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A recently identified class of signaling factors uses critical cysteine motif(s) that act as redox-sensitive 'sulfhydryl switches' to reversibly modulate specific signal transduction cascades regulating downstream proteins with similar redox-sensitive sites. For example, signaling factors such as redox factor-1 (Ref-1) and transcription factors such as the AP-1 complex both contain redox-sensitive cysteine motifs that regulate activity in response to oxidative stress. The mammalian thioredoxin reductase-1 (TR) is an oxidoreductase selenocysteine-containing flavoprotein that also appears to regulate multiple downstream intracellular redoxsensitive proteins. Since ionizing radiation (IR) induces oxidative stress as well as increases AP-1 DNA-binding activity via the activation of Ref-1, the potential roles of TR and thioredoxin (TRX) in the regulation of AP-1 activity in response to IR were investigated. Permanently transfected cell lines that overexpress wild type TR demonstrated constitutive increases in AP-1 DNAbinding activity as well as AP-1-dependent reporter gene expression, relative to vector control cells. In contrast, permanently transfected cell lines expressing a TR gene with the active site cysteine motif deleted were unable to induce AP-1 activity or reporter gene expression in response to IR. Transient genetic overexpression of either the TR wild type or dominant-negative genes demonstrated similar results using a transient assay system. One mechanism through which TR regulates AP-1 activity appears to involve TRX sub-cellular localization, with no change in the total TRX content of the cell. These results identify a novel function of the TR enzyme as a signaling factor in the regulation of AP-1 activity via a cysteine motif located in the protein.

Pulmonary function (PF) was studied in 69 consecutive patients with hematologic diseases, with a minimum 5-year (range, 5-13 years) follow-up after allogeneic stem cell transplantation from an HLA-matched sibling. Fifty-six patients (81%) received total body irradiation based myeloablative stem cell transplantation (MT) and 13 (19%) underwent nonmyeloablative stem cell transplantation (NST). Thirty-one patients (45%) developed a late decrease in PF from baseline, 25 with a restrictive and 6 with an obstructive pattern PF abnormality. Twelve patients (17%) were symptomatic, 8 with a severe restrictive PF defect, but none required supplemental oxygen. The incidence of developing a late PF abnormality was comparable in MT (24 of 56) and NST (5 of 13; P = .51). In multivariate analysis, chronic graft-versus-host disease (relative risk, 16) and pretransplantation diffusion capacity for carbon monoxide or forced expiratory volume in the first second <80% predicted were independently associated with a late decrease in PF from baseline (relative risk, 7). Our results indicate that late PF abnormality is common after MT and NST. Patients with a low pretransplantation diffusion capacity for carbon monoxide of or forced expiratory volume in the first second who developed chronic graft-versus-host disease were most severely affected. Longer follow-up is needed to determine whether PF will continue to decrease or reach a plateau and whether more patients with PF abnormality will eventually become symptomatic.

A new technique of spine IMRT is presented in combination with a quality assurance method. This method improves target dose uniformity compared to the conventional CSI technique. Longer follow-up will be required to determine any benefit with regard to toxicity and disease control.

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Anaplastic thyroid carcinoma (ATC) is a highly aggressive neoplasm with a poor prognosis. Curative management of these tumors has been difficult secondary to delayed diagnosis and advanced disease at presentation. Treatment modalities including surgery and fractionated radiotherapy have had limited success in controlling these tumors. Median survival time is often measured in months. A review of all patients treated between 1952 and 1999 identified 32 patients with anaplastic or poorly differentiated thyroid carcinoma. Patients were divided into two groups: those treated between 1952 to 1980 (9 patients, group 1) and those treated between 1981 and 1999 (23 patients, group 2). Most group 1 patients received once-daily radiotherapy and most group 2 patients received twice-daily radiotherapy with concurrent chemotherapy. A variety of radiotherapy techniques were used. Chemotherapy consisted of doxorubicin, paclitaxel, vincristine, or cisplatin. Eleven patients presented with lymph node metastasis and two patients had distant metastases at diagnosis. The most common clinical presentation was a neck mass in 17 patients. In group 1, one patient was treated with surgery only, four with surgery and radiotherapy and four with radiotherapy alone. In group 2, 1 patient was treated with surgery only; 3 with surgery and radiotherapy; 10 with radiotherapy and chemotherapy; 5 with surgery, radiotherapy, and chemotherapy; and 5 with radiotherapy alone. Overall 2-year survival rates were 44% for group 1 and 52% for group 2. Two-year progression-free survival (PFS) was 53% for group 1 and 38% for group 2. Five (16%) patients died within 60 days of diagnosis. Severe side effects included skin sequelae (one patient) and osteoradionecrosis of the mandible (one patient). There were 10 (52%) long-term survivors (>2 years). Clinicopathologic features associated with extended survival were limited extent of disease and inclusion in group 2. Among patients with ATC surgery, hyperfractionated radiotherapy in conjunction with chemotherapy is associated with better survival but not PFS compared to conventional radiotherapy.

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