No abstract

Approximately 10% of all renal cell carcinomas (RCCs) present a distinctive papillary histology. Familial papillary RCC (PRCC) has been described, but the majority of cases appear to be sporadic. Recently, germline mutations in the MET proto-oncogene on chromosome 7 have been identified in families with hereditary PRCC. We evaluated 59 patients with PRCC for the frequency of MET germline mutations to determine the value of genetic screening of this patient population. Between 1976 and 1997, 165 patients were identified with PRCC by retrospective chart review. Fifty-nine of 133 surviving patients agreed to provide a family history, a blood specimen, and informed consent for genetic research. DNA was isolated from peripheral blood leukocytes. Denaturing high-performance liquid chromatography (DHPLC) followed by genomic sequencing was performed on eight exons of the MET proto-oncogene, including exons 5-7 of the extracellular domain, exon 14, and exons 16-19 of the tyrosine kinase domain. The 59 patients in this study included 49 men and 10 women with a mean age at diagnosis of 61 years. Bilateral and/or multifocal disease was present in 13 cases (22%). No germline mutations were detected in the studied exons of the MET proto-oncogene (exons previously reported to contain deleterious mutations in familial PRCC). No pathological MET proto-oncogene germline mutations were identified in 59 patients with PRCC. The germline mutation rate in this clinic-based population of individuals with PRCC approaches 0% (CI = 0-6.18). MET proto-oncogene germline mutation screening does not appear to be clinically indicated in patients with PRCC without additional evidence for a genetic predisposition (positive family history, unusual age at onset, bilateral disease).

Purpose: Intensity‐modulated proton therapy (IMPT) has a great potential to further advance proton therapy. However, it is widely accepted that IMPT is very sensitive to uncertainties. The worst‐case analysis (WA) originally proposed by Lomax has been adopted in our institute to evaluate IMPT plan sensitivity to range and setup uncertainties. Here, we propose an evaluation method by exhaustively sampling uncertainties and apply it to validate WA. Methods: A series of perturbations to modify proton beam ranges and to shift the iso‐center in x‐, y‐ and z‐directions were sampled for 500 times to generate the probability distribution of plan qualities. The magnitude of a perturbation was assigned randomly following a normal distribution with specified standard deviations in each perturbation dimension. Perturbed dose was calculated for each sampling and compared to the WA dose. Dose‐volume‐histograms (DVH) were obtained for all perturbed doses. The distribution of DVHs and dose‐volume indices were examined. Prostate and head/neck cases were selected for demonstration. Results: In both cases, the DVHs of 500 perturbed doses spread over bands with various widths, and the DVH curves of WA lie within these bands and near the “worst” edges. for CTV, 97.6% in the prostate case and 97% in the head/neck case of the perturbed doses show a D95 value higher than the value given by WA. For normal tissues, at least 96.4% of the perturbed doses show lower dose‐volume indices (e.g. V70 of rectum and bladder) than the ones by WA. Conclusions: After exhaustively sampling the possible uncertainties, we verified that the worst‐case analysis may reasonably evaluate the IMPT plan sensitivity to setup and range uncertainties without considerably over‐ or under‐estimating it. The exhaustively sampling approach proposed here could offer a great outset toward comprehensively evaluating the IMPT plan sensitivity to a broader spectrum of planning and delivery uncertainties.

Purpose: To examine the adequacy of the planning target volume (PTV) dose distribution as the worst‐case representation of clinical target volume (CTV) dose distribution in prostate volumetric‐modulated arc therapy (VMAT) plans. Methods: Ten intact prostate cancer cases treated by VMAT at our institution were randomly selected. Isocenter was shifted in the three cardinal directions by a displacement equal to the PTV expansion on the CTV (±3 mm) for a total of six shifted plans per original plan. Rotationally‐perturbed plans were generated with a couch rotation of ±1° to simulate patient yaw. The eight perturbed dose distributions were recalculated in the treatment planning system using the same, fixed fluence map as the original plan. The voxel‐wise worst‐case CTV dose distribution was constructed from the minimum value per voxel from the eight perturbed doses. The resulting dose volume histograms (DVH) were evaluated for statistical correlation between the worst‐case CTV and nominal PTV dose distributions based on D95% by Wilcoxon signed‐rank test with significance level p ≤ 0.05. Results: Inspection demonstrates the PTV DVH in the nominal dose distribution is bounded by the CTV DVH in the worst‐case dose distribution. Comparison of D95% for the two dose distributions by Wilcoxon signed‐rank test gives p = 0.131. Therefore the null hypothesis cannot be rejected since the difference in median values is not statistically significant. Conclusion: The assumption that the nominal dose distribution for PTV represents the worst‐case dose distribution for CTV appears valid for the ten plans under examination. Although the worst‐case dose distribution is unphysical since the dose per voxel is chosen independently, it serves as a lower bound for the possible CTV coverage. Furthermore, this is consistent with the unphysical nature of the PTV. Minor discrepancies between the two dose distributions are expected since the dose cloud is not strictly static. Funding Support: NIH/NCI K25CA168984, Eagles Cancer Research Career Development, The Lawrence W. and Marilyn W. Matteson Fund for Cancer Research, Mayo ASU Seed Grant, and The Kemper Marley Foundation