To determine the role of matrix metalloproteinase-8 (MMP-8) in acute lung injury (ALI), we delivered LPS or bleomycin by the intratracheal route to MMP-8(-/-) mice versus wild-type (WT) mice or subjected the mice to hyperoxia (95% O(2)) and measured lung inflammation and injury at intervals. MMP-8(-/-) mice with ALI had greater increases in lung polymorphonuclear neutrophils (PMNs) and macrophage counts, measures of alveolar capillary barrier injury, lung elastance, and mortality than WT mice with ALI. Bronchoalveolar lavage fluid (BALF) from LPS-treated MMP-8(-/-) mice had more MIP-1alpha than BALF from LPS-treated WT mice, but similar levels of other pro- and anti-inflammatory mediators. MIP-1alpha(-/-) mice with ALI had less acute lung inflammation and injury than WT mice with ALI, confirming that MIP-1alpha promotes acute lung inflammation and injury in mice. Genetically deleting MIP-1alpha in MMP-8(-/-) mice reduced the increased lung inflammation and injury and mortality in MMP-8(-/-) mice with ALI. Soluble MMP-8 cleaved and inactivated MIP-1alpha in vitro, but membrane-bound MMP-8 on activated PMNs had greater MIP-1alpha-degrading activity than soluble MMP-8. High levels of membrane-bound MMP-8 were detected on lung PMNs from LPS-treated WT mice, but soluble, active MMP-8 was not detected in BALF samples. Thus, MMP-8 has novel roles in restraining lung inflammation and in limiting alveolar capillary barrier injury during ALI in mice by inactivating MIP-1alpha. In addition, membrane-bound MMP-8 on activated lung PMNs is likely to be the key bioactive form of the enzyme that limits lung inflammation and alveolar capillary barrier injury during ALI. less...

BACKGROUND AND PURPOSE: Venous malformations are the most common of all vascular anomalies, 40% of which are found in the head and neck. We discuss results of percutaneous sclerotherapy using bleomycin for facial VMs by using subjective clinical assessment and objective changes on MR imaging. MATERIALS AND METHODS: Thirty-seven patients with facial VMs were treated by percutaneous sclerotherapy with bleomycin. Of these, 31 patients with 32 lesions had pre- and posttreatment MR imaging. Each lesion received between 1 and 9 sclerotherapy sessions (average, 3.5). MR findings and clinical results of treatment were retrospectively reviewed. Clinical results were based on the physician's physical examination and interview of the patient; these were classified as worse, unchanged, or better. Objective results on MR imaging were classified as worse, no change, minor improvement (<50% decrease in size), marked improvement (>/=50% decrease), or cure. Objective and subjective results were compared. RESULTS: Twenty-one lesions showed objective improvement on MR imaging. Of these, 10 showed minor decrease in size and 11 showed marked decrease. Eleven lesions showed no change on MR imaging. No VMs were worse or completely cured. Subjectively, 29 patients and 30 clinicians thought that lesions improved. Four of 32 (12.5%) patients suffered minor transient complications. CONCLUSIONS: Percutaneous sclerotherapy by using bleomycin is a safe technique to objectively decrease size and subjectively alleviate symptoms of facial VMs. Subjective clinical improvement is not always associated with visual size reduction on MR imaging. Minimal size reduction or partial fibrosis of the lesion may be enough to achieve subjective clinical improvement. less...

Tallysomycin (TLM) H-1, a novel TLM analog, is the major product isolated from Streptoalloteichus hindustanus SB8005, a genetically engineered strain from S. hindustanus E465-94 ATCC 31158. Based on the structural comparison and experimental assays, TLM H-1 represents a novel bleomycin (BLM) analog displaying DNA cleavage activity similar to its parent compounds TLM and BLM, both representatives of the glycopeptide anticancer antibiotics. The low titer of TLM H-1 in the engineered SB8005 strain has greatly limited its further study. In this paper, fermentation optimization for TLM H-1 production in the SB8005 strain is described; single-factor optimization and response surface methodology proved invaluable. The results indicated that three variables including distiller's grains and solubles, copper sulfate, and maltose out of eight parameters could significantly influence the TLM H-1 production. With systematic comparison and evaluation, the final optimized fermentation medium was determined. The optimized yield of TLM H-1 in the bench-top fermentor was 249.9 mg/L, which is 26.8 times higher than reported using the original medium, and 12.9-fold higher than that of the parent compound TLM produced by the wild-type strain. This work provides important parameters for TLM H-1 production by fermentation and should facilitate further mechanistic studies and clinical developments of TLM H-1 as an anticancer agent. less...

The endothelin system participates in a number of critical biologic pathways, including normal wound healing. In addition, emerging basic science, and animal and human data all suggest that endothelin-1 (EDN1, also known as ET-1) is a potentially important contributor in the pathobiology of fibrosing disorders, including those that affect the lung. For example, EDN1 drives fibroblast activation, proliferation, as well as differentiation into myofibroblasts - processes that lead to excessive collagen deposition. Patients with idiopathic pulmonary fibrosis (IPF) have increased levels of EDN1 in both their bronchoalveolar lavage fluid and lung tissue. Beyond this, rodent models suggest that endothelin receptor antagonists can limit bleomycin-induced lung fibrosis. This suggests a biologic rationale for the blockade of EDN1 to limit the evolution of lung fibrosis in humans. Initial results from a trial examining the efficacy of a dual endothelin receptor antagonist suggest that this approach may delay disease progression in a subset of patients with IPF. less...

PURPOSE: To provide a radiation pneumonitis risk estimate and investigate the correlation of clinical and dosimetric factors in pediatric patients receiving chest irradiation. METHODS AND MATERIALS: A total of 122 patients diagnosed with sarcoma or Hodgkin lymphoma who received radiotherapy to the chest were evaluated for symptomatic radiation pneumonitis (Common Toxicity Criteria Grade 1 with respiratory symptom or higher grade). Pneumonitis data were collected from either prospective toxicity screenings as part of a clinical trial or through chart review. Dosimetric parameters including V(10)-V(25), mean lung dose, binned lung dose, and tissue complication probability models were used, as well as clinical features to correlate with the development of pneumonitis. RESULTS: The 1- and 2-year cumulative incidence of symptomatic radiation pneumonitis for all patients was 8.2% and 9.1%, respectively. Nine patients experienced symptomatic Grade 1 toxicity, and 2 experienced Grade 2. From univariate analysis, chemotherapy containing bleomycin (chi(2) test, p = 0.027) and V(24) (logistic regression, p = 0.019) were the clinical and dosimetric factors that resulted in statistically significant differences in the occurrence of pneumonitis. The probability of pneumonitis increased more dramatically with increasing V(24) in patients receiving bleomycin than in those who did not. Adult tissue complication models did not differentiate pediatric patients with radiation pneumonitis from those without. CONCLUSIONS: The incidence of symptomatic radiation pneumonitis in pediatric patients is low and its severity mild. Parameters frequently used in adult radiation oncology provide some guidance as to risk, but pediatric patients warrant their own specific models for risk assessment, incorporating dosimetry and clinical factors. less...

Choriocarcinoma in the testis is very rare, and it represents less than 1% (0.3%) of all the testicular germ cell tumors. It is a particularly aggressive variant of non-seminoma tumor, which is characterized by a high serum beta-HCG level and multiple lung metastases. The optimal management for this disease remains undefined. We report here on a case of choriocarcinoma with multiple lung metastases, and the patient has achieved continuous remission for 2 years after combination chemotherapy of BEP (bleomycin, etoposide and cisplatin) and sequential high-dose chemotherapy with autologous peripheral stem cell rescue. less...

We report a case of a 28-year-old man with a dry cough and chest pain. Chest X-ray film showed a huge mass in the right lung field. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a huge mass which occupied most of the right thoracic cavity and invaded the superior vena cava, heart atrium and right pulmonary vein. Positron emission tomography (PET) showed metastasis of bone, right adrenal grand and lymph nodes. A tumor specimen was biopsied percutaneously, and the diagnosis was pathologically confirmed as an inflammatory myofibroblastic tumor. Immunohistochemical staining also showed an overexpression of ALK in the tumor. He was treated with a non-steroid anti-inflammation drug and steroid, but they were ineffective. He underwent chemotherapy with bleomicin, etoposide and cisplatin. After two cycles of chemotherapy, the tumor slightly reduced in size, but was eventually refractory to the regimen finally. He also underwent with paclitaxel and carboplatin. At present, if operative extirpation is not possible, there is no way to treat an inflammatory myofibroblastic tumor. In the future, new therapy incorporating ALK inhibitors would be expected to treat those cases of IMT in which local recurrences and distant metastases occur. less...

The effects of maternal cigarette smoking during pregnancy on structural chromosome aberrations were evaluated in peripheral lymphocytes from 239 mothers and their 241 newborns to determine whether smoking during pregnancy, genetic susceptibility, and race are associated with chromosome aberrations including translocations. Demographic information and cigarette smoking data were obtained via questionnaire. There were 119 Caucasian Americans, 118 African Americans, and 2 Asian Americans. The average maternal age was 24.9+/-5.8 (mean+/-S.D.) years. Thirty-nine percent of the Caucasian Americans and 45.4% of the African Americans self-reported that they were active smokers during the index pregnancy. The average number of cigarettes smoked per day was 2.65+/-5.75 and 1.37+/-3.17 for Caucasian and African American mothers, respectively. Peripheral blood lymphocytes from the mother and from the fetal side of the placenta were evaluated for chromosome aberrations by whole chromosome painting. Aliquots from the same blood samples were also used to assess genetic susceptibility with an in vitro bleomycin challenge assay. Spontaneous translocation frequencies in both maternal and newborn lymphocytes were not associated with cigarette smoking, socioeconomic status, or education. The absence of a smoking effect may be attributable to the low level of cigarette usage in these subjects. The average bleomycin-induced damage in the maternal and newborn populations was 0.37+/-0.27 and 0.15+/-0.14 breaks per cell, respectively, a difference that was highly significant (p<0.0001). In newborns there was a positive association between bleomycin sensitivity and the frequencies of aberrations as measured by chromosome painting: p</=0.0007 for dicentrics and fragments, and p</=0.002 for translocations. Caucasian American newborns demonstrated a significant association between dicentrics and fragments as measured by painting, and bleomycin sensitivity (p</=0.0002), but no such association was observed for African American newborns. The results of this study indicate that while differences were observed between African Americans and Caucasian Americans, race does not appear to be a major contributor to chromosome damage in newborns or their mothers. However, peripheral lymphocytes in pregnant women are more susceptible to genetic damage than peripheral lymphocytes in newborns. less...

Electrochemotherapy is an effective treatment of cutaneous and subcutaneous metastases in patients with malignant melanoma. During the treatment, electric pulses are applied to tumor nodules to deliver non-permeante or poorly permeante chemotherapeutic agents into the cells thereby increasing local cytotoxicity of anticancer drugs. Methods: In 7 patients 81 cutaneous and subcutaneous melanoma metastases were treated with electrochemotherapy. All treatments were performed under general anesthesia using intravenous bleomycin injection. Median follow-up was 218 days. Results: Complete response rate was 25%, partial response rate was 43%. We observed no change in 26%, and progressive disease in 6%. Conclusions: Electrochemotherapy is a simple and effective treatment of single or multiple cutaneous and subcutaneous metastases of melanoma, with minimal side effects. Our results confirm the results of recently published studies that the treatment used for palliation has clinical benefit and impact on the quality of life. less...

Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease for which no effective therapy has been identified. The disease is characterized by excessive collagen deposition, possibly in response to dysregulated wound healing. Mediators normally involved in would healing induce proliferation of fibroblasts and their differentiation to myofibroblasts that actively secrete collagen. Curcumin, a polyphenolic compound from turmeric, has been shown to exert a variety of biological effects. Effects on IPF and associated cell types remain unclear, however. We accordingly tested the ability of curcumin to inhibit proliferation and differentiation to myofibroblasts by human lung fibroblasts, including those from IPF patients. To further examine the potential usefulness of curcumin in IPF, we examined its ability to reduce fibrosis in bleomycin-treated mice. We show that curcumin effectively reduces profibrotic effects in both normal and IPF fibroblasts in vitro and that this reduction is accompanied by inhibition of key steps in the TGF-beta signaling pathway. In vivo, oral curcumin treatment showed no effect on important measures of bleomycin-induced injury in mice, whereas intraperitoneal curcumin administration effectively inhibited inflammation and collagen deposition, along with a trend toward improved survival. Intraperitoneal curcumin reduced fibrotic progression even when administered after the acute bleomycin-induced inflammation had subsided. These results encourage further research on alternative formulations and routes of administration for this potentially attractive IPF therapy. Key words: myofibroblast, TBF-beta, HPLC, Smad. less...