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Biomedical subjects

J P Lynch

Publications and source records attributed to J P Lynch.

At least 19 recordsLinked to original sources
PubMed2004

Thiotepa and fractionated TBI conditioning prior to allogeneic stem cell transplantation for advanced hematologic malignancies: a phase II single institution trial.

Relapse of hematologic malignancies after allogeneic stem cell transplantation remains a common problem, in particular for patients who have advanced disease at the time of transplantation. Thiotepa has excellent antileukemic and immunosuppressive activity, and could therefore be a useful drug in the conditioning regimen for patients with advanced hematologic neoplasms. We retrospectively analyzed toxicity, engraftment and survival data of 41 patients who received a conditioning regimen of thiotepa (600 mg/m2) and hyperfractionated TBI (10 Gy) prior to matched related (n = 25) or matched unrelated (n = 16) allogeneic stem cell transplantation. The mean age at transplantation was 37.8 years (range 20-59), all but five patients had advanced hematologic malignancies at the time of transplantation. GVHD prophylaxis was with standard cyclosporine and methotrexate. Engraftment was excellent, but the regimen was associated with a high incidence of grade III renal (41%) and hepatic (15%) toxicity, and high transplant-related mortality (44% at day +90). The 3-year event-free survival was 13% and overall survival 14%. We conclude that this regimen requires modification to reduce toxicity.

Acute Disease↗
PubMed2003

Difficult treatment issues in sarcoidosis.

The management of sarcoidosis includes several crucial decisions. Not all patients with sarcoidosis need treatment. At least a third of patients will never be treated. It is unclear whether asymptomatic patients ever need therapy, even if they have extensive lung disease. One reason that clinicians are reluctant to start therapy is that many patients who are started on corticosteroids have a difficult time getting off therapy, even after 2 years. In the chronic patient, alternatives to corticosteroids have been developed. These include drugs such as methotrexate, azathioprine and hydroxychloroquine. These agents have been the standard second line of therapy for patients with chronic disease. However, these drugs do not always work. In addition, they are associated with their own toxicities. Another group of sarcoidosis patients have also emerged. These are the refractory patients, who have progressive disease whilst on therapy. For these patients, new agents such as thalidomide and the monoclonal antibodies to tumour necrosis factor have been occasionally helpful. This paper reviews several important issues in the management of sarcoidosis.

Antibodies, Monoclonal↗
PubMed2003

Radiological versus histological diagnosis in UIP and NSIP: survival implications.

BACKGROUND: High resolution computed tomography (HRCT) has an important diagnostic role in idiopathic interstitial pneumonia (IIP). We hypothesised that the HRCT appearance would have an impact on survival in patients with IIP. METHODS: HRCT scans from patients with histological usual interstitial pneumonia (UIP; n=73) or histological non-specific interstitial pneumonia (NSIP; n=23) were characterised as definite UIP, probable UIP, indeterminate, probable NSIP, or definite NSIP. Cox regression analysis examined the relationships between histopathological and radiological diagnoses and mortality, controlling for patient age, sex, and smoking status. RESULTS: All 27 patients with definite or probable UIP on HRCT had histological UIP; 18 of 44 patients with probable or definite NSIP on HRCT had histological NSIP. Patients with HRCT diagnosed definite or probable UIP had a shorter survival than those with indeterminate CT (hazards ratio (HR) 2.43, 95% CI 1.06 to 5.58; median survival 2.08 v 5.76 years) or HRCT diagnosed definite or probable NSIP (HR 3.47, 95% CI 1.58 to 7.63; median survival 2.08 v 5.81 years). Patients with histological UIP with no HRCT diagnosis of probable or definite UIP fared better than patients with histological UIP and an HRCT diagnosis of definite or probable UIP (HR 0.49, 95% CI 0.25 to 0.98; median survival 5.76 v 2.08 years) and worse than those with a histological diagnosis of NSIP (HR 5.42, 95% CI 1.25 to 23.5; median survival 5.76 v >9 years). CONCLUSIONS: Patients with a typical HRCT appearance of UIP experience the highest mortality. A surgical lung biopsy is indicated for patients without an HRCT appearance of UIP to differentiate between histological UIP and NSIP.

Algorithms↗
PubMed2002

Clinical significance of histological classification of idiopathic interstitial pneumonia.

Patients with idiopathic interstitial pneumonias (IIPs) can be subdivided into groups based on the histological appearance of lung tissue obtained by surgical biopsy. The quantitative impact of histological diagnosis, baseline factors and response to therapy on survival has not been evaluated. Surgical lung biopsy specimens from 168 patients with suspected IIP were reviewed according to the latest diagnostic criteria. The impact of baseline clinical, physiological, radiographic and histological features on survival was evaluated using Cox regression analysis. The predictive value of honeycombing on high-resolution computed tomography (HRCT) as a surrogate marker for usual interstitial pneumonia (UIP) was examined. The response to therapy and survival of 39 patients treated prospectively with high-dose prednisone was evaluated. The presence of UIP was the most important factor influencing mortality. The risk ratio of mortality when UIP was present was 28.46 (95% confidence interval (CI) 5.5-148.0; p=0.0001) after controlling for patient age, duration of symptoms, radiographic appearance, pulmonary physiology, smoking history and sex. Honeycombing on HRCT indicated the presence of UIP with a sensitivity of 90% and specificity of 86%. Patients with nonspecific interstitial pneumonia were more likely to respond or remain stable (9 of 10) compared to patients with UIP (14 of 29) after treatment with prednisone. Patients remaining stable had the best prognosis. The risk ratio of mortality for stable patients compared to nonresponders was 0.32 (95% CI 0.11-0.93; p=0.04) in all patients and 0.33 (95% CI 0.12-0.96; p=0.04) in patients with UIP. The histological diagnosis of usual interstitial pneumonia is the most important factor determining survival in patients with suspected idiopathic interstitial pneumonia. The presence of honeycombing on high-resolution computed tomography is a good surrogate for usual interstitial pneumonia and could be utilized in patients unable to undergo surgical lung biopsy. Patients with nonspecific interstitial pneumonia are more likely to respond or remain stable following a course of prednisone. Patients remaining stable following prednisone therapy have the best prognosis.

Female↗
PubMed2001

ENA-78 is an important angiogenic factor in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and often fatal disorder. Fibroplasia and deposition of extracellular matrix are dependent, in part, on angiogenesis and vascular remodeling. We obtained open lung biopsies from patients undergoing thoracic surgery for reasons other than interstitial lung disease (control) (n = 78) and from patients with IPF (n = 91). We found that levels of epithelial neutrophil-activating peptide 78 (ENA-78) were greater from tissue specimens of IPF patients, as compared with control subjects. When ENA-78 was depleted from IPF tissue specimens, tissue-derived angiogenic activity was markedly reduced. Immunolocalization of ENA-78 demonstrated that hyperplastic Type II pneumocytes and macrophages were the predominant cellular sources of ENA-78. These findings support the notion that ENA-78 may be an important additional factor that regulates angiogenic activity in IPF.

Angiogenesis Inducing Agents↗
PubMed2001

Histopathologic variability in usual and nonspecific interstitial pneumonias.

Findings of surgical lung biopsy (SLB) are important in categorizing patients with idiopathic interstitial pneumonia (IIP). We investigated whether histologic variability would be evident in SLB specimens from multiple lobes in patients with IIP. SLBs from 168 patients, 109 of whom had multiple lobes biopsied, were reviewed by three pathologists. A diagnosis was assigned to each lobe. A different diagnosis was found between lobes in 26% of the patients. Patients with usual interstitial pneumonia (UIP) in all lobes were categorized as concordant for UIP (n = 51) and those with UIP in at least one lobe were categorized as discordant for UIP (n = 28). Patients with nonspecific interstitial pneumonia (NSIP) in all lobes were categorized as having fibrotic (n = 25) or cellular NSIP (n = 5). No consistent distribution of lobar histology was noted. Patients concordant for UIP were older (63 +/- 9 [mean +/- SD] yr; p < 0.05 as compared with all other groups) than those discordant for UIP (57 +/- 12 yr) or with fibrotic NSIP (56 +/- 11 yr) or cellular NSIP (50 +/- 9 yr). Semiquantitative high-resolution computed tomography demonstrated a varied profusion of fibrosis (p < 0.05 for all group comparisons), with more fibrosis in concordant UIP (2.13 +/- 0.62) than in discordant UIP (1.42 +/- 0.73), fibrotic NSIP (0.83 +/- 0.58), or cellular NSIP (0.44 +/- 0.42). Survival was better for patients with NSIP than for those in both UIP groups (p < 0.001), although survival in the two UIP groups was comparable (p = 0.16). Lobar histologic variability is frequent in patients with IIP, patients with a histologic pattern of UIP in any lobe should be classified as having UIP.

Analysis of Variance↗
PubMed2001

Relationship of cytomegalovirus viral load in blood to pneumonitis in lung transplant recipients.

We developed a multiplex, quantitative, real-time, polymerase chain reaction assay for cytomegalovirus (CMV) and used it to measure the CMV viral load in weekly blood specimens from 43 lung transplant recipients. The median viral load in blood samples immediately preceding bronchoscopy was 1150 copies/microg human DNA for 12 subjects with pneumonitis compared to 91 copies for 31 subjects without (P=0.02, Mann-Whitney U test). Each log10 increase in CMV viral load resulted in an increase of 1.92 in the odds ratio for CMV pneumonitis (95% confidence interval 1.03-3.56). CMV viral load was elevated (>100 copies/microg human DNA) for a median of 21 days before bronchoscopy in those subjects with pneumonitis versus 0 days in those without (P=0.004). We conclude that the risk of CMV pneumonitis after lung transplantation is related to the level of CMV DNA in blood. Quantitative PCR should be evaluated prospectively for the preemptive management of CMV in lung transplant recipients.

Computer Systems↗
PubMed2001

Steroids in idiopathic pulmonary fibrosis: a prospective assessment of adverse reactions, response to therapy, and survival.

PURPOSE: We evaluated the risk and potential benefit of high-dose corticosteroid therapy in patients with idiopathic pulmonary fibrosis. SUBJECTS AND METHODS: We prospectively studied 41 patients with previously untreated, biopsy-proven idiopathic pulmonary fibrosis. Before treatment, we calculated clinical, radiographic, and physiologic severity-of-illness scores for each patient. We scored high-resolution computerized tomographic (CT) scans for ground glass and interstitial opacity. We determined the extent of cellular infiltration, interstitial fibrosis, desquamation, and granulation in open lung biopsy samples. Patients were monitored monthly for steroid-related side effects, response to therapy at 3 months, and mortality. RESULTS: All patients experienced at least one steroid-induced side effect. Eleven (27%) patients were nonresponders, 11 (27%) were responders, and 19 (46%) remained stable. Of the 19 patients who died during a mean (+/- SD) follow-up of 3.3 +/- 2.3 years, 8 (42%) lost weight during the initial 3 months of steroid therapy; only 3 (14%) of the 22 patients still living (P = 0.08) experienced weight loss. In a multivariate analysis, greater fibrosis (hazard ratio [HR] = 1.4 per unit increase; 95% confidence interval [CI]: 1.0 to 1.9; P = 0.03) and cellularity (RR = 1.9 per unit increase; 95% CI: 1.3 to 2.8; 3, P <0.001) in the biopsy sample and whether a patient was classified as a responder (RR = 0.4 versus nonresponder; 95% CI: 0.2 to 1.0; P = 0.05) or stable (RR = 0.2 versus nonresponder; 95% CI: 0.1 to 0.6, P <0.001) after steroid therapy were associated with mortality. CONCLUSION: Corticosteroid treatment for idiopathic pulmonary fibrosis is associated with substantial morbidity. Patients who remain stable or respond to corticosteroid therapy have better survival than those who fail to respond. Whether this difference reflects an effect of treatment or less severe disease can be determined only in a randomized trial.

Adrenal Cortex Hormones↗
PubMed2001

Pulmonary function tests in interstitial lung disease: what role do they have?

Pulmonary function tests have been widely accepted and utilized in the management of interstitial lung diseases. Although the tests performed have changed little over the past several decades, extensive literature has been published highlighting their clinical role in the diagnosis, staging, prognostication, and follow-up of patients with a wide variety of interstitial lung diseases.

Humans↗
PubMed2001

Lymphoproliferative disease after lung transplantation: comparison of presentation and outcome of early and late cases.

BACKGROUND: Post-transplantation lymphoproliferative disease (PTLD) after lung transplantation has not been fully characterized. In previous studies, the incidence has varied substantially, and most cases have been reported during the first year after transplantation. The purpose of this study was to review our center's experience with PTLD and to analyze the pattern of disease and determinants of outcome. METHODS: Among 494 adult lung (n = 491) or heart-lung (n = 3) recipients, 30 cases of PTLD were retrospectively identified. The cases were classified by site(s) of involvement, histology and time of onset (early, < or =1 year, and late, >1 year after transplantation). The outcome of each case was ascertained, and risk factors for death were analyzed in a multivariate model. RESULTS: PTLD was identified in 30 (6.1%) of the recipients during 1,687 patient-years (median 2.8 years) of follow-up. The incidence density was 1.8 cases per 100 patient-years. Fourteen cases were diagnosed during the first year after transplantation, and 16 cases in subsequent years. The incidence density was significantly higher in the first year than in later years (3.3 cases/100 patient-years versus 1.3 cases/100 patient years; p <.008). Presentation in the thorax and involvement of the allograft were significantly more common in the early cases (thorax: 12 of 14, 86%; allograft: 9 of 14, 64%) than in the late cases (thorax: 2 of 16, 12%; allograft: 2 of 16, 12%). There was no difference in survival after the diagnosis of PTLD between the early and late cases, but survival time after diagnosis was significantly longer in cases with, than those without, allograft involvement (median 2.6 years vs 0.2 year, respectively; log rank p = 0.007). The presentation and pattern of organ involvement of PTLD after lung transplantation is related to the time of onset. CONCLUSIONS: Disease in the thorax and involvement of the allograft are common in the first year after transplantation, but other sites, especially the gastrointestinal tract, predominate later. PTLD that is confined to the allograft appears to have a somewhat better prognosis than disease that involves other sites.

Adult↗
PubMed2001

Prolonged sedation with propofol in the rat does not result in sleep deprivation.

UNLABELLED: The use of propofol provides sedation without prolonging emergence in patients in the Intensive Care Unit. When prolonged, however, continuous sedation may overlap with naturally occurring sleep periods and potentially increase the risk of sleep deprivation. We modified an established rat model of sleep to determine whether prolonged, continuous sedation results in sleep deprivation. Rats were continuously sedated for a 12-h period overlapping completely with their normal sleep phase. Electroencephalogram (EEG) and movement data were collected before and after the sedation period. Rats were evaluated for EEG and movement evidence of sleep deprivation after sedation. When compared with baseline, the time spent in rapid eye movement (REM) and non-REM sleep was decreased during the first 4 h after sedation. The duration of non-REM sleep bouts was not altered. Power in the delta band (0.5-4 Hz) during non-REM sleep was diminished during the first 2 h only. Movements were reduced during the first hour after emergence from sedation only. In summary, no EEG or behavioral evidence of sleep deprivation was observed on emergence from sedation. These results imply that sedation is associated with a restorative process reversing the natural accumulation of sleep need that occurs during wakefulness. IMPLICATIONS: Prolonged sedation in the Intensive Care Unit may alter the restorative effects of naturally occurring sleep. We sedated rats during their sleep phase to determine whether sedation interferes with sleep. Upon emergence, no evidence of sleep deprivation was observed. Sedation may thus be associated with a restorative effect similar to sleep.

Animals↗
PubMed2001

Corticosteroids in idiopathic pulmonary fibrosis.

Corticosteroids were the mainstay of therapy for idiopathic pulmonary fibrosis (IPF) for more than four decades, but their efficacy is unproven and toxicities are substantial. The course of IPF is characterized by progressive respiratory insufficiency, leading to death within 3 to 8 years from the onset of symptoms. Although a subset (10-20%) of patients survives more than 10 years, there is no evidence that any form of therapy alters the natural history of the disease. Nonetheless, given the poor prognosis, a trial of corticosteroids is often given. Because of the rarity of IPF, randomized, placebo-controlled therapeutic trials have not been done. Further, no studies have compared differing dosages or duration of corticosteroid in matched patients. Interpretation of therapy efficacy is obscured by several factors including heterogeneous patient populations, inclusion of patients with histologic entities other than usual interstitial pneumonia, lack of objective, validated endpoints, different criteria for "response." We review published data regarding corticosteroid therapy for IPF and present a rationale for stratifying therapy based on host, demographic, and clinical factors that influence prognosis as well as risk for corticosteroid complications.

Adrenal Cortex Hormones↗
PubMed2001

Induction of a major leaf acid phosphatase does not confer adaptation to low phosphorus availability in common bean.

Acid phosphatase is believed to be important for phosphorus scavenging and remobilization in plants, but its role in plant adaptation to low phosphorus availability has not been critically evaluated. To address this issue, we compared acid phosphatase activity (APA) in leaves of common bean (Phaseolus vulgaris) in a phosphorus-inefficient genotype (DOR364), a phosphorus-efficient genotype (G19833), and their F(5.10) recombinant inbred lines (RILs). Phosphorus deficiency substantially increased leaf APA, but APA was much higher and more responsive to phosphorus availability in DOR364 than in G19833. Leaf APA segregated in the RILs, with two discrete groups having either high (mean = 1.71 micromol/mg protein/min) or low (0.36 micromol/mg protein/min) activity. A chi-square test indicated that the observed difference might be controlled by a single gene. Non-denaturing protein electrophoresis revealed that there are four visible isoforms responsible for total APA in common bean, and that the difference in APA between contrasting genotypes could be attributed to the existence of a single major isoform. Qualitative mapping of the APA trait and quantitative trait loci analysis with molecular markers indicated that a major gene contributing to APA is located on linkage group B03 of the unified common bean map. This locus was not associated with loci conferring phosphorus acquisition efficiency or phosphorus use efficiency. RILs contrasting for APA had similar phosphorus pools in old and young leaves under phosphorus stress, arguing against a role for APA in phosphorus remobilization. Our results do not support a major role for leaf APA induction in regulating plant adaptation to phosphorus deficiency.

Acid Phosphatase↗
PubMed2001

Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome (BOS) is the major limitation to survival after lung transplantation. Acute rejection, its main risk factor, is characterized by perivascular/bronchiolar leukocyte infiltration. BOS is characterized by persistent peribronchiolar leukocyte recruitment leading to airway fibrosis and obliteration. The specific mechanism(s) by which these leukocytes are recruited are unknown. Because MCP-1, acting through its receptor CCR2, is a potent mononuclear cell chemoattractant, we hypothesized that expression of this chemokine during an allogeneic-response promotes persistent recruitment of leukocytes and, ultimately, rejection. We found that elevated levels of biologically active MCP-1 in human bronchial lavage fluid (BALF) were associated with the continuum from acute to chronic allograft rejection. Translational studies in a murine model of BOS demonstrated increased MCP-1 expression paralleling mononuclear cell recruitment and CCR2 expression. Loss of MCP-1/CCR2 signaling, as seen in CCR2(-/-) mice or in WT mice treated with neutralizing antibodies to MCP-1, significantly reduced recruitment of mononuclear phagocytes following tracheal transplantation and led to attenuation of BOS. Lymphocyte infiltration was not reduced under these conditions. We suggest that MCP-1/CCR2 signaling plays an important role in recruitment of mononuclear phagocytes, a pivotal event in the pathogenesis of BOS.

Animals↗
PubMed2001

Spectrum of Aspergillus infection in lung transplant recipients: case series and review of the literature.

STUDY OBJECTIVES: (1) To define the incidence and natural history of Aspergillus colonization and infection in lung transplant recipients, and (2) to assess the impact of prophylaxis, surveillance, and therapy on the incidence and outcome of the disease. DESIGN: Retrospective review of 133 consecutive single or bilateral lung transplantations performed at a single institution, and review of the published literature. RESULTS: Airway colonization, isolated tracheobronchitis, and invasive pneumonia due to Aspergillus species occurred in 29%, 5%, and 8% of our series, and in 26%, 4%, and 5% of the pooled published data (all series, including ours), respectively. Greater than 50% of all diagnoses were made in the first 6 months after transplantation in both our series and the published literature. Incidence of progression from airway colonization to invasive disease was 1 in 38 in our series and 3 of 97 (3%) in the pooled published data. In patients with isolated tracheobronchitis, all 6 patients in our series and 41 of 50 patients (82%) in all published series, including ours, responded to antifungal therapy and/or surgical debridement. Among patients with invasive pneumonia or disseminated disease, however, 5 of 10 patients in our series and 26 of 64 patients (41%) in the pooled series survived their infection. CONCLUSIONS: The role of antifungal therapy in Aspergillus airway colonization in lung transplant recipients is unclear. Data support a strategy of scheduled screening bronchoscopy followed by aggressive treatment for isolated Aspergillus tracheobronchitis in lung transplant recipients.

Adolescent↗
PubMed2001

Hospital-acquired pneumonia: risk factors, microbiology, and treatment.

Pneumonia complicates hospitalization in 0.5 to 2.0% of patients and is associated with considerable morbidity and mortality. Risk factors for hospital-acquired pneumonia (HAP) include mechanical ventilation for > 48 h, residence in an ICU, duration of ICU or hospital stay, severity of underlying illness, and presence of comorbidities. Pseudomonas aeruginosa, Staphylococcus aureus, and Enterobacter are the most common causes of HAP. Nearly half of HAP cases are polymicrobial. In patients receiving mechanical ventilation, P aeruginosa, Acinetobacter, methicillin-resistant S aureus, and other antibiotic-resistant bacteria assume increasing importance. Optimal therapy for HAP should take into account severity of illness, demographics, specific pathogens involved, and risk factors for antimicrobial resistance. When P aeruginosa is implicated, monotherapy, even with broad-spectrum antibiotics, is associated with rapid evolution of resistance and a high rate of clinical failures. For pseudomonal HAP, we advise combination therapy with an antipseudomonal beta-lactam plus an aminoglycoside or a fluoroquinolone (eg, ciprofloxacin).

Anti-Bacterial Agents↗