Renal plasma flow (RPF) did not change in Tx recipients (243 +/- 27 vs. 235 +/- 25 ml/minute) but rose significantly in all other groups (257 +/- 17 vs. 344 +/- 33 in NX, 364 +/- 6l vs. 441 +/- 55 in CsA, 412 +/- 49 vs. 472 +/- 72 ml/min in NC subjects; P<0.05 vs. basal). Basal renal vascular resistances were significantly higher in Tx (0.29 +/- 0.04 mmHg/mlxmin; P<0.01 vs. all other groups) than in Nx (0.21 +/- 0.01 mmHg/mlxmin), CsA (0.23 +/- 0.04 mmHg/mlxmin) (both P<0.01 vs. NC subjects), and NC subjects (0.13 +/- 0.02 mmHg/mlxmin). Renal vascular resistance failed to decline in Tx (0.31 +/- 0.04 mmHg/mlxmin) during AA infusion but declined significantly in all other groups. In Tx, basal GFR was positively correlated to renal allograft volume (r=0.547, P<0.03); however, no relationship was found between the latter and basal RPF or the AA induced changes in GFR. In summary, the present study demonstrates that in kidney transplant recipients and in CsA-treated subjects, the renal functional reserve to hyperaminoacidemia is impaired. This is at variance to what is observed in normal controls and uninephrectomized subjects. In renal transplant recipients, basal but not amino acid stimulated GFR correlates with renal allograft volume. We conclude that basal GFR is related to renal volume in Tx and that the response to hyperaminoacidemia seems to be affected by chronic CsA administration.

Ventilatory and metabolic changes as a result of exercise training in COPD patients.

Patients with COPD feel better and are able to sustain a given level of activity longer after a program of exercise training, but the underlying physiologic mechanisms have not been completely elucidated. Since the physical performance of patients with COPD is limited mainly by pathophysiologic derangements of the ventilatory system, the exercise performance can be ameliorated by increasing the level of ventilation that they can sustain or by reducing the ventilatory requirement for a given level of activity. Almost all studies have yielded negative results in patients with COPD in terms of exercise training having the ability to improve VEmax. The only way to reduce the ventilatory requirement is to reduce CO2 output. Lower levels of lactate result in less nonmetabolic CO2 produced by bicarbonate buffering and this is the likely mechanism responsible for a lower ventilatory requirement for work rates above the pretraining anaerobic threshold. We specifically wished to determine whether a program of intensity, frequency, and duration known capable of producing a physiologic training effect in healthy subjects would do so in patients with COPD. Further, we sought to determine whether exercise training at a work rate associated with lactic acidosis is more effective in inducing a training effect in patients with COPD than a work rate not associated with lactic acidosis. Nineteen patients with COPD were selected and performed an incremental test as well as 2 square wave tests at a low and a high work rate. Identical tests were performed after an 8-week program of cycle ergometer training either for 45 min/day at a high work rate or for a proportionally longer time at a low work rate. For the high work rate training group, identical work rates engendered less lactate (4.5 vs 7.2 mEq/L) and less VE (48 vs 55 L/min) after training; the low work rate training group had significantly less lactate and VE decrease (p less than 0.01). Further, in the first group, there was an increase in exercise tolerance averaging 71% in the high constant work rate test. There was a good correlation (r = 0.73, p less than 0.005) between the decrease in blood lactate and the decrease in ventilation. The major findings of this study are that patients with COPD who experience lactic acidosis during exercise can achieve physiologic training responses from a program of endurance training and that training work rates engendering high levels of blood lactate are more effective than work rates eliciting low lactate levels.