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The standard curative approach for the treatment of inoperable non-small cell lung cancer (NSCLC) is definitive radiotherapy. Advanced treatment techniques have been developed that maximize radiation dose delivery to the tumor while minimizing the dose to critical surrounding structures. These radiation therapy techniques include three-dimensional conformal radiotherapy, intensity modulated radiation therapy, stereotactic body radiotherapy, and particle beam radiotherapy. Biological imaging with (18)F-FDG-PET and other novel tracers in development have shown the potential to improve target delineation and patient selection for curative treatment. Tumor motion control with respiratory gating techniques and image-guided radiation therapy are recent developments that provide the radiation oncologist with accurate tumor localization on the treatment machine. This review article summarizes the literature on these topics and other state-of-the-art radiation therapy techniques in the management of inoperable NSCLC.

Mutated ras has been identified in approximately 30% of human tumors, and dysregulation of ras function and signal transduction pathways is a critical step in tumorigenesis. Herein, we review the early data that supports the concept that the intrinsic radiosensitivity of tumor cells can be altered by oncogenic ras expression and that this impacts the PI3K-dependent signaling cascade. This ras-induced radioresistance can be reversed using prenyl transferase inhibitors (PTIs.). We discuss the effects of PTIs as a radiosensitizer in both in vivo and in vitro studies and show that PTIs can lead to increased radiosensitization in vivo through a variety of potential mechanisms that enhance radiation-induced cell kill. We critically evaluate the use of ras biomarkers in predicting the clinical response to PTIs that may explain the mixed results seen thus far in clinical trials using PTIs as a clinical radiosensitizer. We conclude that Ras-mediated radioresistance is the result of multiple intercommunicating pathways functioning against a complex genetic background and a solitary biomarker may not be adequate to predict for PTI-mediated radiosensitization. Nonetheless, our knowledge of the ras-signaling pathway has led to development and testing of specific therapies directed against PI3K-AKT signaling pathways as a future approach towards clinical radiosensitization.

Background: The primary objective of this study was to determine the long-term outcome of sphincter preservation with preoperative radiation therapy (RT) and surgical resection in the treatment of distal rectal adenocarcinoma., Patients and Methods: Between April 1988 and December 1996, 36 (cT2, n=9; cT3, n=27) patients with rectal adenocarcinoma were enrolled on a phase I/II trial of preoperative RT followed by surgical resection. All patients had distal tumors that were clinically judged to require an abdominoperineal resection and received preoperative RT (50.4 Gy) followed by surgery. The median follow-up was 94.5 months (range, 4-187 months)., Results: Of the 35 patients in this study who underwent resection, 77% were able to undergo sphincter preservation after preoperative RT. The pathologic complete response rate for these patients was 14%. The 10-year rates of overall survival and local failure for patients undergoing sphincter preservation were 54% and 21%, respectively. The 10-year local failure was 26% in patients with cT3 disease who underwent sphincter preservation. All local failures in this study occurred in patients with cT3 disease undergoing sphincter preservation; however, none of the patients with cT3 disease that was downstaged by preoperative RT experienced local failure. In contrast, 10-year local failure was 67% in the patients with cT3 disease that was not downstaged by RT. Sphincter function was good or excellent in 85% of patients at the time of last follow-up., Conclusion: This approach provides excellent long-term results in all patients with cT2 disease and those with cT3 disease that is downstaged by RT. However, patients with cT3 disease that is not downstaged by RT have an increased risk of local failure. These data underscore the impact of tumor response to radiation on long-term oncologic outcome.

Purpose: To compare tumor volume delineation using registered positron emission tomography (PET)/CT vs. side-by-side image sets., Methods and Materials: A total of 19 patients with non-small-cell lung cancer had 18-fluorine-deoxyglucose (FDG)-PET scans registered with planning CT scans. The disease was Stage I-II in 26%, IIIA in 42%, and IIIB in 32%. Two radiation oncologists contoured 9 tumor volumes using registered images (registered) and 10 using separate FDG-PET images as a guide (nonregistered). A third physician, who had done the treatment planning for these patients a median of 40 months before using registered images, repeated all contours: 10 on registered images (registered/registered) and 9 without registration (registered/nonregistered). Each pair of volumes (A and B) was compared. Quantitative comparison used the concordance index, (A intersection B)/(A union or logical sum B). For qualitative analysis, pairs of volumes were projected onto digitally reconstructed radiographs. The differences were graded as insignificant, minor, moderate, or major., Results: The median interobserver percentage of concordance among nonregistered pairs was 61% vs. 70% in the registered group (p <0.05). On qualitative analysis, in the nonregistered group, the differences were insignificant in 5, minor in 3, and moderate in 2 of 10. The differences in the registered group were insignificant in 7 and minor in 2 of 9. The median intraobserver percentage of concordance in the registered/nonregistered group was 58% vs. 71% in the registered/registered group (p = 0.10). On qualitative analysis, the intraobserver differences in the registered/nonregistered group were insignificant in 2, minor in 2, moderate in 0, and major in 5 of 9. In the registered/registered group, the differences were insignificant in 2, minor in 6, moderate in 2, and major in 0 of 10., Conclusion: Registration of FDG-PET and planning CT images results in greater consistency in tumor volume delineation.

Purpose: It has been suggested that larger tumor volume is associated with poor survival in patients with non-small-cell lung cancer (NSCLC). We investigated whether high-dose radiation improved local control in patients with large-volume Stage III NSCLC., Methods and Materials: Seventy-two patients with Stage III NSCLC and gross tumor volumes (GTV) of greater than 100 cc were treated with three-dimensional conformal radiotherapy (3D-CRT). Patients were divided into two groups: those treated to less than 64 Gy (37 patients) and those treated to 64 Gy or higher (35 patients)., Results: The 1-year and 2-year local failure rates were 27% and 47%, respectively, for Stage III patients treated to 64 Gy or higher, and 61% and 76%, respectively, for those treated to less than 64 Gy (p = 0.024). The median survival time for patients treated to 64 Gy or higher was 20 months vs. 15 months for those treated to less than 64 Gy (p = 0.068). Multivariate analysis revealed that dose and GTV are predictors of local failure-free survival. A 10 Gy increase in dose resulted in a 36.4% decreased risk of local failure., Conclusions: Our data suggest that administration of higher doses using 3D-CRT improves local control in Stage III NSCLC patients with large GTVs.

Molecules of the title compound, alternatively called (R,R)-N,N'-bis(3-methoxysalicylidene)-trans-cyclohexane-1,2-diamine, C(22)H(26)N(2)O(4), contain two intramolecular O-H.N hydrogen bonds and adopt a conformation with approximate twofold rotational symmetry. The molecules are linked by three C-H.O hydrogen bonds [H.O = 2.45-2.55 A, C.O = 3.329 (2)-3.398 (2) A and C-H.O = 142-172 degrees ] into a continuous framework.

Mutations in the Wiskott-Aldrich syndrome protein (WASP) have been hypothesized to cause defective actin cytoskeletal function. This resultant dysfunction of the actin cytoskeleton has been implicated in the pathogenesis of Wiskott-Aldrich syndrome (WAS). In contrast, it was found that stimulated actin polymerization is kinetically normal in the hematopoietic lineages affected in WAS. It was also found that the actin cytoskeleton in WAS platelets is capable of producing the hallmark cytoarchitectural features associated with activation. Further analysis revealed accelerated cell death in WAS lymphocytes as evidenced by increased caspase-3 activity. This increased activity resulted in accelerated apoptosis of these cells. CD95 expression was also increased in these cells, suggesting an up-regulation in the FAS pathway in WAS lymphocytes. Additionally, inhibition of actin polymerization in lymphocytes using cytochalasin B did not accelerate apoptosis in these cells. This suggests that the accelerated apoptosis observed in WAS lymphocytes was not secondary to an underlying defect in actin polymerization caused by mutation of the WAS gene. These data indicate that WASP does not play a universal role in signaling actin polymerization, but does play a role in delaying cell death. Therefore, the principal consequence of mutations in the WAS gene is to accelerate lymphocyte apoptosis, potentially through up-regulation of the FAS-mediated cell death pathway. This accelerated apoptosis may ultimately give rise to the clinical manifestations observed in WAS. (Blood. 2000;95:1283-1292)

The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency associated with thrombocytopenia, bloody diarrhea, eczema, recurrent infections, and a high incidence of malignancies. X-linked thrombocytopenia (XLT) is a milder form with predominant platelet abnormalities. Both are caused by mutations of the cytoplasmic WAS protein (WASP). To date, mutations of WASP have been identified in over 340 families and consist of missense and nonsense mutations, deletions and insertions, and splice site mutations. There is a striking correlation between phenotype and genotype. The complex gene product of WASP has multiple functional domains that contribute to actin polymerization, cell motility, intracellular signaling, and apoptosis. Understanding the molecular basis of WAS/XLT not only explains the highly variable clinical phenotype, but also affects the medical management of this serious congenital disorder.

Stimulation of neutrophils with LTB(4) or PAF results in the production of a rapidly oscillating actin polymerization/depolymerization response. Treatment of neutrophils with inhibitors of PKC prior to stimulation with ligand resulted in a masking of the F-actin oscillations. Because myosin has been shown to be a substrate for neutrophil PKC, this protein was investigated as a potential downstream mediator of F-actin oscillations. Stimulation of neutrophils with LTB(4) resulted in myosin light chain being serine phosphorylated in a PKC-dependent manner. This phosphorylation was shown to occur in a manner that is kinetically distinct from the myosin phosphorylation induced by FMLP, a potent activator of actin polymerization that alone does not induce F-actin oscillations. Additionally, disruption of intracellular actin-myosin interactions resulted in inhibition of LTB(4)- as well as PAF-induced F-actin oscillations. These data suggest that PKC and downstream phosphorylation of myosin as well as actin-myosin interaction may play roles in mediating the production of neutrophil F-actin oscillations., (Copyright 1999 Academic Press.)