Phase II trial of PALA in combination with 5-fluorouracil in advanced pancreatic cancer

Summary Phosphonacetyl-l-aspartate (PALA), an inhibitor of aspartate transcarbamylase that depletes uridine nucleotide pools, selectively potentiates the antitumor activity of 5-fluorouracil (5-FU) in preclinical models. Due to the promising results we obtained using PALA/5-FU in colorectal cancer, we performed a phase II trial in patients presenting with advanced pancreatic cancer. PALA was given intravenously at 250 mg/m² on day 1, followed 24 h later by 2,600 mg/m² 5-FU given by 24-h infusion. Treatments were repeated weekly. A total of 41 patients who had not previously undergone chemotherapy were entered in the trial; of these, 35 were evaluable for response. Toxicity was generally mild to moderate; neurotoxicity (13/35) and diarrhea (8/35) predominated. Among the 35 patients, 1 achieved a complete response and 4, a partial remission, for an overall response rate of 14%. The median survival was 5.1 months. Pretreatment with PALA alone was not sufficient to enhance the activity of 5-FU in pancreatic cancer.Supported in part by grant CA 06927 from the National Cancer Institute     

Pediatric nutrition surveillance system--United States, 1980-1991.

The CDC Pediatric Nutrition Surveillance System (PedNSS) monitors the general health and nutritional characteristics of low-income U.S. children who participate in multiple public health programs. This system is intended to characterize trends and patterns in key indicators of nutritional status so that the information can be used for program planning and targeting. The indicators monitored by PedNSS are birth weight, childhood growth status, anemia, and breast-feeding patterns. From 1980 through 1991, the trends for low birth weight, low height-for-age (shortness), low weight-for-height (thinness), and high weight-for-height (overweight) were stable for all children monitored by the PedNSS, with the exception of Asian children, who were predominantly of Southeast Asian refugee background. In the early 1980s, the prevalence of low birth weight and shortness was higher among Asian children than among children of other racial or ethnic groups who were monitored by the PedNSS. However, these prevalences declined steadily from 1980 through 1991. By 1991, the prevalences of low birth weight and shortness for Asian children were similar to those observed for children of other races/ethnic groups. Overall, low-income U.S. children had a slightly lower height-for-age than expected, indicating that some of these children were at a health and nutritional disadvantage. The prevalence of overweight varied among different racial/ethnic groups; Hispanic and Native American children had the highest prevalences of overweight. The 20%-30% prevalence of anemia among low-income children monitored by the PedNSS was higher than among the general population, reflecting in part the preferential enrollment and retention of anemic children by public health nutrition programs and also indicating that many children had inadequate iron nutrition. From 1980 through 1991, the prevalence of anemia declined > 5% for most of the age- and race/ethnicity-specific groups monitored by PedNSS. That decline represents an improvement in iron nutritional status. PedNSS is a useful system for the monitoring and characterization of the nutrition status of low-income children at both state and national levels.     

Immunolocalization of cytokines and their receptors in adhesive capsulitis of the shoulder

The purpose of this study was to test the hypothesis that specific cytokines are involved in the initiation and evolution of the fibrotic process in adhesive capsulitis of the shoulder. After approval from the Institutional Review Board, biopsies of shoulder capsule and synovium were collected during shoulder arthroscopy from 19 patients with adhesive capsulitis, 14 patients with nonspecific synovitis and no fibrosis or clinical evidence of adhesive capsulitis, and seven patients undergoing surgery for another pathology who had a normal capsule and synovium. Immunohistochemical localization with monoclonal antibodies to transforming growth factor-β and its receptor, platelet-derived growth factor and its receptor, basic fibroblast growth factor, interleukin-1β, tumor necrosis factor-α, and hepatocyte growth factor was performed using standard immunoperoxidase techniques. The frequency of cytokine staining was correlated with the clinical diagnosis Synovial cells, fibroblasts, T-cells, and B-cells were identified with specific antibodies, and newly synthesized matrix was examined for type-I and type-III collagen by immunohistochemical staining. The predominant cell types present were synovial cells and fibroblasts. Staining for type-III collagen in adhesive capsulitis tissues indicated new deposition of collagen in the capsule. There was staining for transforming growth factor-β and its receptor, platelet-derived growth factor and its receptor, interleukin-1β, and tumor necrosis factor-α in adhesive capsulitis and nonspecific synovitis tissues, compared with minimal staining in normal capsule. Staining was more frequent in snovial cells than in capsular cells. The frequency of cell and matrix staining for transforming growth factor-β, platelet-derived growth factor, and hepatocyte growth factor was greater in adhesive capsulitis tissues than in those from patients with nonspecific synovitis. No difference in the frequency of staining between primary (idiopathic) and secondary adhesive capsulitis was found. The results of this study indicate that adhesive/capsulitis involves both synovial hyperplasia and capsular fibrosis. Cytokines such as transforming growth factor-β and platelet-derived growth factor may be involved in the inflammatory and fibrotic processes in adhesive capsulitis. Matrix-bound transforming growth factor-β may act as a persistent stimulus, resulting in capsular fibrosis. Understanding the basic pathophysiology of adhesive capsulitis is an important step in the development of clinically useful antifibrotic agents that may serve as novel treatments for patients with this condition.     

Accidental bronchial intubation An analysis of AIMS incident reports from 1988 to 1994 inclusive

Accidental bronchial intubation was examined in the first 3947 cases reported to the Australian Incident Monitoring Study and was found to have accounted for 154 (3.7%) of the total incidents reported. Most incidents were detected in the operating theatre (93.5%) and during maintenance of anaesthesia (77.9%), by unexplained oxygen desaturation alone (63.6%). Capnography remained normal or unremarkable during 88.5% of the episodes. One-third of cases were associated with head or neck surgery and possible flexion of the patient's head. A RAE tube was used in 20% of incidents, a greater frequency than occurred in the study overall. A third party was implicated in 36 (23.4%) of cases. Ninety per cent of cases were considered preventable. Major morbidity occurred in three cases and unplanned intensive care admission was required in a further five. Almost two-thirds (61.1%) of the incidents might have been avoided by the proposed markings on the tracheal tube. We conclude that when arterial desaturation occurs at any stage during anaesthesia the possibility of bronchial intubation must be considered. Asymmetrical ventilation may be difficult to detect clinically and in most cases there is no change in capnography.     

Regional differences in matrix formation in the healing flexor tendon

In 20 white leghorn chickens, the effect of proximity (proximal vs. distal) to the repair site and the effect of sheath excision versus sheath repair on biochemical matrix formation in the healing zone 2 flexor tendon were studied. In 14 animals, the profundus tendon of the long toe on both feet was lacerated and repaired in zone 2. In the right foot, the sheath was repaired, and on the left foot, the sheath was excised. Segments proximal and distal to the laceration site were studied at six weeks postrepair compared to control segments. Sheath excision versus sheath repair had no effect on the net matrix formation of the healing flexor tendon. A higher DNA content and lower hydroxyproline and hexosamine contents were present in the healing tendons, indicating the healing process was not complete at six weeks. Sheath excision versus sheath repair had no effect on net matrix formation in the healing tendon. There is no difference in DNA content or glycosaminoglycan content in the proximal versus distal segments. There was a significantly greater net hydroxyproline content in the proximal segment versus the distal segment of the healing tendon, which was not present in similar control segments. These results support the concept that the zone 2 flexor tendon does not respond to injury as a homogeneous structure.     

Driving impairments in teens and adults with attention-deficit/hyperactivity disorder.

Available research provides compelling evidence that ADHD is associated with significantly increased risks for various adverse outcomes while driving, including increased traffic citations (particularly speeding), motor vehicle crashes for which the driver is at fault, repeated crash occurrences,and more severe crashes as determined from dollar damage and likelihood of bodily injuries from the crash. Not surprisingly, teens and adults with ADHD are more likely to have their licenses suspended and even fully revoked. Research further suggests that these driving risks cannot be accounted for by the comorbid disorders likely to be associated with ADHD, such as ODD, conduct disorder (CD), depression, or anxiety, or by lower than normal levels of intelligence.Recent attempts to study the processes or mechanisms involved in driving in adults with ADHD offer some explanation of how the disorder conveys such increased risks. Driving can be conceptualized usefully as involving at least three or more dimensions or levels, including basic cognitive abilities necessary for driving (operational), actual skills for maneuvering the vehicle in traffic (tactical), and the more executive, goal-directed aspects of driving(strategic). The findings of studies indicate that ADHD interferes with the basic operational components of driving by means of the impairments it produces in attention, resistance to distraction, response inhibition, slower and more variable reaction time, and the capacity to follow rules that may compete with ongoing sensory information. Accumulating evidence also points to a problem in the tactical level of driving, such that those with ADHDrate themselves and are rated by others as employing less safe driving habits during their normal operation of a vehicle than are adults in community control groups. Although this has been more elusive to demonstrate through the use of simple laboratory-based driving simulators. more modern virtual reality driving platforms offer greater promise in providing more realistic appraisals of driving performance and thus more direct evidence of the problems that occur at the tactical level from the disorder. Research has not examined the impact of ADHD at the higher strategic level or goal-directed aspects of driving. But given the mounting evidence that ADHD adversely affects executive functioning in adults, the author and colleagues anticipate that this level also will be found to be impaired in adults with ADHD. Indeed,it recently has been shown that adults with ADHD overestimate their driving abilities relative to normal adults, a problem that likely can be ascribed to more limited self-awareness and related meta-cognitive abilities for self-evaluation arising from the disorder.Although further research on the driving problems posed by ADHD is in order, sufficient evidence exists to warrant focus on possible treatments that may serve to improve these driving problems and reduce the risk for these adverse outcomes. High on the list of such treatments deserving further research and clinical attention is the use of stimulant medication. The more recent noradrenergic reuptake inhibitor. atomoxetine, also may have some promise in this regard. Studies are underway in the author's driving laboratory to see if this is the case. Meanwhile, adults with ADHD and parents of teens with ADHD should be advised about these heightened risks and encouraged to take steps that may reduce them, including the consideration of more graduated licensing for adolescents with ADHD and the possible use of stimulant medication in teens and adults with ADHD while they are operating a motor vehicle.