T Stage and Pretreatment Standardized Uptake Values Predict Tumor Recurrence With 5-Fraction SABR in Early-Stage Non-Small Cell Lung Cancer.

Purpose: Five-fraction stereotactic ablative radiotherapy (SABR) regimens are frequently used to treat centrally located early-stage non-small cell lung cancer or disease in the proximity of the chest wall as a means of optimizing tumor control and reducing treatment toxicity. However, increasing these SABR regimens to 5 fractions may reduce tumor control outcomes. We sought to identify the clinical parameters predictive of treatment failures with these 5-fraction courses. Methods: Ninety patients with T1-2 non-small cell lung cancer were treated with 50 or 60 Gy in 5 fractions. Failure over time was modeled using cumulative incidences of local, regional, or distant failure, with death as a competing risk. Cox proportional hazards analysis for incidences of failure was performed to control for patient variables. Results: Of 90 patients, 24 of 53 patients with T1 tumors and 19 of 37 patients with T2 tumors received 50 Gy SABR, and the other 47 patients received 60 Gy. Two-year overall survival and progression-free survival for the whole cohort were 75.8% and 59.3%, respectively. Total SABR dose (50 vs 60 Gy) did not influence survival nor failure rates at 2 and 5 years. Within 2 years of treatment, 7.8% of all patients developed local failure. For all patient and tumor characteristics evaluated, only T stage and pretreatment positron emission tomography standardized uptake values served as predictors of local, regional, and distant failure at 2 and 5 years posttreatment on univariate and multivariable analysis. Conclusions: Five-fraction SABR provides excellent in-field control. T2 and high fluorodeoxyglucose uptake tumors have increased failure rates, suggesting the potential need for adjuvant therapies, which are being assessed in randomized phase 3 trials.

Expanded Radiosurgery Capabilities Utilizing Gamma Knife Icon™.

The indications and techniques for the treatment of intracranial lesions continue to evolve with the advent of novel technologies. The Gamma Knife Icon™ (GK Icon™) is the most recent model available from Elekta, providing a frameless solution for stereotactic radiosurgery. At our institution, 382 patients with 3,213 separate intracranial lesions have been treated with frameless stereotactic radiotherapy using the GK Icon. The wide range of diagnoses include brain metastases, meningiomas, arteriovenous malformations, acoustic neuromas, pituitary adenomas, and several other histologies. The ability to perform both frame and frameless treatments on the GK Icon has significantly increased our daily volume by almost 50% on a single machine. Although the frameless approach allows one to take advantage of the precision in radiosurgery, the intricacies regarding treatment with this frameless system are not well established. Our initial experience will help to serve as a guide to those wishing to implement this novel technology in their practice.

Structural analysis of a type 1 ribosome inactivating protein reveals multiple L­asparagine­N­acetyl­D­glucosamine monosaccharide modifications: Implications for cytotoxicity.

Pokeweed antiviral protein (PAP) belongs to the family of type I ribosome­inactivating proteins (RIPs): Ribotoxins, which function by depurinating the sarcin­ricin loop of ribosomal RNA. In addition to its antibacterial and antifungal properties, PAP has shown promise in antiviral and targeted tumor therapy owing to its ability to depurinate viral RNA and eukaryotic rRNA. Several PAP genes are differentially expressed across pokeweed tissues, with natively isolated seed forms of PAP exhibiting the greatest cytotoxicity. To help elucidate the molecular basis of increased cytotoxicity of PAP isoenzymes from seeds, the present study used protein sequencing, mass spectroscopy and X-ray crystallography to determine the complete covalent structure and 1.7 Å X­ray crystal structure of PAP­S1aci isolated from seeds of Asian pokeweed (Phytolacca acinosa). PAP­S1aci shares ~95% sequence identity with PAP­S1 from P. americana and contains the signature catalytic residues of the RIP superfamily, corresponding to Tyr72, Tyr122, Glu175 and Arg178 in PAP­S1aci. A rare proline substitution (Pro174) was identified in the active site of PAP­S1aci, which has no effect on catalytic Glu175 positioning or overall active­site topology, yet appears to come at the expense of strained main­chain geometry at the pre­proline residue Val173. Notably, a rare type of N­glycosylation was detected consisting of N­acetyl­D­glucosamine monosaccharide residues linked to Asn10, Asn44 and Asn255 of PAP­S1aci. Of note, our modeling studies suggested that the ribosome depurination activity of seed PAPs would be adversely affected by the N­glycosylation of Asn44 and Asn255 with larger and more typical oligosaccharide chains, as they would shield the rRNA­binding sites on the protein. These results, coupled with evidence gathered from the literature, suggest that this type of minimal N­glycosylation in seed PAPs and other type I seed RIPs may serve to enhance cytotoxicity by exploiting receptor­mediated uptake pathways of seed predators while preserving ribosome affinity and rRNA recognition.