Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment

Patients with idiopathic pulmonary fibrosis (IPF) inevitably experience declines in functional status that are most frequently due to progressive pulmonary fibrosis. However, the cause of the clinical deterioration is often uncertain, and disease progression is difficult to distinguish from disease-associated complications or adverse effects of therapy. In studies of the clinical course of IPF, mortality is most frequently due to respiratory failure (38.7%); other causes of death include heart failure (14.4%), bronchogenic carcinoma (10.4%), ischemic heart disease (9.5%), infection (6.5%), and pulmonary embolism (3.4%). Other, usually nonfatal, disease-associated complications include pneumothorax, corticosteroid-induced metabolic side effects and myopathy, and therapy-related immunosuppression. In evaluating clinical deterioration in patients with IPF, disease-associated complications and adverse effects of therapy should be distinguished from progressive pulmonary fibrosis. The cause of clinical deterioration will alter the therapeutic intervention required and will influence patient prognosis and duration of survival. This article examines the causes of clinical deterioration in patients with IPF and the diagnostic procedures for assessing disease-associated complications and staging IPF progression.     

Influence of technique of coronary artery implantation on long-term results in composite aortic root replacement.

BACKGROUND: Long-term results after composite graft aortic root replacement may depend on the insertion technique. The aim of this study is to assess the influence of the technique of coronary artery implantation on long-term results in composite aortic root replacement. METHODS: One hundred fifty consecutive patients (mean age, 55 years; 119 men) with different disorders of the ascending aorta who underwent aortic root replacement with a composite graft prosthesis between January 1985 and December 1999 were retrospectively studied. Thirteen patients had previously undergone cardiovascular surgery. The open button technique was performed in 65 patients (43.3%, group 1) and the inclusion technique in 85 patients (56.7%, group 2). Mean follow-up was 70.5 months. Surgery was elective in 110 procedures (73%). RESULTS: Global actuarial survival was 76.1% +/- 4.3% for group 1 and 73.7% +/- 3.9% for group 2 at 10 years (p = 0.22). Freedom from reoperation excluding early deaths was 81% +/- 3% for group 1 and 86% +/- 2.2% for group 2 at 10 years (p = 0.62). Group 2 demonstrated a statistically significantly higher occurrence of pseudoaneurysm formation versus group 1 (p = 0.04). CONCLUSIONS: Composite graft aortic root replacement is a safe and effective therapy for proximal aortic aneurysm and dissection, resulting in good early and long-term results irrespective of the anastomotic technique. However, the open button technique seems to avoid late false aneurysm formation at the anastomotic sites.     

Attenuated Salmonella targets prodrug activating enzyme carboxypeptidase G2 to mouse melanoma and human breast and colon carcinomas for effective suicide gene therapy

PURPOSE: We engineered the oncolytic Salmonella typhimurium-derived bacterium VNP20009 as a vector to target delivery to tumors of the prodrug-activating enzyme carboxypeptidase G2 (CPG2) and to show enhanced antitumor efficacy on administration of different prodrugs. EXPERIMENTAL DESIGN: We characterized CPG2 expression in vectors by immunoblotting, immunofluorescence, and enzyme activity. We assessed prodrug activation by high-performance liquid chromatography. Target human tumor cell and bacterial vector cell cytotoxicity was measured by flow cytometry and colony-forming assays. Therapy was shown in two human tumor xenografts and one mouse allograft with postmortem analysis of bacterial and CPG2 concentration in the tumors. RESULTS: CPG2 is expressed within the bacterial periplasm. It activates prodrugs and induces cytotoxicity in human tumor cells but not in host bacteria. Following systemic administration, bacteria multiply within xenografts reaching 2 x 10(7)/g to 2 x 10(8)/g at 40 days postinoculation. The concentration of CPG2 in these tumors increases steadily to therapeutic levels of 1 to 6 units/g. The bacteria alone reduce the growth of the tumors. Subsequent administration of prodrugs further reduces significantly the growth of the xenografts. CONCLUSIONS: The bacteria multiply within tumors, resulting in a selective expression of CPG2. The CPG2-expressing bacteria alone reduce the growth of tumors. However, in the presence of prodrugs activated by CPG2, this oncolytic effect is greatly increased. We conclude that bacterial oncolytic therapy, combined with CPG2-mediated prodrug activation, has great potential in the treatment of a range of cancers.     

Incidence of malignant testicular tumors in the population of Rochester, Minnesota, 1935 through 1974

Twenty-four cases of testicular neoplasms detected in male Rochester residents over a 40-year period were identified using the Rochester-Olmsted County epidemiologic data base. This resource contains nearly complete medical information on residents of Rochester, Minnesota, and the surrounding community. An incidence rate of 3.7/100,000 males per year was calculated. This agrees well with other rates reported in the literature which range from 2.5 to 3.7/100,000 per year; there was no detectable trend over time.     

Effects of simultaneous dual-site TENS stimulation on experimental pain

Transcutaneous electrical nerve stimulation (TENS) is commonly used for pain relief. However, little robust research exists regarding the combination of parameters required to provide effective doses. This study investigated the hypoalgesic effects of different parameter combinations, applied simultaneously at two sites (segmental and extrasegmental), on pressure pain threshold (PPT) in pain-free humans. Two-hundred and eight volunteers (median age 22 years, range 20–26) were randomized to eight groups: six active TENS groups, placebo and control. Parameter combinations were such that frequency always differed at each site (110 Hz or 4 Hz), but intensity could be either the same or different levels: high (to tolerance without pain) or low (strong but comfortable). TENS was administered to the forearm over the radial nerve and the ipsilateral leg below the fibular head for 30 min with monitoring for 30 further minutes. PPT measurements were taken bilaterally from the mid-point of first dorsal interosseous muscle, by an independent blinded rater, at baseline and at six subsequent 10-min intervals. Log-transformed data were analysed using repeated-measures analysis of covariance (baseline values and gender as covariates). Those groups using high-intensity stimulation at the segmental stimulation sites showed significantly greater hypoalgesia than placebo (p < 0.025 in each case). The largest hypoalgesic effect was for simultaneous high-intensity stimulation at segmental and extrasegmental sites, using different frequencies. These results reaffirm that high-intensity stimulation (regardless of frequency) is of fundamental importance in effective dosage.     

Development and validation of a patient-specific predictive instrument for the need for dose reduction in chemotherapy for breast cancer: a potential decision aid for the use of myeloid growth factors

A predictive instrument for chemotherapy dose reductions would help optimize delivery of planned chemotherapy and rationalize the use of myeloid growth factors. We analyzed data on 833 women with breast cancer treated with cyclophosphamide, doxorubicin, and fluorouracil, for six cycles in two phase III clinical trials. From the first study ( n=323), we generated a logistic regression model that predicts an individual patient's probability of receiving significantly reduced chemotherapy, defined as less than 85% of the planned dose over cycles 2-6, using data generated from cycle 1. The model was validated on data from the second study ( n=510). The predictive model's variables include nadir absolute neutrophil count (ANC) in cycle 1 (OR: 0.14, 95% CI: 0.06-0.30, P<0.001) and percent drop of platelets between day 1 and the nadir in cycle 1 (OR: 1.04, 95% CI: 1.02-1.05, P<0.001). Both variables are dose adjusted based on the chemotherapy cycle 1 dose. The model's discriminatory performance was good (ROC area=0.82), as was the calibration of predicted with actual frequencies of dose reductions. In the validation dataset, model variables remained significant, with an ROC area of 0.78 and good calibration. In summary, we devised and validated a predictive instrument that uses data from a patient's first cycle of chemotherapy to compute the probability of requiring a significant chemotherapy dose reduction on subsequent cycles. This instrument could help clinicians select patients who will benefit from early administration of myeloid growth factors.     

Cardioprotective effects of acute normovolemic hemodilution in patients with severe aortic stenosis undergoing valve replacement

BACKGROUND: After acute normovolemic hemodilution (ANH), improvement of the rheologic conditions may contribute to optimize tissue oxygen delivery and attenuate ischemia-reperfusion injuries. It was hypothesized that ANH would confer additional cardioprotection in patients with ventricular hypertrophy undergoing open heart surgery. STUDY DESIGN AND METHODS: This study was a randomized controlled trial. Forty patients scheduled for elective aortic valve replacement were randomly assigned to a control group (standard care) or an ANH group (target hematocrit level of 28%). All patients were managed with standard myocardial preservation techniques (cold blood cardioplegia, anesthetic preconditioning). The outcome measures included the release of myocardial enzymes, perioperative hemodynamic changes, the need for pharmacologic cardiovascular support, and cardiac complications. RESULTS: In the ANH group, the postoperative release of troponin I (mean peak plasma concentrations, 1.7 ng/mL; 95% confidence interval, 1.4-2.1 ng/mL) and myocardial fraction of creatine kinase (22 U/L; range, 18-24 U/L) was significantly lower than in the control group (3.6 [range, 3.0-4.2] ng/mL and 45 [range, 39-51] U/L, respectively). In addition, requirement for inotropic support was significantly lower and fewer hemodiluted patients presented adverse cardiac events. After ANH, there was a significant decrease in heart rate (-11 +/- 6%) and rate-pressure product (-16 +/- 8%) until the aortic cross-clamping time and, at the end of surgery, the circulating levels of erythropoietin (EPO) were higher than in control patients (13.6 +/- 4.2 mUI/mL vs. 7.3 +/- 2.4 mUI/mL; p < 0.05). CONCLUSIONS: Besides conventional cardiac preservation techniques, preoperative ANH further attenuates myocardial injuries. Optimization of preischemic myocardial oxygen delivery and/or consumption and the postconditioning effects of endogenous EPO are potential mechanisms for ANH-induced cardioprotection.     

Risk of discontinuation of nevirapine due to toxicities in antiretroviral-naive and -experienced HIV-infected patients with high and low CD4+ T-cell counts

INTRODUCTION: It is unknown whether the increased risk of toxicities in antiretroviral-naive HIV-infected patients initiating nevirapine-based (NVPc) combination antiretroviral therapy (cART) with high CD4+ T-cell counts is also observed when NVPc is initiated in cARTexperienced patients. PATIENTS AND METHODS: 1,571 EuroSIDA patients started NVPc after 1/1/1999, with CD4+ T-cell counts and viral load measured in the 6 months before starting treatment, and were stratified into four groups based on CD4+ T-cell counts at initiation of NVPc (high [H], > 400/mm3 or > 250/mm3 for male or female, respectively, or low [L], < or = 400/mm3 or 5250/mm3 for male or female) and prior antiretroviral experience (antiretroviral-naive [N] or -experienced [E]). Cox proportional hazards models compared the risks of discontinuation of nevirapine due to toxicities or patient/physician choice (TOXPC). RESULTS: After adjustment, there was a significantly lower risk of discontinuation of nevirapine due to TOXPC in the HE group (n = 588; proportion discontinued by 3/12 months: 10/17%, respectively) than in HN (n = 62; 21/32% respectively; overall relative hazard [RH]: 0.56; 95% confidence interval [CI]: 0.34-0.94; P = 0.027). This difference was most pronounced during the first 3 months of NVPc (RH: 0.44; 95% CI: 0.23-0.87; P = 0.017). There were no deaths in the 6 months after starting NVPc resulting from exposure to < 3 months of NVPc exposure within the HE group (incidence: 0; per 1,000 person-years follow up; 95% CI: 0-6.9). After adjustment, there were no differences between the HE and HN groups in discontinuation due to TOXPC in patients starting efavirenz-based cART (RH: 0.91; 95% CI: 0.60-1.38; P = 0.66) or protease-inhibitor-based cART (RH: 1.13; 95% CI: 0.77-1.66; P = 0.52). CONCLUSIONS: Results from this non-randomized study suggest that NVPc might be safer to initiate in antiretroviral-experienced than in antiretroviral-naive patients with high CD4+ T-cell counts.