Suppression of SCARA5 by Snail1 is essential for EMT-associated cell migration of A549 cells.

Accumulating evidence indicates that epithelial-to-mesenchymal transition (EMT) might be a key event for cancer progression. The upregulation of Snail1, one of the most extensively studied EMT regulators, has been implicated in cancer metastasis, but the underlying mechanisms remain unclear. This study aims to identify that Snail1 targets regulating EMT-associated cancer cell migration. Human lung carcinoma A549 cells were treated with transforming growth factor beta 1 (TGF-ß1), and EMT-associated phenotypic and functional alterations were monitored. TGF-ß1 induced typical EMT-like morphological changes, 'cadherin switching' and cell migration in A549 cells. TGF-ß1 stimulation induced rapid and persistent upregulation of Snail1. Moreover, Snail1 upregulation was required for EMT-associated cell migration. Several metastasis suppressors with putative Snail1-binding sites in their promoters were dramatically repressed in A549 cells during TGF-ß1-induced EMT. Gain- and loss-of Snail1 function experiments demonstrated that scavenger receptor class A member 5 (SCARA5) was negatively regulated by Snail1. Importantly, SCARA5 downregulation was essential for EMT-induced migration in A549 cells. The chromatin immunoprecipitation assay revealed that Snail1 could bind to the E-box elements in SCARA5 promoter, implying that SCARA5 is a direct Snail1 target modulating cancer cell mobility during EMT. In addition, we showed that DNA methyltransferase 1 was physically associated with Snail1 to silence SCARA5 expression with an unidentified DNA methylation-independent mechanism, suggesting the complexity of Snail1-mediated epigenetic regulation. Collectively, our data demonstrated that EMT-regulator Snail1 suppresses the expression of SCARA5 to promote cancer progression, highlighting the possibility to target Snail1 and SCARA5 for cancer treatment.

A phase II study of cetuximab and radiation in elderly and/or poor performance status patients with locally advanced non-small-cell lung cancer (N0422).

BACKGROUND: Non-small-cell lung cancer (NSCLC) is a disease of the elderly. Seeking a tolerable but effective regimen, we tested cetuximab + radiation in elderly and/or poor performance status patients with locally advanced NSCLC. PATIENTS AND METHODS: Older patients [≥ 65 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2] or younger patients (performance status of 2) received cetuximab 400 mg/m(2) i.v. on day 1 followed by weekly cetuximab 250 mg/m(2) i.v. with concomitant radiation of 6000 cGy in 30 fractions. The primary end point was the percentage who lived 11+ months. RESULTS: This 57-patient cohort had a median age (range) of 77 years (60-87), and 12 (21%) had a performance status of 2. Forty of 57 (70%) lived 11+ months, thus exceeding the anticipated survival rate of 50%. The median survival was 15.1 months [95% confidence interval (CI) 13.1-19.3 months], and the median time to cancer progression was 7.2 months (95% CI 5.8-8.6 months). No treatment-related deaths occurred, but 31 patients experienced grade 3+ adverse events, most commonly fatigue, anorexia, dyspnea, rash, and dysphagia, each of which occurred in <10% of patients. CONCLUSION: This combination merits further study in this group of patients.

Chemo-biotherapy with 5-fluorouracil, leucovorin, and alpha interferon in metastatic carcinoma of the colon--a Cancer Biotherapy Research Group [CBRG] phase II study.

BACKGROUND: Biochemical modulation of 5-Fluorouracil activity with Leucovorin has been well documented in colorectal cancer. Several studies have shown increased efficacy of 5-fluorouracil in combination with alpha interferon. We therefore initiated a phase II trial of dual modulation of 5-fluorouracil with leucovorin and alpha interferon to evaluate outcomes in patients with metastatic carcinoma of the colon. METHODS: Patients with metastatic colon carcinoma with expected survival > 4 months and performance status of ECOG < or = 2 were treated weekly with Leucovorin 400 mg i.v. followed by 5-FU 600 mg/m2 i.v. bolus. Alpha interferon 3-9 million units was administered subcutaneously every Monday, Wednesday and Friday. Patients were analyzed for toxicity, tumor response and survival. RESULTS: Sixteen patients with a median age of 66 years were treated. Three patients were not evaluable for response but were evaluable for toxicity. Grades 3 and 4 toxicities were neutropenia, diarrhea, mucositis, nausea and vomiting, fatigue, fever, asthenia and elevated hepatic enzymes. One patient died from complications associated with diverticulitis and neutropenia. Objective response rate was 23% (95% confidence interval 4-46%) and median survival was 11.5 months (95% confidence interval 6.3-19 months). Thirty-eight percent of the patients were alive at one year and 19% at two years. CONCLUSION: The combination of 5-fluorouracil, leucovorin and alpha interferon as administered in this phase II study did not result in enhanced response rate or survival. However this regimen was associated with considerable toxicity.

Continuous-infusion floxuridine and alpha interferon in metastatic renal cancer: a national biotherapy study group phase II study.

Eighteen patients with advanced renal cancer were treated with 0.15 mg/kg/day floxuridine by continuous intravenous infusion for 14 days with 3 million IU/m2/day alpha interferon subcutaneously three times weekly. Treatment cycles were repeated every 28 days. Floxuridine dosages were escalated to a maximum of 0.2 mg/kg/day and alpha interferon dosages were escalated to a maximum of 6 million IU/m2/day depending on patient tolerability. A total of 49 treatment courses were administered with a median of 2.7 courses per patient. Of 14 assessable patients, there were no complete or partial responses. Eight patients (57%) had stabilization of disease. The median survival for patients with stable disease was 20.9 months and for all 18 patients was 7.2 months. Grades 3 and 4 toxicities included diarrhea (44%), nausea/vomiting (28%), mucositis (11%), fever (22%), and fatigue (50%). Dose-limiting toxicities were primarily gastrointestinal symptoms. There were no treatment-related deaths. This combination in the dose schedule used did not result in any significant objective tumor response but was associated with considerable toxicity.

Eosinophilia associated with bupropion.

OBJECTIVE: To describe the first incidence of eosinophilia following administration of bupropion. CASE SUMMARY: The patient was a 72-year-old woman admitted for evaluation of chest pain. During hospitalization, the eosinophil count reached 0.60 fraction of 1.00, with absolute eosinophil count of 6693 x 10(6)/L and a white blood cell count of 18.5 x 10(9)/L. She had been receiving bupropion therapy for 5 days prior to this admission. DISCUSSION: Potential causes of the eosinophilia, including disease states and medications, were reviewed comprehensively and ruled out. A review of the literature (MEDLINE 1966-1994) did not identify previous cases of eosinophilia associated with bupropion therapy. Causes of eosinophilia include parasitic infections, allergic diseases, and medication use. A proposed mechanism for the occurrence of eosinophilia in this patient is unknown. CONCLUSIONS: Considering the temporal sequence of events, drugs administered prior to the development of eosinophilia, and the rapid decline of the eosinophil count following discontinuation of the medication, bupropion appears to be the precipitating agent.

Systemic polyclonal B-immunoblastic proliferation with marked peripheral blood and bone marrow plasmacytosis.

The clinical and pathologic features of a case of acute systemic polyclonal B-immunoblastic proliferation characterized by pronounced peripheral blood and bone marrow plasmacytosis and infiltration of the hepatic portal areas by immunoblasts, plasma cells, and lymphocytes are reported. Clinical and laboratory findings during the acute phase and long-term follow-up support the diagnosis of a benign process, possibly related to Pseudomonas aeruginosa septicemia. The patient experienced a dramatic clinical recovery on administration of high-dose intravenous corticosteroids. Pathologists should be aware of this entity so as not to confuse it with non-Hodgkin's lymphoma or a form of plasma cell dyscrasia.