Citations

Purpose To compare once-daily radiation therapy (qdRT) with hyperfractionated accelerated radiation therapy (HART) after two cycles of induction chemotherapy. Patients and Methods Eligible patients were treatment naive, and had stage IIIA and B unresectable non-small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0/1, and normal organ function. Induction chemotherapy consisted of two cycles of carboplatin area under time-concentration curve 6 mg/mL · min plus paclitaxel 225 mg/m2 on day 1. RT consisted of arm 1 (qdRT), 64 Gy (2 Gy/d), versus arm 2 (HART), 57.6 Gy (1.5 Gy tid for 2.5 weeks). A total of 388 patients were needed to detect a 50% increase in median survival from 14 months of qdRT to 21 months of HART; accrual was not achieved and the study closed prematurely. Results Of 141 patients enrolled, 83% were randomly assigned after chemotherapy to qdRT (n = 59) or HART (n = 60). Median survival was 20.3 and 14.9 months for HART and qdRT, respectively (P = .28). Overall response was 25% and 22% for HART and qdRT, respectively (P = .69). Two- and 3-year survival was 44% and 34% for HART, and 24% and 14% for qdRT, respectively. Grade ≥ 3 toxicities included esophagitis in 14 v nine patients, and pneumonitis in 0 v 6 patients for HART and qdRT, respectively. Any subsequent trials of the HART regimen must address the issues that led to early closure, including slow accrual, logistics of HART, mucosal toxicity, and the fact that concurrent chemoradiotherapy now seems more effective than sequential treatment. Conclusion After two cycles of induction chemotherapy with carboplatin-paclitaxel, HART is feasible with an acceptable toxicity profile. Although statistical significance was not achieved and the study closed early, there was a positive statistical trend suggesting a survival advantage with the HART regimen.

SUMMARYMurine experimental autoimmune thyroiditis (EAT), characterized by thyroid destruction after immunization with thyroglobulin (Tg), has long been a useful model of organ-specific autoimmune disease. More recently, porcine thyroid peroxidase (pTPO) has also been shown to induce thyroiditis, but these results have not been confirmed. When (C57BL/6 × CBA)F1 mice, recently shown to be susceptible to mouse TPO-induced EAT, were immunized with plasmid DNA to human TPO (hTPO) and cytokines IL-12 or GM-CSF, significant antibody (Ab) titres were generated, but minimal thyroiditis was detected in one mouse only from the TPO + GM-CSF immunized group. However, after TPO DNA immunization of HLA-DR3 transgenic class II-deficient NOD mice, thyroiditis was present in 23% of mice injected with TPO + IL-12 or GM-CSF. We also used another marker for assessing the closeness of the model to human thyroid autoimmunity by examining the epitope profile of the anti-TPO Abs to immunodominant determinants on TPO. Remarkably, the majority of the anti-TPO Abs was directed to immunodominant regions A and B, demonstrating the close replication of the model to human autoimmunity. TPO protein immunizations of HLA-DR3 transgenic mice with recombinant hTPO did not result in thyroiditis, nor did immunization of other mice expressing HLA class II transgenes HLA-DR4 or HLA-DQ8, with differential susceptibility to Tg-induced EAT. Moreover, our efforts to duplicate exactly the experimental procedures used with pTPO also failed to induce thyroiditis. The success of hTPO plasmid DNA immunization of DR3+ mice, similar to our reports on Tg-induced thyroiditis and thyrotropin receptor DNA-induced Graves’ hyperthyroidism, underscores the importance of DR3 genes for all three major thyroid antigens, and provides another humanized model to study autoimmune thyroid disease.

Purpose Although it is well-established that fluorouracil- (FU-) based adjuvant therapy improves survival for patients with resected high-risk colon cancer, the magnitude of adjuvant therapy benefit across specific subgroups and for individual patients has been uncertain. Patients and Methods Using a pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone, we performed an analysis based on a Cox proportional hazards regression model. Treatment, age, sex, tumor location, T stage, nodal status, and grade were tested for both prognostic and predictive significance. Model derived estimates of 5-year disease-free survival and overall survival (OS) for surgery alone and surgery plus FU-based therapy were calculated for a range of patient subsets. Results Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. In a multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients. Conclusion Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs . This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.

Acute injury to the intestinal mucosa is a major dose-limiting complication of abdominal radiation therapy. We studied the role of the transcription factor NF-κB in protection against radiation-induced apoptosis in the intestinal epithelium in vivo . We use mice in which NF-κB signaling through IκB-kinase (IKK)-β is selectively ablated in intestinal epithelial cells to show that failure to activate epithelial cell NF-κB in vivo results in a significant increase in radiation-induced epithelial cell apoptosis. Furthermore, bacterial lipopolysaccharide, which is normally a radioprotective agent, is radiosensitizing in IKKβ-deficient intestinal epithelial cells. Increased apoptosis in IKKβ-deficient intestinal epithelial cells was accompanied by increased expression and activation of the tumor suppressor p53 and decreased expression of antiapoptotic Bcl-2 family proteins. These results demonstrate the physiological importance of the NF-κB system in protection against radiation-induced death in the intestinal epithelium in vivo and identify IKKβ as a key molecular target for radioprotection in the intestine. Selective preactivation of NF-κB through IKKβ in intestinal epithelial cells could provide a therapeutic modality that allows higher doses of radiation to be tolerated during cancer radiotherapy.

Giant cell arteritis (GCA) is a granulomatous and occlusive vasculitis that causes blindness, stroke, and aortic aneurysm. CD4+ T cells are selectively activated in the adventitia of affected arteries. In human GCA artery–severe combined immunodeficiency (SCID) mouse chimeras, depletion of CD83+ dendritic cells (DCs) abrogated vasculitis, suggesting that DCs are critical antigen-presenting cells in GCA. Healthy medium-size arteries possessed an indigenous population of DCs at the adventitia–media border. Adoptive T cell transfer into temporal artery–SCID mouse chimeras demonstrated that DCs in healthy arteries were functionally immature, but gained T cell stimulatory capacity after injection of lipopolysaccharide. In patients with polymyalgia rheumatica (PMR), a subclinical variant of GCA, adventitial DCs were mature and produced the chemokines CCL19 and CCL21, but vasculitic infiltrates were lacking. Human histocompatibility leukocyte antigen class II–matched healthy arteries, PMR arteries, and GCA arteries were coimplanted into SCID mice. Immature DCs in healthy arteries failed to stimulate T cells, but DCs in PMR arteries could attract, retain, and activate T cells that originated from the GCA lesions. We propose that in situ maturation of DCs in the adventitia is an early event in the pathogenesis of GCA. Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space.

SUMMARYFamilial and twin studies in Caucasians have established that the MHC class II allele HLA-DRB1*0301 (DR3) is a strong susceptibility gene in Graves’ hyperthyroid disease (GD). To determine if a DR3 transgene could help establish an animal model for GD, we expressed DR3 molecules in class II-knockout NOD mice (H2Ag7–). DR3+g7– mice were given cardiotoxin prior to immunization on weeks 0, 3 and 6 with plasmid DNA encoding human thyrotropin receptor (TSHR). Two groups of mice were also coimmunized with plasmid DNA for IL-4 or GM-CSF. Serial bleeds on weeks 8, 11 and 14 showed that approximately 20% of mice produced thyroid-stimulating antibodies (Abs), and approximately 25% had elevated T4 levels. In particular, a subset displayed both signs of hyperthyroidism, resulting in approximately 30% with some aspect of GD syndrome. Additional mice had thyroid-stimulating blocking Abs and/or TSH-binding inhibitory immunoglobulins, while most mice showed strong labelling of TSHR+ cells by flow cytometry. Interestingly, lymphocytic infiltration with thyroid damage and Abs to mouse thyroglobulin were also noted. Vector controls were uniformly negative. Thus, DR3 transgenic mice can serve as a model for GD, similar to our earlier reports that this allele is permissive for the Hashimoto's thyroiditis model induced with human thyroglobulin.

The inverse problems in the area of the acoustic scattering often concern the determination of the size, shape, and orientation of an object using the scattered field data. This paper presents a method to retrieve the shape information of an underwater object using illuminated lengths, which can be obtained from the ramp response signatures of the object. An ellipsoidal object submerged in water is considered. Both the low and high backscattered frequency data have been employed to calculate the illuminated lengths. The calculated results show that the illuminated lengths will be more accurate, if only the high-frequency-range data are employed. For ellipsoidal objects, any three illuminated lengths that are not of a same plane can in theory fully determine the shape of the ellipsoid. As the calculated illuminated lengths contain numerical errors, the calculated results of the three semiaxes of the ellipsoid will deteriorate and become unreliable, especially when the three incident directions of the illuminated lengths become close. The reason is that the condition number of the coefficient matrix becomes big in such situations, which leads to an increase of the relative error upper limit in the calculated results. To avoid such errors in close incident wave cases, it is found that the use of more than three incident waves works very well in the shape identification of an underwater object.