Combination chemotherapy plus methanol extracted residue of bacillus Calmette-Guérin or Corynebacterium parvum in stage III lung cancer.

Seventy-six patients with stage III bronchogenic carcinoma were treated with monthly adriamycin, cyclophosphamide, cis-dichlorodiammineplatinum(II), and vincristine. In addition, they were randomized to receive either no immunotherapy, the methanol extracted residue of bacillus Calmette-Guérin (MER), or Corynebacterium parvum (C. parvum). Age, histology, extent of disease, prior therapy, and performance status were comparable in the three treatment groups. Twelve patients (16%) died having received only one treatment cycle. Sixty-four of the 76 patients received two or more treatments and were evaluable for response. There were no patients with complete responses, 14 patients (18%) with partial responses, 28 patients (37%) with no change, and 22 patients (29%) with progressive disease. Survival among patients receiving C. parvum is significantly longer (P less than 0.05) than that of patients receiving either MER or no immunotherapy.     

Effect of dose on response to adrenocorticotropin in extremely low birth weight infants

CONTEXT: Various cosyntropin doses are used to test adrenal function in premature infants, without consensus on appropriate dose or adequate response. OBJECTIVE: The objective of this study was to test the cortisol response of extremely low birth weight infants to different cosyntropin doses and evaluate whether these doses differentiate between groups of infants with clinical conditions previously associated with differential response to cosyntropin. DESIGN: The design was a prospective, nested study conducted within a randomized clinical trial of low-dose hydrocortisone from November 1, 2001, to April 30, 2003. SETTING: The setting was nine newborn intensive care units. PATIENTS: The patients included infants with 500-999 g birth weight. INTERVENTION: The drug used was cosyntropin, at 1.0 or 0.1 microg/kg, given between 18 and 28 d of birth. MAIN OUTCOME MEASURE: We measured the cortisol response to cosyntropin. RESULTS: Two hundred seventy-six infants were tested. Previous hydrocortisone treatment did not suppress basal or stimulated cortisol values. Cosyntropin, at 1.0 vs. 0.1 microg/kg, yielded higher cortisol values (P < 0.001) and fewer negative responses (2 vs. 21%). The higher dose, but not the lower dose, showed different responses for girls vs. boys (P = 0.02), infants receiving enteral nutrition vs. not (P < 0.001), infants exposed to chorioamnionitis vs. not (P = 0.04), and those receiving mechanical ventilation vs. not (P = 0.02), as well as a positive correlation with fetal growth (P = 0.03). A response curve for the 1.0-microg/kg dose for infants receiving enteral nutrition (proxy for clinically well infants) showed a 10th percentile of 16.96 microg/dl. Infants with responses less than the 10th percentile had more bronchopulmonary dysplasia and longer length of stay. CONCLUSIONS: A cosyntropin dose of 0.1 microg/kg did not differentiate between groups of infants with clinical conditions that affect response. We recommend 1.0 microg/kg cosyntropin to test adrenal function in these infants.     

The role of hemochromatosis susceptibility gene mutations in protecting against iron deficiency in celiac disease

BACKGROUND & AIMS: Celiac disease and hereditary hemochromatosis are common HLA-defined conditions in northwestern Europe. We sought to determine whether there is a genetic relationship between the 2 diseases and if hemochromatosis susceptibility gene (HFE) mutations are protective against iron deficiency in celiac disease. METHODS: Polymerase chain reaction amplification using sequence-specific primers capable of identifying the 2 HFE gene mutations (H63D and C282Y) and the HLA class I and II alleles was used to type 145 white patients with celiac disease and 187 matched controls. Hemoglobin and fasting serum iron levels in celiac patients were measured at diagnosis. RESULTS: HFE gene mutations, H63D or C282Y, were identified in 70 celiac patients (48.3%) and 61 controls (32.6%) (P = 0.004). The C282Y mutation was associated with HLA-A*03 and B*07 alleles in controls and with A*01, A*03, B*08, and DRB1*0301 alleles in celiac patients; the H63D mutation was associated with HLA-A*25 and DRB1*03 alleles in controls and A*29 and DRB1*03 alleles in celiac patients. At diagnosis, celiac patients with the C282Y mutation had higher mean hemoglobin and fasting serum iron levels compared with the HFE wild type (P = 0.0002 and 0.006, respectively). This was not observed with the H63D mutation. CONCLUSIONS: In celiac disease, HFE gene mutations are common and are in linkage disequilibrium with different HLA alleles compared with controls. A disease-specific haplotype that carries C282Y and DQB1*02 is suggested. We propose that HFE gene mutations provide a survival advantage by ameliorating the iron deficiency seen in celiac patients.     

Endoscopic biopsy diagnosis of acute gastrointestinal graft-versus-host disease: rectosigmoid biopsies are more sensitive than upper gastrointestinal biopsies

OBJECTIVES: The diagnosis of gastrointestinal (GI) graft- versus -host disease (GVHD) is based upon histologic findings in endoscopic mucosal biopsy specimens. The portion of the GI tract with the highest diagnostic yield is a topic of debate. Our aim was to evaluate the sensitivity of simultaneous biopsy of the stomach, duodenum, and rectosigmoid in establishing the diagnosis of GI GVHD.
METHODS: We identified 112 patients who had simultaneous endoscopic biopsies of the stomach, duodenum, and rectosigmoid within the first 100 days following allogeneic hematopoietic stem cell transplantation (HSCT). GVHD was defined histologically as the presence of gland apoptosis, not explained by other inflammatory or infectious etiologies. The patient was diagnosed with GI GVHD if at least one biopsy site was positive.
RESULTS: Overall, 81% of the patients had GI GVHD. Of these, 66% had involvement at all three biopsy sites. Rectosigmoid biopsies had the highest sensitivity, specificity, positive predictive value, and negative predictive value for diagnosing GI GVHD, at 95.6%, 100%, 100%, and 84%, respectively. The sensitivities of gastric and duodenal biopsies were 72.5% ( P < 0.0001 vs rectosigmoid) and 79.2% ( P = 0.0018), respectively. The negative predictive values of gastric and duodenal biopsies were 45.6% ( P = 0.0039 vs rectosigmoid) and 52.5% ( P = 0.0205), respectively. Rectosigmoid biopsies had a higher sensitivity and negative predictive value than biopsies at other sites whether the patient presented with diarrhea or nausea/vomiting. No association between the degree of mucosal injury and the presence of GVHD was found at any site.
CONCLUSIONS: Biopsy of the rectosigmoid is the single best test for diagnosing GI GVHD.     

Development of cardiovascular drugs: the U.S. regulatory milieu from the perspective of a participating nonregulator

The Food and Drug Administration (FDA) is responsible for assuring that drugs, devices, and biologicals available in the U.S. are effective and acceptably safe for their intended uses. Both law and regulation define the procedures to be followed by the FDA in judging the effectiveness and safety of therapies. The FDA comprises a cadre of highly skilled public servants who receive and evaluate all data collected by the manufacturer during therapy, not just the portion that reaches publication. To assist in reaching final conclusions about approvability, the FDA can empanel legally constituted advisory committees and external consultants when the need is perceived for additional specific scientific/technical expertise and substantial experience in clinical practice. Evidentiary standards for marketing approval of drugs, biologicals, and devices generally require direct demonstration of clinical benefit, rather than inferences drawn from "surrogate" pharmacologic/device-mediated effects, sufficient exposure to enable a reasonable assessment of countervailing risk, consideration of specific design elements in the pivotal clinical trials (including prespecified hypotheses [implicitly incorporated in "primary end points"], rigorous plans for statistical analyses, and so on), and assessment of persistence of effectiveness and associated stability of safety over time. Finally, sufficient information must be available so that practitioners can receive written instructions for use (the label) adequate to support the likelihood that recipients of the therapy will receive the expected benefits within the envelope of the stated risks. This article will discuss and expand on these issues, with examples.     

Perimount® Bovine Pericardial Valve to Restore Pulmonary Valve Competence Late after Right Ventricular Outflow Tract Repair

Objective. No ideal option exists for restoring pulmonary valve competence late after repair of the congenitally abnormal right ventricular outflow tract (RVOT). This has driven a continued search for new alternatives. Texas Children’s Hospital has recently used the Carpentier‐Edwards Perimount RSR Pericardial Aortic Prosthesis (Edwards Lifesciences, Irvine, Calif, USA) for this indication and reports the initial experience. Design. Retrospective chart review. Setting. Academically affiliated tertiary‐care pediatric hospital. Patients. Twenty‐six patients who underwent pulmonary valve replacement with the Perimount^® valve late after RVOT reconstruction between June 2002 and November 2005. Interventions. No prospective interventions. Outcomes Measures. Hospital morbidity and mortality. Valve function assessed by follow‐up visits and echocardiograms. Results. Mean age and weight of the patients were 20.3 ± 9.8 years (range 7.0–45.1 years) and 56.2 ± 18.1 kg (range 35.8–109 kg). Twenty‐two patients (85%) had severe pulmonary insufficiency (PI), 23 (89%) had symptomatic right heart failure, and 14 (54%) had moderate to severe right ventricular dysfunction. Average prosthetic valve size was 23 mm (range 19–27 mm). Twenty‐one (88%) patients were extubated within 24 hours. There was no hospital mortality. Median length of stay for all patients from day of surgery was 6 days (range 3–56 days). Median length of last echocardiography follow‐up was 12.4 months (range 0.1–37.6 months). At that time, 16 of the 26 (62%) patients had improved right ventricular function, no patient demonstrated significant RVOT obstruction, and 24 patients (92%) have no PI or mild PI. Freedom from death, reintervention, or reoperation on the pulmonary valve is 100% at 2.5 years. Conclusion. Initial results with the Perimount^® bovine pericardial tissue prosthesis for pulmonary valve replacement are encouraging. Further follow‐up is required to define long‐term function and durability.     

Mechanisms and time course for the disappearance of thallium-201 defects at rest in dogs: Relation of time to peak activity to myocardial blood flow

The kinetics of thallium (Tl)-201 in ischemic myocardium was studied with a balloon constrictor to create a fixed reduction in distal left anterior descending coronary arterial pressure in 19 dogs. After 30 to 60 minutes of partial occlusion, Tl-201 was administered intravenously. Tracer activity was monitored continuously for 4 hours in both the normal and reduced flow zones using implanted miniature cadmium telluride radiation detectors. Microsphere-determined regional myocardial blood flow, heart rate, mean arterial pressure, mean left atrial pressure, mean distal left anterior descending coronary arterial pressure and sonomicrometer-determined myocardial wall thickness did not change significantly during each study. Thallium-201 time-activity curves for the normal zones (flow 1.00 ml/min per g or more) demonstrated an initial rapid increase to 80 to 90 percent of peak, an early peak (mean 20 minutes) and then a monoexponential decrease in activity (decay constant λ = 0.0013 min^?1). Thallium-201 time-activity curves for mildly and moderately ischemic zones (flow = 0.40 to 0.99 ml/min per g) demonstrated a progressive delay in the time to peak activity with progressive reductions in flow (r = 0.84). Thallium-201 time-activity curves for severely ischemic zones (flow less than 0.40 ml/min per g) demonstrated a rapid initial increase, and then no further increase in activity, probably because of cell death with a resultant decreased ability to accumulate Tl-201.When the Tl-201 activity ratio (reduced/normal flow zone) was calculated as a function of time for each dog, there was a progressive increase in this ratio over time for all dogs, although the rate of increase was slower for dogs with increasing degrees of flow reduction. This increasing ratio over time would correspond to disappearance of an initial Tl-201 resting scintiscan defect over time. The mechanism for the increasing ratio in dogs with mild or moderate flow reduction was both clearance of Tl-201 from normal zones and accumulation of Tl-201 by ischemic zones. However, the mechanism for the increasing ratio in dogs with severe flow reductions was a faster rate of Tl-201 loss from the normal compared with the reduced flow zone.