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Background: There is strong evidence for the role of the endogenous opioid system in alcohol reinforcement and consumption; however, recent human laboratory studies and clinical trials have reported mixed effects of naltrexone (a nonselective opioid antagonist) on alcohol-related behaviors. This paper reports a secondary data analysis of a human laboratory study that examines the relationship between serum levels of 6-beta-naltrexol, the major, biologically active metabolite of naltrexone, and subjective effects of alcohol. Methods: The study used a within-subjects design to examine the effects of naltrexone (0, 50, and 100 mg/day) on subjective responses to alcohol (none, moderate, and high dose) in heavy drinkers (n= 23). Each subject received three doses of naltrexone in random order; each naltrexone dose was administered over an 8 day period on an inpatient unit, with a 1 week outpatient washout between doses. After stabilization at each of the naltrexone doses, subjects participated in three alcohol challenge sessions (none, moderate, and high dose) in random order; thus, each subject participated in a total of nine alcohol administration sessions. Results: Doubling the naltrexone dose (50 vs. 100 mg/day) doubled the mean serum 6-beta-naltrexol levels. At each naltrexone dose, there was a 4-fold range in 6-beta-naltrexol levels across subjects. Before alcohol administration, higher 6-beta-naltrexol levels were associated with higher ratings of sedation. After high-dose alcohol administration, higher 6-beta-naltrexol levels were associated with significantly lower ratings of liking and best effects. Conclusions: These findings provide further evidence of the involvement of the opioid system in the modulation of alcohol effects and suggest that serum 6-beta-naltrexol concentrations may be important in predicting therapeutic response to naltrexone.

Background Fetal fibronectin (fFN) is used as a biomarker for preterm delivery. Currently, its use is discouraged if there has been vaginal manipulation in the previous 24 hours. Objective Our objective is to determine if there are differences between fFN results before and after vaginal manipulation in the form of sterile vaginal exam or transvaginal ultrasound. Study Design This was a prospective observational cohort study at a single center of women between 22-33 6/7 weeks at risk for preterm delivery due to: (1) a history of preterm delivery, short cervix, or multifetal gestation; or (2) symptoms of preterm labor. We excluded women with vaginal bleeding or infection, placenta previa, ruptured membranes, cervical dilation >3 cm, or any form of vaginal manipulation in the previous 24 hours. Specimen A was collected prior to planned vaginal exam or transvaginal ultrasound and specimen B was collected within 4 hours. The agreement between specimens A and B was assessed using descriptive statistics. Test characteristics of specimens A and B using the outcome of preterm delivery ( Results In all, 310 specimen pairs from 237 women were collected. Specimen A was positive in 37 (12%) instances and negative in 273 (88%) while specimen B was positive in 39 (13%) and negative in 271 (87%). There were discordant results in 26 specimen pairs. Of these, 14 (5%) negative specimen A results subsequently became positive for specimen B, and 12 (32%) positive specimen A results became negative for specimen B. Overall, there was a 92% agreement between specimens A and B (confidence interval, 88–94%). The specificity of specimens A and B for preterm birth was 90% vs 89%, respectively, with a negative predictive value of 87% for both. The false-negative rate was 12.8% for specimen A and 13.3% for specimen B. Conclusion There is a moderately high degree of agreement between prevaginal and postvaginal manipulation fFN results. Their test characteristics for evaluating preterm birth are similar with strong specificity and negative predictive values, and their false-negative rates are not clinically different. Consideration should be made to the utilization of postvaginal manipulation fFN when a prevaginal manipulation specimen is not available.

Objective: We analyzed use of venous thromboembolism (VTE) prophylaxis in patients undergoing oncologic surgery and examined the influence of surgeon and hospital characteristics on prophylaxis. Background: Cancer patients undergoing surgery are at high-risk for VTE. Despite the risk of VTE, the use of prophylaxis is variable. Little is known about the patient, surgeon, and hospital characteristics that influence the use of prophylaxis. Methods: Patients undergoing oncologic surgery from 2003 to 2007 and recorded in the Perspective database were analyzed. Surgeons and hospitals were stratified into volume-based tertiles for analysis. The effects of surgeon and hospital volume on use of any prophylaxis and pharmacologic prophylaxis were examined using generalized estimating equations adjusted for confounding variables. Results: In the cohort of 252,950 patients, some form of prophylaxis was given to 79% of patients whereas 46% received pharmacologic prophylaxis. The rate of VTE prophylaxis was 82.7% at high-volume hospitals compared with 75.6% at low-volume facilities (P < 0.0001). After adjustment for case mix and surgeon volume, the odds ratio for receipt of prophylaxis at high-versus low-volume hospitals was 1.40 (95% CI, 1.20-163). The odds ratio for prophylaxis for patients treated by high-volume surgeons was 1.35 (95% CI, 1.14-160) after adjusting for case mix and hospital volume. The rate of pharmacologic VTE prophylaxis was 53.1% in high-volume hospitals versus 38.8% in low-volume hospitals (P < 0.0001). Treatment at a high-volume hospital was associated with an odds ratio of 1.42 (95% CI, 1.22-1.66) for pharmacologic prophylaxis whereas the odds ratio for pharmacologic prophylaxis for patients treated by high-volume surgeons was 1.28 (95% CI, 1.08-1.51). Conclusion: VTE prophylaxis is underutilized in patients undergoing oncologic surgery. Patients treated by high-volume surgeons and at high-volume hospitals are more likely to receive appropriate prophylaxis.

This paper addresses the dose-finding problem in cancer trials in which we are concerned with the gradation of severe toxicities that are considered dose limiting. In order to differentiate the tolerance for different toxicity types and grades, we propose a novel extension of the continual reassessment method that explicitly accounts for multiple toxicity constraints. We apply the proposed methods to redesign a bortezomib trial in lymphoma patients and compare their performance with that of the existing methods. Based on simulations, our proposed methods achieve comparable accuracy in identifying the maximum tolerated dose but have better control of the erroneous allocation and recommendation of an overdose.

Background The continual reassessment method (CRM) is an adaptive model-based design used to estimate the maximum tolerated dose in dose finding clinical trials. A way to evaluate the sensitivity of a given CRM model including the functional form of the dose-toxicity curve, the prior distribution on the model parameter, and the initial guesses of toxicity probability at each dose is using indifference intervals. While the indifference interval technique provides a succinct summary of model sensitivity, there are infinitely many possible ways to specify the initial guesses of toxicity probability. In practice, these are generally specified by trial and error through extensive simulations. Methods By using indifference intervals, the initial guesses used in the CRM can be selected by specifying a range of acceptable toxicity probabilities in addition to the target probability of toxicity. An algorithm is proposed for obtaining the indifference interval that maximizes the average percentage of correct selection across a set of scenarios of true probabilities of toxicity and providing a systematic approach for selecting initial guesses in a much less time-consuming manner than the trial-and-error method. The methods are compared in the context of two real CRM trials. Results For both trials, the initial guesses selected by the proposed algorithm had similar operating characteristics as measured by percentage of correct selection, average absolute difference between the true probability of the dose selected and the target probability of toxicity, percentage treated at each dose and overall percentage of toxicity compared to the initial guesses used during the conduct of the trials which were obtained by trial and error through a time-consuming calibration process. The average percentage of correct selection for the scenarios considered were 61.5 and 62.0% in the lymphoma trial, and 62.9 and 64.0% in the stroke trial for the trial-and-error method versus the proposed approach. Limitations We only present detailed results for the empiric dose toxicity curve, although the proposed methods are applicable for other dose—toxicity models such as the logistic. Conclusions The proposed method provides a fast and systematic approach for selecting initial guesses of probabilities of toxicity used in the CRM that are competitive to those obtained by trial and error through a time-consuming process, thus, simplifying the model calibration process for the CRM.

Objective We report a single-institution Phase I or II trial of surgical debulking, intraperitoneal chemotherapy, and immunotherapy followed by whole abdominal radiotherapy in patients with malignant peritoneal mesothelioma. Methods Between 1997 and 2000, 27 patients with malignant peritoneal mesothelioma were enrolled: 23 with epithelial subtype and 4 with sarcomatoid or mixed subtype. The treatment regimen consisted of surgical debulking followed by 4 intraperitoneal courses of cisplatin alternating with 4 courses of doxorubicin, 4 doses of intraperitoneal gamma interferon, a second laparotomy with resection of residual disease plus intraoperative intraperitoneal mitomycin and cisplatin heated to 41 degrees C, and finally whole abdominal radiotherapy. Results The median overall survival was 70 months with a 3-year survival of 67% (95% confidence interval, 46%-81%). Fourteen patients have died of their disease with a median time to death of 17 months (range, 0.4-71 months) after consenting to treatment. Seven patients are alive without evidence of disease with a median follow-up of 90 months (range, 71-110 months), and 6 are alive with disease with a median follow-up of 86 months (range, 70-106 months). The regimen was well tolerated. There were no patients with Grade III or IV hematological toxicities, 2 patients with Grade III ototoxicity, and 3 patients with Grade III gastrointestinal toxicity. Conclusion Based on the results of this study, intensive multimodality therapy appears feasible and effective in this group of patients.

The second-order nonlinear optical susceptibility of a quantum well with an applied electric field is studied theoretically with use of both a parabolic-band model and a valence-band-mixing model. The electronic properties of the asymmetric quantum-well system due to an applied electric field and their effects on the second-order nonlinear susceptibility are illustrated. It is shown that the applied electric field may change the second-order susceptibility significantly. The dispersion of the nonlinear susceptibility using the valence-band-mixing model also shows more features than that using the simple parabolic-band model of previous studies of quantum-well systems.

Pulmonary rehabilitation is an established treatment in patients with chronic lung disease but is not widely utilized. Most trials have been conducted in single centers. The National Emphysema Treatment Trial (NETT) provided an opportunity to evaluate pulmonary rehabilitation in a large cohort of patients who were treated in centers throughout the United States.Prospective observational study of cohort prior to randomization in a multicenter clinical trial.University-based clinical centers and community-based satellite pulmonary rehabilitation programs.A total of 1,218 patients with severe emphysema underwent pulmonary rehabilitation before and after randomization to lung volume reduction surgery (LVRS) or continued medical management. Rehabilitation was conducted at 17 NETT centers supplemented by 539 satellite centers.Lung function, exercise tolerance, dyspnea, and quality of life were evaluated at regular intervals. Significant (p0.001) improvements were observed consistently in exercise (cycle ergometry, 3.1 W; 6-min walk test distance, 76 feet), dyspnea (University of California, San Diego Shortness of Breath Questionnaire score, -3.2; Borg breathlessness score: breathing cycle, -0.8; 6-min walk, -0.5) and quality of life (St. George Respiratory Questionnaire score, -3.5; Quality of Well-Being Scale score, +0.035; Medical Outcomes Study 36-item short form score: physical health summary, +1.3; mental health summary, + 2.0). Patients who had not undergone prior rehabilitation improved more than those who had. In multivariate models, only prior rehabilitation status predicted changes after rehabilitation. In 20% of patients, exercise level changed sufficiently after rehabilitation to alter the NETT subgroup predictive of outcome. Overall, changes after rehabilitation did not predict differential mortality or improvement in exercise (primary outcomes) by treatment group.The NETT experience demonstrates the effectiveness of pulmonary rehabilitation in patients with severe emphysema who were treated in a national cross-section of programs. Pulmonary rehabilitation plays an important role in preparing and selecting patients for surgical interventions such as LVRS.

PURPOSE: To study the effect of lubricant eye drop instillation on ocular wavefront aberrations. METHODS: The wavefront aberrations of the entire optical path of 30 eyes of 15 patients before and following instillation of lubricant eye drops (Bion Tears; Alcon Laboratories Ine, Ft Worth, Tex) were obtained over a 6-mm pupil using a Hartmann-Shack wavefront sensor (WaveScan; VISX Ine, Santa Clara, Calif). Additional computation of root-mean-square (RMS) errors of higher order aberrations from third to sixth order were done using Zernike Tool Software (VISX Ine). Main outcome measures include the mean changes of total higher order aberrations RMS, higher order aberrations, and point spread function (PSF) of the higher order aberrations. RESULTS: The mean changes of total higher order aberrations following instillation of lubricant eye drops on the right eyes were -0.07 ??? (95% confidence interval [Cl], -0.11 to -0.03) and -0.03 ??? on the left eyes (95% Cl, -0.07 to 0.01). Significant mean changes were noted for coma and trefoil aberrations with a magnitude of -0.08 ??? (95% Cl, -0.12 to -0.03) and -0.09 (95% Cl, -0.13 to -0.05), respectively, as well as a mean change of the PSF of the higher order aberrations (-0.05 diopters, 95% Cl, -0.08 to -0.02) on the right eyes. Although no significant changes in these parameters were demonstrated on the left eyes, a similar trend of changes was observed. CONCLUSIONS: Ocular wavefront aberrations may change following eye drop instillation as measured objectively by the WaveScan system. This effect should be taken into consideration in the assessment of patients for wavefront-guided laser vision correction procedures. [J Refract Surg. 2005;21:709-715.]

Purpose To compare the central corneal thickness (CCT) measurements obtained with noncontact optical low-coherence reflectometry (OLCR) and ultrasound (US) pachymetry. Design Prospective, comparative observational study. Methods Three sequential ultrasonic measurements and a set of five OLCR scans of 52 eyes of 26 healthy subjects were recorded. Noncontact measurement was repeated five minutes after anesthetic drop instillation. Results Mean CCT values for noncontact OLCR and US pachymetry were 544.03 μm and 548.66 μm, respectively, with mean SDs of 0.97 μm and 4.63 μm, respectively. Noncontact OLCR measured on average 4.64 μm less than US pachymetry (95% confidence interval −7.56 to −1.72; P = .003). The OLCR measured 1.68 μm less than US pachymetry in the thinner cornea group (≤548.7 μm, n=24) and 7.48 μm less in the thicker group (n = 25). This difference was statistically significant ( P = .04). Conclusions There was agreement between the two pachymetric measurements. Noncontact OLCR appeared to measure slightly smaller than US pachymetry.

BackgroundThe National Emphysema Treatment Trial, a randomized trial comparing lung volume reduction surgery with medical therapy for severe emphysema, included randomized and nonrandomized comparisons of the median sternotomy and video-assisted thoracoscopic approaches for lung volume reduction surgery.MethodsLung volume reduction surgery was performed by median sternotomy only at 8 centers and video-assisted thoracoscopy only at 3 centers; 6 centers randomized the approach to lung volume reduction surgery. Mortality, morbidity, functional status, and costs were assessed.ResultsIn the nonrandomized comparison, 359 patients received lung volume reduction surgery by median sternotomy, and 152 patients received lung volume reduction surgery by video-assisted thoracoscopy. The 90-day mortality was 5.9% for median sternotomy and 4.6% for video-assisted thoracoscopy (P = .67). Overall mortality was 0.08 deaths per person-year for median sternotomy and 0.10 deaths per person-year for video-assisted thoracoscopy (video-assisted thoracoscopy-median sternotomy risk ratio, 1.18; P = .42). Complication rates were low and not statistically different for the 2 approaches. The median hospital length of stay was longer for median sternotomy than for video-assisted thoracoscopy (10 vs 9 days; P = .01). By 30 days after surgery, 70.5% of median sternotomy patients and 80.9% of video-assisted thoracoscopy patients were living independently (P = .02). Functional outcomes were similar for median sternotomy and video-assisted thoracoscopy at 12 and 24 months. Costs for the operation and the associated hospital stay and costs in the 6 months after surgery were both less for video-assisted thoracoscopy than for median sternotomy (P < .01 in both cases). Similar results were noted for the randomized comparison.ConclusionsMorbidity and mortality were comparable after lung volume reduction surgery by video-assisted thoracoscopy or median sternotomy, as were functional results. The video-assisted thoracoscopic approach to lung volume reduction surgery allowed earlier recovery at a lower cost than median sternotomy.

We assess the feasibility of a urinary test for prostate cancer detection in a high-risk patient cohort based on methylation-specific PCR analysis of the pi class glutathione S-transferase (GSTP1) gene promoter.A total of 45 men underwent transrectal ultrasound-guided biopsy of the prostate for suspected malignancy. Clean-catch voided urine specimens were prospectively collected from each patient immediately after biopsy. Genomic DNA was isolated from urine specimens and subjected to sodium bisulfite modification. Methylation of the GSTP1 promoter was examined in a blinded manner by methylation-specific PCR analysis and correlated with pathology results, and clinical information was obtained from the patient record.Methylation of GSTP1 in the urine was detected in a total of 18 of 36 (50%) informative cases. A total of 7 of 18 (39%) patients with prostate adenocarcinoma identified on their initial biopsy had detectable urinary GSTP1 methylation (58% sensitivity among informative cases). Abnormal urinary GSTP1 methylation was also detected in 7 of 21 (33%) patients without evidence of cancer on biopsy and in 4 of 6 (67%) patients diagnosed with atypia or high-grade prostatic intraepithelial neoplasia.We have demonstrated the feasibility of a novel, noninvasive molecular approach for the detection of epigenetic changes associated with prostate cancer. A screening test based on GSTP1 methylation in the urine specimens of patients with suspected prostate malignancy may be a useful adjunct to serum screening tests and digital rectal examination findings for identification of men at increased risk of harboring cancer despite a negative biopsy. This molecular assay has potential application for stratification of patients into low- and high-risk groups for surveillance versus repeat biopsy.

The National Emphysema Treatment Trial (NETT) is a randomized, multicenter, clinical trial comparing two different methods of lung volume reduction surgery plus medical therapy to medical treatment alone in patients with advanced emphysema. The purpose of this article was to use the data obtained from the NETT to assess the ability of the single-breath diffusing capacity of the lung for carbon monoxide (DLCO) to predict the need for supplemental oxygen during rest and exercise, as well as overall exercise capacity.One thousand seventy-one patients with a mean (+/- SD) FEV(1) of 0.76 +/- 0.24 L were studied.The mean DLCO was 8.0 +/- 3.1 mL/min/mm Hg (28 +/- 10% of predicted). The mean resting PaO(2) was 64 +/- 10 mm Hg. There was a positive association between DLCO and both resting PaO(2) and the requirement for oxygen during a walk at 1 mile per hour (mph). The odds of requiring supplemental oxygen while walking at 1 mph was nine times greater in patients with a DLCO ofor = 20% of predicted than for patients with a DLCO of35% of predicted, after adjusting for age and gender. Eighty four percent of individuals with a DLCO ofor = 20% required supplemental oxygen with low levels of exercise compared to 38% of those with a DLCO of35%.Our results demonstrated that patients with reduced DLCO, particularly whenor = 20% of predicted, are more likely to have reduced PaO(2) at rest and are more likely to require supplemental oxygen with low levels of activity. Thus, DLCO is useful in evaluating whether supplemental oxygen is required for exercise.

The 6-minute walk test is used in clinical practice and clinical trials of lung diseases; however, it is not clear whether replicate tests need to be performed to assess performance. Furthermore, little is known about the impact of walking course layout on test performance. We conducted 6-minute walks on 761 patients with severe emphysema (mean +/- SD FEV1% predicted = 26.3 +/- 7.2) who were participants in the National Emphysema Treatment Trial. Four hundred seventy participants had repeated walks on a separate day. The second test was improved by an average of 7.0 +/- 15.2% (66.1 +/- 146 feet, p < 0.0001, by paired t test), with an intraclass correlation coefficient of 0.88 between days. The course layout had an effect on the distance walked. Participants tested on continuous (circular or oval) courses had a 92.2-foot longer walking distance than those tested on straight (out and back) courses. Course length had no significant effect on walking distance. The training effect found in these patients with severe emphysema is less than in previous reports of patients with chronic obstructive pulmonary disease. Furthermore, the layout of the track may influence the 6-minute walk performance.

Background: Allelic imbalance (AI), the loss or gain of chromosomal regions, is found in many cancers. AI can be detected in genomic tumor DNA released into the blood after necrosis or apoptosis. We evaluated plasma DNA concentration, allelic status in plasma DNA, and serum CA 125 level as screening tests for ovarian and other cancers. Methods: Plasma samples were obtained from 330 women (44 normal healthy control individuals, 122 patients with various cancers, and 164 control patients with non-neoplastic diseases). Plasma DNA concentration was determined in all samples. Allelic status was determined by digital single nucleotide polymorphism (SNP) analysis with eight SNP markers in plasma DNA from 54 patients with ovarian cancer and 31 control patients. CA 125 was determined in 63 samples. Receiver-operating characteristic (ROC) curves were plotted, and the areas under the ROC curves—a measure of the overall ability of a diagnostic test with multiple cutoffs to distinguish between diseased and nondiseased individuals— were determined. Results: The area under the ROC curve for plasma DNA concentration was 0.90 for patients with neoplastic disease versus healthy control individuals and 0.74 for patients with neoplastic diseases versus control patients with non-neoplastic diseases. For control subjects given a specificity of 100% (95% confidence interval [CI] = 92% to 100%), the highest sensitivity achieved was 57% (95% CI = 49% to 67%). AI in at least one SNP was found in 87% (95% CI = 60% to 98%) of patients with stage I/II ovarian cancer and 95% (95% CI = 83% to 99%) of patients with stage III/IV ovarian cancer, but AI was not found in 31 patients with non-neoplastic diseases (specificity = 100%, 95% CI = 89% to 100%). The area under the ROC curve assessing AI was 0.95. Combining the serum CA 125 level with the plasma DNA concentration increased the area under the ROC curve from 0.78 (CA 125 alone) to 0.84. Conclusion: Plasma DNA concentration may not be sensitive or specific enough for cancer screening or diagnosis, even when combined with CA 125. AI was detected with high specificity in plasma DNA from patients with ovarian cancer and should be studied further as a screening tool. [J Natl Cancer Inst 2002;94:1697–1703]

We evaluated the postoperative clinical course of patients with renal cancer identified preoperatively by microsatellite analysis to examine the correlation between microsatellite alterations and risk of disease recurrence and patient mortality 2 years after nephrectomy.A panel of 28 microsatellite markers was used previously to assess loss of heterozygosity and microsatellite instability in urine, serum, and tumor DNA of 30 patients with clinically organ-confined renal masses who underwent partial or radical nephrectomy. The clinical reports and imaging data in the medical records of patients with a minimum follow-up of 2 years were retrospectively reviewed to determine their postoperative course.Two-year follow-up was available for the 30 patients (100%) who entered the study. Mean age was 61.6 +/- 12.9 years (range, 21-77 years). Tumor stage was associated with patient mortality (P = 0.03). Tumor grade was associated with mortality (P = 0.03) and disease recurrence (P0.01). The frequency of microsatellite alterations (loss of heterozygosity) found in the preoperative serum of patients with renal masses served as a prognostic indicator for disease recurrence (P0.01).Analysis of microsatellite alterations found in preoperative blood samples is a promising method for the detection of renal cancer. The presence of frequent molecular changes in preoperative serum was associated with disease recurrence. These findings suggest a role for microsatellite analysis in future studies attempting to stratify patients with clinically organ-confined renal cancer into low- and high-risk prognostic groups. Larger prospective randomized trials are needed to validate the clinical utility of this observation.

Between January 1987 and January 1997, 69 eligible patients with acute myeloid leukaemia (AML) in either second (CR2) or third (CR3) complete remission (CR2 = 60, CR3 = 9) underwent 4-hydroperoxycyclophosphamide-purged autologous bone marrow transplantation (BMT) at the Johns Hopkins Oncology Center. The patients' median age was 27 years (range 1-62) and all received busulphan and cyclophosphamide as their preparative regimen. The probability of event-free survival (EFS) at 5 years was 30% [95% Confidence Interval (CI): 19-42%] for CR2 patients and 22% (3-51%) for those in CR3, with a median follow up of 8 years in the surviving group. The median time to an absolute neutrophil count of 0.5 x 109/l was 45 d (range 20-185). Relapse was the major cause of failure with a relapse rate of 55% in CR2 and 44% in CR3, while the non-relapse, transplant-related mortality rate was 15% in CR2 and 33% in CR3. In univariate analysis, patient age, cytogenetics, white blood cell count at presentation, CR1 duration and the sensitivity of clonogeneic leukaemia (CFU-L) in the graft to 4HC were all prognostic for EFS. Using each of these significant variables in multivariate modelling, patient age and sensitivity of CFU-L to 4HC were determined to be predictors of EFS. 4HC-purged autologous BMT produced results similar to allogeneic BMT for AML patients beyond first remission.

Corticosteroids remain essential for controlling active chronic graft-versus-host disease (cGVHD). However, the optimum dose and administration schedule is unknown. We have reviewed our results in 61 patients with severe refractory cGVHD who were treated with a high-dose pulse steroid regimen (PS) consisting of methylprednisolone at 10 mg/kg per day for 4 consecutive days, with subsequent tapering doses. After 4 days, all patients received a course of additional immunosuppressive therapy. The median age of the 56 patients who were evaluable for response was 32 years (range, 0.2-57 years). Patients had failed a median of 2 (range, 1-5) treatments prior to the PS. The median follow-up for 45 surviving patients after PS was 1.5 years. The probability of survival at 1 year and 2 years after PS was 88% (95% confidence interval [CI], 76%-95%) and 81% (95% CI, 65%-91%), respectively. Twenty-seven patients (48%) showed a major response to PS with substantial improvement of cGVHD manifestations, including softening of the skin, increased range of motion, and improved performance status; 15 patients (27%) showed a minor response, defined as improvement in some but not all symptoms of cGVHD. Of the 42 responders, 21 (50%) had progression of their cGVHD afterwards. The median time to progression was 1.9 years. The probability of progression at 1 and 2 years after PS was 36% (95% CI, 23%-53%) and 54% (95% CI, 38%-71%), respectively. The probability of progression at 1 year was 25% (95% CI, 12%-47%) and 55% (95% CI, 32%-81%) for patients who had major and minor response, respectively (hazard ratio, 2.13). Ten of the 42 responders (24%) were able to discontinue all systemic immunosuppressive treatments. The probability of discontinuation at 1 and 2 years after PS was 9% (95% CI, 3%-25%) and 27% (95% CI, 15%-48%), respectively. The treatment was well tolerated with no serious adverse events. Our results suggest that PS is a well-tolerated regimen for achieving rapid clinical response in the majority of patients with cGVHD who failed on multiple previous therapies. Further studies are warranted to maintain the efficacy of this regimen by combining with new active agents in cGVHD. Biol Blood Marrow Transplant 2001;7(9):495-502.

Severe aplastic anemia is a life-threatening bone marrow failure disorder. High-dose cyclophosphamide therapy followed by allogeneic bone marrow transplantation cures the disease. However, it requires a suitable donor and carries the risk for graft-versus-host disease. A small pilot study demonstrated that high-dose cyclophosphamide therapy without bone marrow transplantation leads to durable, treatment-free complete remission.To confirm the safety and efficacy of high-dose cyclophosphamide therapy alone in patients with severe aplastic anemia.Uncontrolled clinical trial.Three tertiary care hospitals.19 patients with untreated severe aplastic anemia.Cyclophosphamide, 50 mg/kg of body weight per day for 4 consecutive days.Probability of response and overall survival were measured. Complete remission was defined as normal blood count for age and sex. Partial remission was defined as independence from transfusion and an absolute neutrophil count greater than 0.5 x 10(9) cells/L without growth factor support. Nonresponders were patients who remained transfusion dependent or died. Relapse was defined as no longer meeting criteria for partial or complete remission.The median time to an absolute neutrophil count of 0.5 x 10(9) cells/L was 49 days. The probability of survival was 84% (95% CI, 59% to 95%) at 24 months. The probability of achieving treatment-free remission was 73% (CI, 51% to 91%) at 24 months, and the probability of achieving complete remission was 65% (CI, 39% to 89%) at 50 months. No responding patients have had relapse or have developed secondary clonal disorders.High-dose cyclophosphamide therapy without bone marrow transplantation produces durable treatment-free remission in severe aplastic anemia. This approach deserves further study in patients with severe aplastic anemia who are not suitable candidates for allogeneic bone marrow transplantation.

Bone marrow (BM) aspiration and biopsy are used commonly in clinical practice to diagnose invasive tissue infections caused by Mycobacterium avium intracellulare (MAC), Mycobacterium tuberculosis (TB), and Histoplasma capsulatum (HC) in patients with human immunodeficiency virus-1 (HIV) infection. However, the value of these invasive procedures relative to other diagnostic approaches has not been clearly defined. To determine the value of BM culture and BM histology in the diagnosis of opportunistic MAC/TB and HC infections in immunosuppressed patients with HIV, we retrospectively reviewed the records of 56 adult patients with HIV who underwent a single BM aspiration, biopsy, and culture because of unexplained fever and/or other clinical features suggestive of MAC/TB or HC infection. Thirty-two patients (57%) were ultimately diagnosed with MAC/TB or HC infection by positive cultures of BM, blood, sputum, or bronchoalveolar lavage fluid or by the histologic detection of organisms in biopsies of BM or other tissues. The diagnostic sensitivity of BM cultures was equal to that of blood cultures (20/32, or 63%). Granuloma and/or histologically apparent organisms were seen in BM biopsy specimens in 11 of 32 individuals (34%) ultimately diagnosed with MAC/TB or HC infections. Among these 11 cases, both granuloma and acid-fast staining organisms were found in the BM biopsy specimens of 2 individuals for whom both BM and blood cultures were negative. Certain clinical symptoms and signs at the time of BM examination were found by logistic regression analysis to be significantly associated with a subsequent diagnosis of MAC/TB or HC infections; these included high fever, long duration of febrile days prior to BM examination, and elevated direct bilirubin. In conclusion, while the diagnostic sensitivity of BM cultures was found to be no greater than that of blood cultures in detecting MAC/TB or HC infections in immunosuppressed HIV+ patients, histopathologic examination of BM specimens resulted in the relatively rapid identification of nearly one third of infected patients who underwent BM examination, and also identified infections in some patients who were culture negative. These findings support the continued use of BM aspiration, biopsy, and culture for the diagnosis of opportunistic MAC/TB or HC infections in immunosuppressed HIV+ patients, particularly when selected clinical features are present.

Surface contamination of insulators in high voltage transmission and distribution systems may lead to troublesome flashovers which interrupt service. Insulator contamination may be monitored using direct measurement of equivalent salt deposit density (ESDD), which directly relates to the flashover voltage. A fiber-optic evanescent- coupling fiber-optic ESDD monitor is presented. The use of a piece of D-shape E-core fiber as sensor head can provide a sensitive and large area ESDD monitoring system. We have demonstrated the use of D-shape fiber in monitoring ESDD on insulator surfaces. A simple process has been developed to precisely etch the D-fiber. The polarimetric and evanescent loss sensors have been investigated. The evanescent loss sensor is particularly suitable for in-situ ESDD monitoring in power transmission lines and substations.© (1996) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

An all fiber-optic in-line photopolarimeter is disclosed. This photopolarimeter replaces the conventional 1×2 coupler, bulk beamsplitter and accompanying optics with a single 1×5 star coupler. This system can measure state of polarization of light in a fiber in situ.

ContextHepatitis C is the leading cause of chronic liver disease in the United States. Several trials have found that interferon and ribavirin combination therapy is more efficacious than interferon monotherapy for previously untreated patients and those who relapsed after prior interferon monotherapy, but its effectiveness for nonresponders to prior interferon monotherapy is unclear.ObjectiveTo assess the efficacy and safety of interferon and ribavirin vs interferon alone for treatment of patients with chronic hepatitis C who previously did not respond to interferon monotherapy.Data SourcesA systematic search was performed using MEDLINE and the Science Citation Index for publications from 1966 to December 1999. A manual reference search and a manual review of relevant specialty journals also were performed, and input from clinical hepatology experts was sought.Study SelectionIncluded studies were randomized, controlled clinical trials comparing interferon and ribavirin with interferon alone and reporting virological and biochemical outcomes after a follow-up period. Of 50 identified studies, 12 trials (941 patients) were included in the analysis.Data ExtractionTwo investigators reviewed trials independently for methods, inclusion and exclusion criteria, and outcomes. Disagreements were resolved by discussion. Abstracted data included study and patient characteristics and virological, biochemical, and histological outcomes. A quality evaluation questionnaire was used to score studies.Data SynthesisThe pooled virological response rate for combination therapy was 14% (95% confidence interval [CI], 11%-17%), with a risk difference favoring combination therapy of 7% (95% CI, 2%-13%). Use of interferon alfa-2a/2b and ribavirin, 1000 to 1200 mg/d, was associated with a pooled virological response rate of 18% and a risk difference of 16% (95% CI, 11%-21%). When interferon alfa-n/n3 and a lower dosage of ribavirin (600-800 mg/d) were used, the risk difference was 0% (95% CI, –7% to 7%). Combination therapy was associated with more adverse effects and an increased rate of discontinuation of treatment compared with interferon monotherapy.ConclusionsFor chronic hepatitis C that is nonresponsive to prior interferon monotherapy, combination therapy is more effective than re-treatment with interferon alone. Response rates remain less than 20% even in the most responsive subgroups, demonstrating a need for better therapeutic options.

A novel finite-difference vectorial-beam-propagation method using Yee’s mesh is demonstrated to be a simple, efficient, and versatile method to analyze the modal characteristics of waveguide structures with arbitrary cross section. The method is derived from directly discretizing Maxwell’s equations with the use of Yee’s mesh. A von Neumann stability analysis indicates that there is a stable region for the wave front to propagate along the imaginary waveguide axis. Such a direct propagation method is efficient in terms of CPU time and memory requirements. Therefore the propagation constants and their corresponding vectorial-modal-field distributions for waveguides of variable cross sections are obtained efficiently and simultaneously. Results in close agreement with published results using either analytic or numerical methods for several waveguides are shown.