17 research outputs found
Clinical Trial of Oral Nelfinavir before and during Radiation Therapy for Advanced Rectal Cancer
Purpose
Nelfinavir, a PI3-kinase pathway inhibitor, is a radiosensitizer which increases tumor
blood flow in preclinical models. We conducted an early-phase study to demonstrate
the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to
develop biomarkers of tumor perfusion and radiosensitization for this combinatorial
approach.
Patients and Methods
Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1250
mg bd) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days).
Perfusion CT (p-CT) and DCE-MRI scans were performed pre-treatment, after 7
days of nelfinavir and prior to last fraction of RT. Biopsies taken pre-treatment and 7
days after the last fraction of RT were analysed for tumor cell density (TCD).
Results
There were 3 drug-related grade 3 adverse events: diarrhea, rash, lymphopenia. On
DCE-MRI, there was a mean 42% increase in median Ktrans, and a corresponding
median 30% increase in mean blood flow on p-CT during RT in combination with
nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken
7 days after RT (P=0.01). Overall, 5/9 evaluable patients exhibited good tumor
regression on MRI assessed by Tumor Regression Grade (mrTRG).
Conclusions
This is the first study to evaluate nelfinavir in combination with RT without concurrent
chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated
with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT
alone merits clinical evaluation, including measurement of tumor blood flow
Examining the generalizability of research findings from archival data
This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizabilityâfor the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples
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Objective assessment of deformable image registration in radiotherapy: A multi-institution study
The looming potential of deformable alignment tools to play an integral role in adaptive radiotherapy suggests a need for objective assessment of these complex algorithms. Previous studies in this area are based on the ability of alignment to reproduce analytically generated deformations applied to sample image data, or use of contours or bifurcations as ground truth for evaluation of alignment accuracy. In this study, a deformable phantom was embedded with 48 small plastic markers, placed in regions varying from high contrast to roughly uniform regional intensity, and small to large regional discontinuities in movement. CT volumes of this phantom were acquired at different deformation states. After manual localization of marker coordinates, images were edited to remove the markers. The resulting image volumes were sent to five collaborating institutions, each of which has developed previously published deformable alignment tools routinely in use. Alignments were done, and applied to the list of reference coordinates at the inhale state. The transformed coordinates were compared to the actual marker locations at exhale. A total of eight alignment techniques were tested from the six institutions. All algorithms performed generally well, as compared to previous publications. Average errors in predicted location ranged from 1.5 to 3.9 mm, depending on technique. No algorithm was uniformly accurate across all regions of the phantom, with maximum errors ranging from 5.1 to 15.4 mm. Larger errors were seen in regions near significant shape changes, as well as areas with uniform contrast but large local motion discontinuity. Although reasonable accuracy was achieved overall, the variation of error in different regions suggests caution in globally accepting the results from deformable alignment