Craniospinal irradiation with spinal IMRT to improve target homogeneity.

PURPOSE: To report a new technique for the spinal component of craniospinal irradiation (CSI) in the supine position, to describe a verification procedure for this method, and to compare this technique with conventional plans. METHODS AND MATERIALS: Twelve patients were treated between 1998 and 2006 with CSI using a novel technique. Sixteen children were treated with a conventional field arrangement. All patients were followed for outcomes and toxicity. CSI was delivered using a posteroanterior (PA) intensity-modulated radiation therapy (IMRT) spinal field matched to conventional, opposed lateral cranial fields. Treatment plans were generated for each patient using the IMRT technique and a standard PA field technique. The resulting dosimetry was compared to determine target homogeneity, maximum dose to normal tissues, and total monitor units delivered. RESULTS: Evaluation of the spinal IMRT technique compared with a standard PA technique reveals a 7% reduction in the target volume receiving > or =110% of the prescribed dose and an 8% increase in the target volume receiving > or =95% of the prescribed dose. Although target homogeneity was improved, the maximum dose delivered in the paraspinal muscles was increased by approximately 8.5% with spinal IMRT compared to the PA technique. Follow-up evaluations revealed no unexpected toxicity associated with the IMRT technique. CONCLUSIONS: 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.

Pretransplant pulmonary function tests predict risk of mortality following fractionated total body irradiation and allogeneic peripheral blood stem cell transplant.

PURPOSE: To determine the value of pulmonary function tests (PFTs) done before peripheral blood stem cell transplant (PBSCT) in predicting mortality after total body irradiation (TBI) performed with or without dose reduction to the lung. METHODS AND MATERIALS: From 1997 to 2004, 146 consecutive patients with hematologic malignancies received fractionated TBI before PBSCT. With regimen A (n=85), patients were treated without lung dose reduction to 13.6 gray (Gy). In regimen B (n=35), total body dose was decreased to 12 Gy (1.5 Gy twice per day for 4 days) and lung dose was limited to 9 Gy by use of lung shielding. In regimen C (n=26), lung dose was reduced to 6 Gy. All patients received PFTs before treatment, 90 days after treatment, and annually. RESULTS: Median follow-up was 44 months (range, 12-90 months). Sixty-one patients had combined ventilation/diffusion capacity deficits defined as both a forced expiratory volume in the first second (FEV1) and a diffusion capacity of carbon dioxide (DLCO)<100% predicted. In this group, there was a 20% improvement in one-year overall survival with lung dose reduction (70 vs. 50%, log-rank test p=0.042). CONCLUSION: Among those with combined ventilation/diffusion capacity deficits, lung dose reduction during TBI significantly improved survival.

Thioredoxin reductase regulates AP-1 activity as well as thioredoxin nuclear localization via active cysteines in response to ionizing radiation.

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 redox-sensitive 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 DNA-binding 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.

Anaplastic thyroid carcinoma: comparison of conventional radiotherapy and hyperfractionation chemoradiotherapy in two groups.

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.

Chronic GVHD and pretransplantation abnormalities in pulmonary function are the main determinants predicting worsening pulmonary function in long-term survivors after stem cell transplantation.

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.