Validation of an electronic tool for flagging surgical site infections based on clinical practice patterns for triaging surveillance: Operational successes and barriers.

BACKGROUND: Surveillance is an effective strategy for reducing surgical site infections (SSIs); however, current identification methods are resource-intensive. Therefore, we sought to validate an electronic SSI triaging tool for detection of probable infections and identify operational barriers and challenges. METHODS: A retrospective cohort study was conducted among all Veterans Affairs Surgical Quality Improvement Program (VASQIP)-reviewed surgeries at 2 Veterans Affairs medical centers from October 1, 2011-September 30, 2014. During the postoperative period, clinical and administrative variables associated with SSI (relevant microbiology order, antibiotic order, radiology order, and administrative codes) were extracted from the electronic medical record and used to score the probability (high, intermediate, and low) that an SSI occurred. VASQIP manual chart review was used as the gold standard of comparison. RESULTS: VASQIP manual review identified 118 SSIs out of 3,700 surgeries (3.2%). There were 2,041, 1,428, and 231 surgeries that met criteria for low, intermediate, and high probability for SSI. The tool's area under the curve was 0.86 (95% confidence interval, 0.82-0.89). The sensitivity among low-probability surgeries was 92.4%, and the specificity among high-probability surgeries was 95.1%. CONCLUSIONS: The electronic SSI tool has the potential to be used for triaging VASQIP surveillance toward the high-probability surgeries and to avoid manual review of surgeries with low probability of SSI.

MODULACIÓN DE LA RESPUESTA ALÉRGICA POR LOS CAROTENOIDES DE LA DIETA / Modulation of the allergic response by dietary carotenoids

Los carotenoides son pigmentos isoprenoides, que están presentes de manera natural y en altas concentraciones en la mayoría de alimentos vegetales, por ejemplo, aguacate (palta), papaya, tomate y zanahoria, pero también se encuentran como aditivos y colorantes en diversos productos cárnicos, aceites vegetales, salsas, aderezos, harinas, entre otros. En los últimos años, varios grupos de investigación han descrito que los carotenoides de la dieta participan en varios procesos fisiopatológicos, incluyendo, la respuesta inmune de tipo alérgico. Las tasas de prevalencia para este tipo de enfermedades se han incrementado de manera alarmante durante las últimas cinco décadas en todo el mundo, y varios factores e hipótesis se han planteado tratando de explicar este fenómeno. Uno de ellos es la hipótesis de la dieta, la cual plantea que la composición de varios micro- y macronutrientes de la alimentación, así como los cambios en los patrones dietarios, serían los responsables de dicho fenómeno. En adición, evidencia epidemiológica y experimental señala que los carotenoides de la dieta participan en la regulación de la inflamación alérgica y, por ello, se postulan como coadyuvantes en la terapia de estos padecimientos. En el presente manuscrito se revisará el estado del arte en relación con los efectos de los carotenoides de la dieta sobre el estado inflamatorio alérgico.(AU)

The carotenoids are isoprenoids pigments, which are naturally present in high concentrations and in most vegetables foods e.g., avocado, papaya, tomato and carrot, but also as additives and dyes found in various meat products, vegetable oils, sauces, dressings, flour, among others. In recent years, several research groups have reported that dietary carotenoids participate in many pathophysiological processes, including the allergic immune response. The prevalence rates for these diseases have increased alarmingly over the past five decades in the world and a number of factors and assumptions have been proposed trying to explain this phenomenon, one of them is the hypothesis of the diet, which has arisen that the composition of several micro and macronutrients of foods, as well as changes in the dietary patterns would be responsible for thisphenomenon.In addition, epidemiological and experimental evidence indicates that dietary carotenoids are involved in the regulation of allergic inflammation and thus postulated as adjuvants in the therapy of these diseases. In this manuscript, we will review the state of art in relation to the effects of dietary carotenoids on the allergic inflammatory state.(AU)

Survival benefit of repeat liver transplantation in the United States: a serial MELD analysis by hepatitis C status and donor risk index.

Survival benefit (SB) for first liver transplantation (LT) is favorable at Model for End-Stage Liver Disease (MELD)≥15. Herein, we identify the MELD threshold for SB from repeat liver transplantation (ReLT) by recipient hepatitis C virus (HCV) status and donor risk index (DRI). We analyzed lab MELD scores in new United Network for Organ Sharing registrants for ReLT from March 2002 to January 2010. Risk of ReLT graft failure≤1 year versus waitlist mortality was calculated using Cox regression, adjusting for recipient characteristics. Of 3057 ReLT candidates, 54% had HCV and 606 died while listed. There were 1985 ReLT recipients, 52% had HCV and 567 ReLT graft failures by 1 year. Unadjusted waitlist mortality and post-ReLT graft failure rates were 416 (95% confidence interval [CI] 384-450) and 375 (95% CI 345-407) per 1000 patient-years, respectively. Waitlist mortality was higher with increasing waitlist MELD (p<0.001). The MELD for SB from ReLT overall was 21 (21 in non-HCV and 24 in HCV patients). MELD for SB varied by DRI in HCV patients (MELD 21, 24 and 27 for low, medium and high DRI, respectively) but did not vary for non-HCV patients. Compared to first LT, ReLT requires a higher MELD threshold to achieve an SB resulting in a narrower therapeutic window to optimize the utility of scarce liver grafts.

Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon and pancreatic cancers combined. Current research suggests that standard chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway-involving AKT, CREB, Bcl-xL, survivin, and Bcl-2-downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that short hairpin RNA (shRNA) knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl have complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl.

No association of vitamin D intake or 25-hydroxyvitamin D levels in childhood with risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young (DAISY).

AIMS/HYPOTHESIS: The aim of the study was to investigate the association between vitamin D intake and status and the risk of islet autoimmunity (IA) and subsequent type 1 diabetes in children at increased risk of type 1 diabetes. METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) in Denver, CO, USA, has been following children at increased risk of diabetes since 1993. As of February 2011, 198 children developed IA during follow-up of 2,644 DAISY children. Vitamin D intake and plasma 25-hydroxyvitamin D [25(OH)D] were measured longitudinally. Proportional hazards regression analyses of time to IA, or type 1 diabetes in IA-positive children, were conducted, with vitamin D intake and 25(OH)D as time-varying covariates. HRs were calculated for a standard deviation difference in exposure, with adjustment for confounders. RESULTS: Intake of vitamin D was not associated with the risk of IA (adjusted HR 1.13; 95% CI 0.95, 1.35; p = 0.18) nor progression to diabetes in IA-positive children (adjusted HR 1.30; 95% CI 0.91, 1.86; p = 0.15). Moreover, 25(OH)D level was not associated with the risk of IA (adjusted HR 1.12; 95% CI 0.88, 1.43; p = 0.36), nor progression to diabetes in IA-positive children (adjusted HR 0.91; 95% CI 0.68, 1.22; p = 0.54). In the 128 children in whom we measured 25(OH)D at 9 months of age, 25(OH)D was not associated with risk of IA (n = 30 IA-positive children) (adjusted HR 1.02; 95% CI 0.96, 1.07; p = 0.58). CONCLUSIONS/INTERPRETATION: Neither vitamin D intake nor 25(OH)D levels throughout childhood were associated with the risk of IA or progression to type 1 diabetes in our population.

HOX expression patterns identify a common signature for favorable AML.

Deregulated HOX expression, by chromosomal translocations and myeloid-lymphoid leukemia (MLL) rearrangements, is causal in some types of leukemia. Using real-time reverse transcription-PCR, we examined the expression of 43 clustered HOX, polycomb, MLL and FLT3 genes in 119 newly diagnosed adult acute myeloid leukemias (AMLs) selected from all major cytogenetic groups. Downregulated HOX expression was a consistent feature of favorable AMLs and, among these cases, inv(16) cases had a distinct expression profile. Using a 17-gene predictor in 44 additional samples, we observed a 94.7% specificity for classifying favorable vs intermediate/unfavorable cytogenetic groups. Among other AMLs, HOX overexpression was associated with nucleophosmin (NPM) mutations and we also identified a phenotypically similar subset with wt-NPM. In many unfavorable and other intermediate cytogenetic AMLs, HOX levels resembled those in normal CD34+ cells, except that the homogeneity characteristic of normal samples was not present. We also observed that HOXA9 levels were significantly inversely correlated with survival and that BMI-1 was overexpressed in cases with 11q23 rearrangements, suggesting that p19(ARF) suppression may be involved in MLL-associated leukemia. These results underscore the close relationship between HOX expression patterns and certain forms of AML and emphasize the need to determine whether these differences play a role in the disease process.

Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis.

OBJECTIVES: To investigate factors that may influence the prevalence and timing of appearance of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies during the preclinical phase of rheumatoid arthritis (RA) development. METHODS: 243 serial prediagnosis serum samples from 83 subjects with RA were examined for the presence of RF and anti-CCP antibodies. RESULTS: Of the 83 cases, 47 (57%) and 51 (61%) subjects had at least one prediagnosis sample positive for RF or anti-CCP, respectively. Gender and race were not significantly associated with the prevalence or timing of preclinical antibody appearance. Preclinical anti-CCP positivity was strongly associated with the development of erosive RA (odds ratio = 4.64; 95% confidence interval 1.71 to 12.63; p<0.01), but RF was not (p = 0.60). Additionally, as age at the time of diagnosis of RA increased the duration of prediagnosis antibody positivity for RF and anti-CCP increased, with the longest duration of preclinical antibody positivity seen in patients diagnosed with RA over the age of 40. In no subjects did symptom onset precede the appearance of RF or anti-CCP antibodies. CONCLUSIONS: The period of time that RF and anti-CCP are present before diagnosis lengthens as the age at the time of diagnosis of RA increases. This finding suggests that factors such as genetic risk or environmental exposure influencing the temporal relationship between the development of RA-related autoantibodies and clinically apparent disease onset may differ with age.

The effect of total body water on the relationship between alcohol consumption and carbohydrate-deficient transferrin.

BACKGROUND: Clinicians agree that alcoholism commonly is overlooked in their patients, and that treating the symptoms without directing therapy to the underlying cause at best delays an inevitable decline in the patient's general health and well-being. The current analysis focused on carbohydrate-deficient transferrin (CDT), a promising biological marker of dangerous alcohol consumption. METHODS: Included in our study were men (730) and women (613) from study sites in Canada, Brazil, and Japan. All subjects were participants in the WHO/ISBRA Study on State and Trait Markers of Alcoholism, who completed an extensive demographic, medical, and behavioral survey and provided blood samples for determination of CDT levels. ANOVA and chi2 test for equality were used to examine the effect of total body water (TBW) on the alcohol consumption/CDT relationship. To examine whether accounting for differences in TBW improved the diagnostic properties of CDT when used as a state marker for alcohol consumption, odds ratios were calculated for men and women separately. RESULTS: Our results show that accounting for individual differences in TBW significantly influenced the alcohol consumption/CDT dose-response relationship. The effect of TBW was different for men compared with women. When we used a consumption cutoff value of 40 g/day and the CDTect recommended cutoffs (20 for men; 27 for women), adjusting for differences in TBW significantly increased diagnostic performance of CDT in men but not women. CONCLUSIONS: The dependence of CDT measures on body water content needs to be taken into account to maximize the performance of CDT as an effective state marker of alcohol consumption in males.

Normal bone mineral density after treatment for childhood acute lymphoblastic leukemia diagnosed between 1991 and 1998.

OBJECTIVE: We investigated whether previous reports of reduced bone mineral density after management for childhood acute lymphoblastic leukemia (chALL) were confirmed in a more recently treated cohort. STUDY DESIGN: In a cross-sectional study 75 subjects who were given the diagnosis of chALL between January 1, 1991, and December 31, 1997 (69% standard, 31% high risk), at Denver Children's Hospital and who were 11 to 82 months post-diagnosis with no history of relapse, secondary malignancy, or transplant underwent whole body areal bone mineral densitometry (BMD(A) expressed as age- and sex-standardized z scores), a food frequency questionnaire, and a weight-bearing activity survey. RESULTS: Overall, the mean whole body BMD(A) z score was normal (+0.22 +/- 0.96). A significant positive association was found with whole body BMD(A) z score and years elapsed since the beginning of maintenance (linear regression coefficient = +0.2 Deltaz score/year; 95% CI = 0.09 to 0.3) after adjustment was done for risk status/age category, history of cranial radiation, and total days hospitalized. No association was found with high risk/older age at diagnosis, nutrient intake, chemotherapy dosage, or weight-bearing activity. CONCLUSION: Contrary to previous reports in which cranial radiation and longer hospitalizations were prominent components of therapy, our study suggests that more recently treated patients with chALL do not have persistent abnormalities of bone mineral density after completion of therapy.

Thromboembolic disease: variability of interobserver agreement in the interpretation of CT venography with CT pulmonary angiography.

OBJECTIVE: The objective of this study was to determine interobserver agreement in the diagnosis of acute deep venous thrombosis on CT venography performed in addition to CT pulmonary angiography. SUBJECTS AND METHODS: One hundred forty-six CT venograms of 144 patients (mean age, 61.74 years) clinically suspected of having pulmonary embolism were analyzed prospectively and independently by two experienced thoracic and body imaging radiologists and later by consensus of the two radiologists. The CT venography protocol consisted of 5-mm-thick axial images at 20-mm intervals from the popliteal fossa to the renal veins. Images were acquired 3-4 min after the start of 100-150 mL of undiluted contrast medium administration at 4 mL/sec. Thirteen venous segments were analyzed in each patient. There were 1586 analyzable venous segments. RESULTS: Interobserver agreement, with the patient as the unit of analysis, was moderately good (kappa, 0.59; 95% confidence interval [CI], 0.39-0.78). Kappa values were similar for CT venography studies performed with 150 mL of contrast medium and 4-min delay (kappa, 0.62; 95% CI, 0.30-0.88) and with 3-min delay and 100 mL of contrast medium (kappa, 0.56; 95% CI, 0.32-0.80). Interobserver disagreement occurred in 17 (12%) of 146 CT venography studies. Findings of 11 CT venography studies were interpreted as negative, and six were interpreted as positive after consensus interpretation. CONCLUSION: Interobserver agreement for deep venous thrombosis with CT venography is moderately good.

Thromboembolic disease: comparison of combined CT pulmonary angiography and venography with bilateral leg sonography in 70 patients.

OBJECTIVE: The purpose of this study was to compare combined CT pulmonary angiography and venography with leg sonography for accuracy and relative efficacy in diagnosis of deep venous thrombosis from the popliteal vein to the common femoral vein. SUBJECTS AND METHODS: Seventy consecutive patients with clinically suspected pulmonary embolism underwent both combined CT pulmonary angiography and venography and bilateral leg sonography within 24 hr. CT venograms were analyzed independently in a blinded fashion for quality of venous opacification and patency by two observers. CT venography was compared with sonography for femoropopliteal vein thrombosis, and the final assessment based on multiple subjective and objective clinical and imaging criteria was recorded in three categories: 1, CT venography better than sonography; 2, CT venography equivalent to sonography; and 3, sonography better than CT venography. RESULTS: Sixty-eight patients (97%) had a satisfactory or good quality CT venography examination. Two CT venography studies had false-positive findings due to flow artifacts. Both CT venography and sonography had positive findings for deep venous thrombosis in five patients, and both had negative findings in 63 patients (100% sensitivity, 97% specificity, 100% negative predictive value, and 71% positive predictive value). CT venography was better and more efficacious than sonography (category 1) in 25 patients (36%). CT venography was equivalent to sonography (category 2) in 26 patients (37%), and sonography was better than CT venography (category 3) in 19 patients (27%). CONCLUSION: Compared with sonography, CT venography in addition to CT pulmonary angiography is a relatively accurate method for evaluation of femoropopliteal venous thrombosis. Combined CT pulmonary angiography and CT venography may be more efficacious than sonography or two separate examinations in selected patients.

Prediction of cervical intraepithelial neoplasia grade 2-3 using risk assessment and human papillomavirus testing in women with atypia on papanicolaou smears.

OBJECTIVE: To determine whether human papillomavirus (HPV) DNA testing and risk assessment can predict cervical intraepithelial neoplasia (CIN) 2-3 on biopsies in women with atypia on Papanicolaou smears. METHODS: One hundred ninety-five consenting women were referred for colposcopy because of atypia on Papanicolaou smears between September 1997 and April 1999. Before colposcopy, women completed risk assessments and had cervical swabs collected for HPV testing using the Hybrid Capture-II assay (Digene Corporation, Silver Spring, MD). Associations of demographic and clinical variables were assessed by chi(2) analysis, and logistic regression was used to assess factors associated with CIN 2-3. The cost-effectiveness of routine colposcopy versus reflex HPV testing by either conventional or liquid-based Papanicolaou smear media was compared. RESULTS: Cervical intraepithelial neoplasia was diagnosed in 70 of 195 women (35.9%), 55 (28.2%) with CIN 1 and 15 (7.7%) with CIN 2-3. High-risk HPV types were detected in 31.3% of all subjects, 36.4% of those with CIN 1, and 93.3% of those with CIN 2-3. By logistic regression, CIN 2-3 was associated only with detection of high-risk HPV (odds ratio 110.08, 95% confidence interval 8.35, 999. 00). The sensitivity of high-risk HPV for detecting CIN 2-3 was 93. 3%, specificity 73.9%, positive predictive value 23.0%, and negative predictive value 99.3%. The cost of reflex HPV testing using conventional smear or liquid-based media was less than routine colposcopy ($4809 and $4308, respectively, versus $4875 per case detected). CONCLUSIONS: Triage based on HPV testing would result in referral of approximately 31% of patients to colposcopy and appears to be a sensitive and cost-effective alternative to colposcopy.

Linear discriminant models for unbalanced longitudinal data.

This paper discusses statistical methods for the classification of observations into one of two or more groups based on longitudinal observations. Measurements on subjects in longitudinal medical studies are often collected at different times and on a different number of occasions. Classical multivariate methods for linear discriminant analysis are difficult to apply to repeated measurements due to the highly unbalanced structure observed in these data. Linear models for the analysis of longitudinal data proposed by Laird and Ware and non-linear models proposed by Lindstrom and Bates can be used to estimate population parameters for a discriminant model that classifies individuals into distinct predefined groups or populations. An example is presented using data from a study in 150 pregnant women in Santiago, Chile, in order to predict normal versus abnormal pregnancy outcomes.

Platelet adenylyl cyclase activity as a trait marker of alcohol dependence. WHO/ISBRA Collaborative Study Investigators. International Society for Biomedical Research on Alcoholism.

BACKGROUND: There is compelling evidence that genetic factors play a major role in the development of alcohol dependence. Platelet adenylyl cyclase (AC) activity has been proposed as a biochemical marker for differentiating alcohol-dependent and nondependent subjects, but the sensitivity and specificity of this marker have not been ascertained. The objective of this study was to determine the sensitivity and specificity of platelet AC activity in identifying alcohol-dependent subjects and to ascertain the effect of medical/ psychiatric variables, drinking and smoking history, and age and body weight on AC activity. METHODS: The cross-sectional study was conducted from 1995 to 1998. Participants were 210 Australian White men who were community volunteers and alcohol treatment inpatients in Sydney, Australia. There were 41 nondrinkers, 140 drinkers, and 29 men who were entering alcohol treatment. The main outcome measure was platelet AC activity. Classification variables were plasma ethanol, gamma-glutamyltransferase, aspartate aminotransferase, serum carbohydrate-deficient transferrin (CDT), and urinary 5-hydroxytryptophol/5-hydroxyindoleacetic acid (5-HTOL/5-HIAA) levels, and World Health Organization/International Society for Biomedical Research on Alcoholism Interview Schedule variables, which included alcohol use and dependence criteria. RESULTS: Among subjects who reported abstinence for at least 4 days, both cesium fluoride (CsF)- and forskolin-stimulated platelet AC activities were significantly lower in those with a lifetime history of alcohol dependence compared with those with no such history (p < 0.005 and p < 0.05, respectively). The sensitivity and specificity of CsF-stimulated AC activity to discriminate individuals with a lifetime history of alcohol dependence were 75% and 79%, respectively. Similar values for sensitivity and specificity for CsF-stimulated AC activity were calculated when discriminating current alcohol dependence in the subjects in our sample. Irrespective of the history of alcohol dependence, persons who had consumed alcohol recently (within the last 3-4 days) showed significantly higher mean basal, CsF-stimulated, and forskolin-stimulated AC activity (p < 0.001), as did those who had elevated 5-HTOL/5-HIAA ratios or CDT levels, indicative of recent (heavy) drinking. The "normalization" of platelet AC activity to baseline levels after an individual stops drinking may be related to the generation of new platelets during the abstinence period. Conduct disorder and antisocial personality disorder were not associated with low AC activity, but low forskolin-stimulated AC activity was associated with major depression. CONCLUSIONS: We found that CsF- and forskolin-stimulated platelet AC activity discriminates between subjects with and without alcohol dependence in a population of subjects who had not consumed significant quantities of ethanol recently. Recent alcohol consumption is a confounding variable that can alter the measured levels of AC activity. Forskolin-stimulated platelet AC activity also may be influenced by a history of major depression.

Optic disc and retinal microvasculopathy after high-dose chemotherapy and autologous hematopoietic progenitor cell support.

The purpose of this study was to prospectively evaluate the retinal and optic nerve changes in patients undergoing high-dose chemotherapy (HDC) followed by autologous hematopoietic progenitor cell support (AHPCS). One hundred and forty patients undergoing HDC and AHPCS underwent extensive pre- and post-transplant ophthalmologic evaluations for development of retinal microvascular complications. One hundred and ten patients received high-dose cyclophosphamide, cisplatin and BCNU; thirty received identical doses of cyclophosphamide and cisplatin, but received paclitaxel instead of BCNU. Thirty-four patients (24%) had retinal findings of either cotton wool spots (CWS) (n = 20) or retinal hemorrhages (n = 18) during follow-up, which ranged from 1 to 12 months. Ten (7%) of these patients, all of whom received BCNU, showed ocular toxicity characterized by CWS 1 to 4 months post transplant (n = 10); optic disc edema (n = 3); and variable vision loss associated with the onset of BCNU-induced pulmonary toxicity. Retinal and optic disc microvascular complications may occur after high-dose chemotherapy followed by AHPCS. The association of ischemic retinal lesions and/or optic disc edema with BCNU-induced pulmonary toxicity and the lack of ocular toxicity in patients that did not receive BCNU may suggest that BCNU is the etiologic agent.

Cognitive functioning and impairment among rural elderly Hispanics and non-Hispanic whites as assessed by the Mini-Mental State Examination.

We conducted a cross-sectional study to determine the distribution of cognitive functioning as measured by the Mini-Mental State Examination (MMSE) among a sample of Hispanic and non-Hispanic White (NHW) residents from two counties in rural, southern Colorado. Residents aged 60 years and older (N = 1,360) were administered the full MMSE, a sociodemographic and medical interview. Protocols were developed to administer the MMSE equitably in both ethnic groups. Younger Hispanics tended to be categorized as severely impaired more than similarly aged NHWs (OR at age 70 = 4.14), however, older Hispanics and NHWs performed similarly after adjusting for education and gender (OR at age 90 = 1.00). The use of a modified MMSE scale that removed the ethnic bias demonstrated that NHWs and Hispanics had similar levels of severe impairment after full adjustment (OR = 0.93). Given the widespread use of the MMSE, these findings indicate the need for further validation of this instrument.

High-dose chemotherapy with autologous hematopoietic progenitor-cell support as part of combined modality therapy in patients with inflammatory breast cancer.

PURPOSE: To evaluate the feasibility of high-dose chemotherapy (HDC) with autologous hematopoietic progenitor-cell support (AHPCS) as part of combined modality therapy (CMT) in patients with inflammatory breast cancer (IBC). PATIENTS AND METHODS: From April 1993 to March 1997, 30 patients with IBC were treated at our program. Twenty-three patients received neoadjuvant chemotherapy (NAC) before HDC; 18 patients also received adjuvant chemotherapy following surgery, but before HDC. All patients received HDC with high-dose cyclophosphamide, cisplatin, and carmustine (BCNU) with AHPCS. Every patient underwent surgery either before (27 patients) or after (three patients) HDC. Patients received radiotherapy after HDC in addition to tamoxifen if their tumors were estrogen receptor-positive. RESULTS: Thirteen patients experienced grade 3 or 4 nonhematologic noninfectious toxicities. In 12 patients (40%), this represented drug-induced lung injury, which in all cases responded to a 10-week course of corticosteroids. The only treatment-related death was secondary to hemolytic-uremic syndrome (HUS). Another patient suffered grade 4 CNS toxicity, which was completely reversible. All patients engrafted promptly. Eight patients relapsed, five of whom had a poor pathologic response to NAC. Relapses were local (five patients), local plus systemic (one), or systemic only (two). Median follow-up time from diagnosis and HDC is 23.5 (range, 7 to 49) and 19 (range, 4 to 44) months, respectively. Twenty-one patients (70%; 95% confidence interval [CI], 51% to 86%) remain alive and free of disease 4 to 44 months after HDC. Median disease-free survival (DFS) and overall survival have not yet been reached. CONCLUSION: HDC as part of CMT is feasible in patients with IBC. The toxicity of this treatment program is significant, but tolerable. Despite the short follow-up duration, the promising DFS observed in this group of patients warrants randomized studies that include a HDC-containing arm in patients with IBC.

Effects of abstinence and family history for alcoholism on platelet adenylyl cyclase activity.

Platelet adenylyl cyclase (AC) activity was measured in 32 alcohol-dependent subjects and 27 control subjects who were categorized as either family history-positive (FHP) or family history-negative (FHN) for alcoholism. The interview and blood sample collections were performed shortly after cessation of heavy drinking in the alcoholic group, and repeat blood samples were obtained at the end of the first and second weeks of monitored abstinence. Control subjects received the same interview and provided blood samples at the time of the interview. When subjects were not segregated for FHP or FHN status, there were no statistically significant differences in basal, cesium fluoride (CsF)-, or forskolin-stimulated mean AC activities between the controls and the alcoholics, at study entry or with 1 or 2 weeks of abstinence. On the other hand, over the 2-week course of sobriety from heavy drinking, the CsF-stimulated AC activity of FHP alcohol-dependent subjects decreased significantly (p = 0.03). FHP alcohol-dependent subjects after 2 weeks of sobriety had significantly lower mean CsF-stimulated AC activity than FHN controls (p = 0.04), whereas the FHN alcoholic subjects' CsF-stimulated AC activity did not differ significantly from FHN controls at this point in time. When all subjects were pooled and then categorized as either FHP or FHN, there was a significant difference in mean CsF-stimulated AC activity (p = 0.02) between the FHP and FHN subject groups. Genetic factors and abstinence appear to have roles in determining low platelet AC activity in alcoholic and nonalcoholic subjects. CsF-stimulated platelet AC activity, in particular, appears to act as a trait marker for a genetic vulnerability to developing alcoholism, but recent heavy drinking in male alcoholics is a factor that can mask differences between FHP and FHN subjects.

Treatment of hepatic venocclusive disease with recombinant human tissue plasminogen activator and heparin in 42 marrow transplant patients.

The purpose of this report is to review the Fred Hutchinson Cancer Research Center experience of treating patients with venocclusive disease of the liver (VOD) after marrow transplantation using recombinant human tissue plasminogen activator (rh-tPA) and heparin. The charts of 42 patients who had received rh-tPA and heparin for the treatment of VOD between February 1991 and December 1995 were reviewed. Response to rh-tPA and heparin was defined as a reduction in total serum bilirubin by 50% within 10 days of starting treatment. Total serum bilirubin, percent weight gain, and serum creatinine before, after, and at the start of rh-tPA and heparin were examined to determine whether these laboratory values distinguished patients who responded to treatment from those who did not. We also evaluated whether evidence of multiorgan failure (requirement for supplemental oxygen, requirement for hemodialysis, requirement for mechanical ventilation) or whether the calculated probability of a fatal outcome from VOD could discriminate responders from nonresponders. In addition, the incidence and outcome of bleeding as a major complication of thrombolytic therapy was examined. Twelve patients responded to rh-tPA and heparin and 30 patients did not. There were no statistically significant differences between responders and nonresponders in the day treatment was started, dose of rh-tPA, total serum billirubin, and percent weight gain before, after, or at the start of treatment, or the calculated probability of dying from VOD on the day treatment with rh-tPA and heparin was begun. More nonresponding patients required dialysis or mechanical ventilation (11 of 30) before or at the start of rh-tPA and heparin than responding patients (0 of 12), P = .0183. Serum creatinine was greater at the start of treatment in nonresponding patients (1.9 +/- 1.3 mg/dL) than in responding patients (1.1 +/- 0.4 mg/dL), P = .0794. Ten patients had severe bleeding episodes, which resulted in death in three patients and may have contributed to death in an additional three patients. Treatment for VOD using rh-tPA and heparin was successful in 29% of patients but was associated with a significant risk of life-threatening hemorrhage. Requirement for supplemental oxygen, dialysis, or mechanical ventilation before the start of treatment were prognostic indicators of no response to thrombolytic therapy. We do not recommend treatment using tPA and heparin in patients with severe VOD who have already developed multiorgan dysfunction.