A phase I study of sequential versus concurrent interleukin-3 and granulocyte-macrophage colony-stimulating factor in advanced breast cancer patients treated with FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy

Cumulative thrombocytopenia is a dose-limiting toxicity of dose- intensive chemotherapy for advanced breast cancer. In this phase I study, we have studied the hematologic toxicity associated with sequential interleukin-3 (IL-3) and granulocyte-macrophage colony- stimulating factor (GM-CSF; molgramostim) administration after multiple cycles of FLAC (5-fluorouracil, leucovorin, doxorubicin, cyclophosphamide) chemotherapy compared with that after concurrent cytokine administration or to each cytokine administered alone. Ninety- three patients with advanced breast cancer were treated with five cycles of FLAC chemotherapy and either IL-3 alone, GM-CSF alone, sequential IL-3 and GM-CSF administered by schedule A (5 days of IL-3 followed by 10 days of GM-CSF) or schedule B (9 days of IL-3 followed by 6 days of GM-CSF), or concurrent administration of IL-3 and GM-CSF for 15 days. Cohorts of patients were treated with one of four dose levels of IL-3 (1,2.5, 5, and 10 micrograms/kg) administered subcutaneously for each schedule of cytokine administration. The GM-CSF dose in all schedules was 5 micrograms/kg/day. Sequential IL-3 and GM- CSF (schedule B) was associated with higher platelet nadirs, shorter durations of platelet counts less than 50,000/microL, and the need for fewer platelet transfusions over five cycles of FLAC chemotherapy compared with concurrent cytokines, sequential IL-3 and GM-CSF schedule A, and GM-CSF alone. Concurrent IL-3 and GM-CSF was associated with unexpected platelet toxicity. The duration of granulocytopenia after FLAC chemotherapy was significantly worse with IL-3 alone compared with each of the GM-CSF-containing cytokine regimens. Although no cycle 1 maximum tolerated dose for IL-3 was defined in this study, 5 micrograms/kg was well tolerated over multiple cycles of therapy and is recommended for future studies. The data from this phase I study suggest that sequential IL-3 and GM-CSF with IL-3 administered for 9 days before beginning GM-CSF may be superior to shorter durations of IL- 3 administered sequentially with GM-CSF, to concurrent IL-3 and GM-CSF, and to either colony-stimulating factor alone in ameliorating the cumulative hematologic toxicity associated with multiple cycles of FLAC chemotherapy. Additional studies of sequential IL-3 and GM-CSF are warranted.     

Prospective Evaluation of Oropharyngeal Findings in Human Immunodeficiency Virus-infected Patients with Esophageal Ulceration

Objective: Although the presence of oropharyngeal (OP) candidiasis plays an important role in the evaluation of human immunodeficiency virus (HIV)-infected patients with esophageal symptoms, there is little information on the utility of OP findings in patients with esophageal ulceration.
Methods: Over a 54-month period, all HIV-infected patients with esophageal ulceration had careful inspection of the oropharynx at the time of presentation with esophageal complaints and at endoscopy. HIV-infected patients without esophageal ulceration undergoing endoscopy during the last 30 months had OP findings similarly documented. OP ulceration was not routinely biopsied. The cause of esophageal ulceration was determined based on clinical, en-doscopic, and histopathological findings.
Results: Of the 124 patients identified with esophageal ulcer, 14 (11%) had coexistent OP ulceration: herpes simplex virus, four; idiopathic esophageal ulcer, four; cytomegalovirus, three; herpes simplex virus and cytomegalovirus, two; idiopathic and cytomegalovirus, one. Four patients had OP ulcer without esophageal ulcer; only one of these patients had esophageal symptoms. All OP lesions healed with therapy for the esophageal ulcer. Twenty-eight patients with esophageal ulcer had OP candidiasis (23%); 21 of these patients (75%) also had Candida esophagitis. The sensitivity and specificity of OP ulcer for esophageal ulcer were 11% and 97%, respectively. The positive and negative predictive values of OP candidiasis for esophageal candidiasis were 90% and 82%, respectively.
Conclusions: OP ulceration is uncommon in patients with esophageal ulceration, with the exception of herpes simplex virus esophagitis. OP candidiasis is common in patients with underlying esophageal ulcer, potentially resulting in diagnostic confusion. OP candidiasis appears to be a moderately useful diagnostic marker for Candida esophagitis.     

Asymmetric dimethylarginine and reactive oxygen species: unwelcome twin visitors to the cardiovascular and kidney disease tables

Plasma levels of asymmetric dimethylarginine or markers of reactive oxygen species are increased in subjects with risk factors for cardiovascular disease or chronic kidney disease. We tested the hypothesis that reactive oxygen species generate cellular asymmetric dimethylarginine that together cause endothelial dysfunction that underlies the risk of subsequent disease. Rat preglomerular vascular smooth muscle cells transfected with p22(phox) had increased NADPH oxidase activity, enhanced activity and expression of protein arginine methyltransferase, and reduced activity and protein expression of dimethylarginine dimethylaminotransferase and of cationic amino acid transferase 1 resulting in increased cellular levels of asymmetric dimethylarginine. Rats infused with angiotensin II had oxidative stress. The endothelial function of their mesenteric arterioles was changed from vasodilatation to vasoconstriction, accompanied by increased vascular asymmetric dimethylarginine. All of these changes were prevented by Tempol. In vivo silencing of dimethylarginine dimethylaminotransferase 1 increased plasma levels of asymmetric dimethylarginine, whereas silencing of dimethylarginine dimethylaminotransferase 2 impaired endothelial function. We suggest that initiation factors, such as angiotensin II, expressed in blood vessels or tissues of subjects with cardiovascular and kidney disease risk factors generate reactive oxygen species from NADPH oxidase that enhances cellular asymmetric dimethylarginine in an amplification loop. This leads to adverse changes in vascular and organ functions, as a consequence of reduced tissue levels of NO and increased reactive oxygen species. Thus, we conclude that reactive oxygen species and asymmetric dimethylarginine form a tightly coupled amplification system that translates cardiovascular/kidney risk into overt disease.     

Tumour necrosis factor-related apoptosis-inducing ligand is a novel therapeutic target in pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension is a fatal disease characterised by progressive narrowing of pulmonary arterioles, driven by aberrant cellular proliferation. Identification of key pathways in disease pathogenesis is required for the development of new-targeted therapies. We have previously reported tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) immunoreactivity within pulmonary vascular lesions from patients with idiopathic pulmonary arterial hypertension and animal models. Since TRAIL induces endothelial cell apoptosis and smooth muscle cell proliferation, we hypothesised that TRAIL is an important driver of disease in pulmonary arterial hypertension.MethodsWe characterised the expression of TRAIL in human and rodent pulmonary arterial hypertension and determined the effects of TRAIL on pulmonary artery smooth muscle cells (PASMCs) in vitro. Using genetic deletion, pharmacological overexpression, antibody blockade, and bone marrow transplant (BMT) chimera experiments we determined the direct pathogenic role of TRAIL in three independent rodent models of pulmonary arterial hypertension. We then tested the efficacy of inhibiting TRAIL in halting or regressing established disease in two preclinical models. Terminal phenotyping included cardiac catheterisation, echocardiography, and pulmonary vascular immunohistochemistry.FindingsTRAIL mRNA and protein expression was upregulated in PASMCs from patients with pulmonary arterial hypertension. In vitro, TRAIL was a mitogen for PASMCs. TRAIL-deficient mice were protected from both hypoxia-induced and diet-induced pulmonary arterial hypertension. Antibody blockade prevented rats from developing toxin-induced disease. In BMT chimeras, only mice with expression of TRAIL restricted to tissue developed pulmonary arterial hypertension. In rodents with established pulmonary arterial hypertension, an anti-TRAIL antibody reversed pulmonary vascular remodelling, through reducing proliferation and inducing apoptosis, improved pulmonary haemodynamics, and significantly improved survival.InterpretationOur studies are the first to determine the importance of TRAIL in the pathogenesis of pulmonary arterial hypertension and demonstrate its potential for translation into a novel therapeutic targetFundingBritish Heart Foundation.     

Modified LSA2-L2 treatment in 53 children with E-rosette-positive T- cell leukemia: results and prognostic factors (a Pediatric Oncology Group Study)

In an attempt to improve the poor outlook for children with T-cell leukemia (T-ALL), the Southwest Oncology Group, Pediatric Division, used a modified LSA2-L2 multidrug regimen to treat 53 patients with E- rosette-positive T-ALL. This regimen was chosen because of its demonstrated efficacy in T-cell (mediastinal) non-Hodgkin's lymphoma. Complete remission (CR) rate was 88%. Range of follow-up for those patients remaining in CR is 24-49 mo (median 39 mo). Life table analysis estimates that 40% (SE 8.3%) of all patients who started induction therapy will remain failure-free at 3 yr. For patients achieving CR, 46% (SE 9%) are projected to remain in both marrow and extramedullary CR at 3 yr. Median failure-free duration was 13 mo, but only 1 patient has relapsed beyond 16 mo. Twenty-nine percent of initial relapses were isolated CNS relapses. The following presenting factors did not relate significantly to outcome: hemoglobin, platelet count, uric acid, race, and mediastinal mass. Age greater than 10 yr was a poor prognosis indicator only in the less than 50,000/microliter WBC group. Sex was not a significant factor after adjusting for WBC. WBC was the most important prognostic factor: 19% (SE 8%) of patients with WBC greater than 50,000/microliter are projected to remain failure- free at 3 yr as compared to 67% (SE 11%) of patients with WBC less than 50,000/microliter. Although the overall results are better than those previously reported for pediatric patients with T-ALL, the long-term failure-free rate remains low for patients presenting with greater than 50,000/microliter WBC.     

Exacerbation of pulmonary fibrosis following single lung transplantation

Acute exacerbations of interstitial lung disease present as clinical deteriorations, with progressive hypoxemia and parenchymal consolidation not related to infection, heart failure or thromboembolic disease. Following single lung transplantation, patients receive maintenance immunosuppression, which could mitigate the development of acute exacerbations in the native lung. A 66-year-old man with fibrotic, nonspecific interstitial pneumonitis presented with fever, hypoxemia and parenchymal consolidation limited to the native lung four years after single lung transplantation. Investigations were negative for infection, heart failure and thromboembolic disease. The patient worsened over the course of one week despite broad-spectrum antimicrobial therapy, but subsequently improved promptly with augmentation of prednisone dosed to 50 mg daily and addition of N-acetylcysteine. Hence, the patient fulfilled the criteria for a diagnosis of an acute exacerbation of pulmonary fibrosis in his native lung. Clinicians should consider acute exacerbation of parenchymal lung disease of the native lung in the differential diagnosis of progressive respiratory deterioration following single lung transplantation for pulmonary fibrosis.     

Tumor necrosis factor-α and interleukin-6 in cirrhotic patients with spontaneous bacterial peritonitis

AIM: To evaluate the role of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cirrhotic patients who have hepatic and renal impairment with spontaneous bacterial peritonitis (SBP).METHODS: We prospectively studied 120 cirrhotic patients with SBP and 80 cirrhotic patients with sterile ascitic fluid. They included 144 males and 56 females with ages ranging between 34 and 62 years. The diagnosis of cirrhosis was established by clinical and laboratory criteria that did not require histological confirmation. The severity of underlying liver disease was evaluated using Pugh’s modification of Child’s criteria (Child-Pugh scores). Ascitic fluid was sent to the laboratory for cell count, culture, sensitivity testing, and measurement of chemical elements (i.e., albumin, glucose). Specimens were inoculated into aerobic and anaerobic blood culture bottles. Serum and ascitic fluid were also collected in sterile tubes at study entry (before the initiation of antibiotic treatment) and 48 h later. Assays for TNF-α and IL-6 in the serum and ascitic fluid were performed with an immunoenzymometric assay using manufacture’s instructions.RESULTS: Cytokine levels in serum and ascitic fluid were significantly higher in the patients with SBP. (plasma TNF-α: 135.35 ng/mL ± 11.21 ng/mL vs 92.86 ng/mL ± 17.56 ng/mL, P < 0.001; plasma IL-6: 32.30 pg/mL ± 7.07 pg/mL vs 12.11 pg/mL ± 6.53 pg/mL, P < 0.001; ascitic fluid TNF-α: 647.54 ± 107.11 ng/mL vs 238.43 ng/mL ± 65.42 ng/mL, P < 0.001); ascitic fluid IL-6: 132.84 ng/mL ± 34.13 vs 40.41 ± 12.85 pg/mL, P < 0.001). About 48 (40%) cirrhotic patients with SBP developed renal and hepatic impairment and showed significantly higher plasma and ascitic fluid cytokine levels at diagnosis of infection. [(plasma TNF-α: 176.58 ± 17.84 vs 135.35 ± 11.21 ng/mL) (P < 0.001) and (IL-6: 57.83 ± 7.85 vs 32.30 ± 7.07 pg/mL) (P < 0.001); ascitic fluid TNF-α: 958.39 ± 135.72 vs 647.54 ± 107.11 ng/mL, (P < 0.001), ascitic fluid IL-6: 654.74 ± 97.43 vs 132.84 ± 34.13 pg/mL, (P < 0.001)]. Twenty nine patients (60.4%) with SBP and renal impairment died whereas, only four patients (5.55%) with SBP but without renal impairment died from gastrointestinal hemorrhage (P < 0.0005).CONCLUSION: It appears that TNF-α production may enhance liver cell injury and lead to renal impairment. This correlated well with the poor prognosis and significantly increased mortality associated with SBP in cirrhotic patients.     

Clostridium difficile: changing epidemiology and new treatment options

PURPOSE OF REVIEW: The review summarizes changes in the epidemiology and treatment of Clostridium difficile-associated disease. RECENT FINDINGS: Recent outbreaks of Clostridrium difficile-associated diarrhoea with increased severity, high relapse rate and significant mortality, have been related to the emergence of a new, hypervirulent C. difficile strain in north America, Japan and Europe. Definitions have been proposed by the European Centre for Disease Prevention and Control to identify severe cases of Clostridrium difficile-associated diarrhoea and to differentiate community-acquired cases from nosocomial-acquired cases. The emerging strain is referred to as North American pulsed-field type 1 and polymerase chain reaction ribotype 027. The emerging strain has also been detected in calf diarrhoea and ground meat samples in Canada. Attempts to prevent outbreaks caused by type 027 should focus on controlling the overall use of antibiotics, and high-risk antibiotics such as cephalosporins, clindamycin and fluoroquinolones. Several new antibiotic and non-antibiotic alternatives have become available; there is currently no place for probiotic treatments. Patients who suffer multiple relapses of C. difficile-associated diarrhoea present a major therapeutic challenge. SUMMARY: The early recognition of Clostridrium difficile-associated diarrhoea caused by NAP1/027 is necessary to start rapid treatment, to prevent complications, and to prevent further spread of the bacterium.