Uncertainty in magnetic resonance imaging-based prostate postimplant dosimetry: Results of a 10-person human observer study, and comparisons with automatic postimplant dosimetry.

PURPOSE: Uncertainties in postimplant quality assessment (QA) for low-dose-rate prostate brachytherapy (LDRPBT) are introduced at two steps: seed localization and contouring. We quantified how interobserver variability (IoV) introduced in both steps impacts dose-volume-histogram (DVH) parameters for MRI-based LDRPBT, and compared it with automatically derived DVH parameters. METHODS AND MATERIALS: Twenty-five patients received MRI-based LDRPBT. Seven clinical observers contoured the prostate and four organs at risk, and 4 dosimetrists performed seed localization, on each MRI. Twenty-eight unique manual postimplant QAs were created for each patient from unique observer pairs. Reference QA and automatic QA were also performed for each patient. IoV of prostate, rectum, and external urinary sphincter (EUS) DVH parameters owing to seed localization and contouring was quantified with coefficients of variation. Automatically derived DVH parameters were compared with those of the reference plans. RESULTS: Coefficients of variation (CoVs) owing to contouring variability (CoVcontours) were significantly higher than those due to seed localization variability (CoVseeds) (median CoVcontours vs. median CoVseeds: prostate D90-15.12% vs. 0.65%, p < 0.001; prostate V100-5.36% vs. 0.37%, p < 0.001; rectum V100-79.23% vs. 8.69%, p < 0.001; EUS V200-107.74% vs. 21.18%, p < 0.001). CoVcontours were lower when the contouring observers were restricted to the 3 radiation oncologists, but were still markedly higher than CoVseeds. Median differences in prostate D90, prostate V100, rectum V100, and EUS V200 between automatically computed and reference dosimetry parameters were 3.16%, 1.63%, -0.00 mL, and -0.00 mL, respectively. CONCLUSIONS: Seed localization introduces substantially less variability in postimplant QA than does contouring for MRI-based LDRPBT. While automatic seed localization may potentially help improve workflow efficiency, it has limited potential for improving the consistency and quality of postimplant dosimetry.

Proton therapy for the management of localized prostate cancer: Long-term clinical outcomes at a comprehensive cancer center.

BACKGROUND AND PURPOSE: Proton therapy (PT) has emerged as a standard-of-care treatment option for localized prostate cancer at our comprehensive cancer center. However, there are few large-scale analyses examining the long-term clinical outcomes. Therefore, this article aims to evaluate the long-term effectiveness and toxicity of PT in patients with localized prostate cancer. MATERIALS AND METHODS: Review of 2772 patients treated from May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 850]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high [VHR, n = 116]. Biochemical failure and toxicity were analyzed using Kaplan-Meier estimates and multivariate models. RESULTS: The median patient age was 66 years; the median follow-up time was 7.0 years. Pelvic lymph node irradiation was prescribed to 28 patients (1%) (2 [0.2%] U-IR, 11 [3.5%] HR, and 15 [12.9%] VHR). The median dose was 78 Gy in 1.8-2.0 Gy(RBE) fractions. Freedom from biochemical relapse (FFBR) rates at 5 years and 10 years were 98.2% and 96.8% for the LR group; 98.3% and 93.6%, F-IR; 94.2% and 90.2%, U-IR; 94.3% and 85.2%, HR; and 86.1% and 68.5%, VHR. Two patients died of prostate cancer. Overall rates of late grade ≥ 3 GU and GI toxicity were 0.87% and 1.01%. CONCLUSIONS: Proton therapy for localized prostate cancer demonstrated excellent clinical outcomes in this large cohort, even among higher-risk groups with historically poor outcomes despite aggressive therapy.

Prospective Evaluation of Prostate and Organs at Risk Segmentation Software for MRI-based Prostate Radiation Therapy.

The segmentation of the prostate and surrounding organs at risk (OARs) is a necessary workflow step for performing dose-volume histogram analyses of prostate radiation therapy procedures. Low-dose-rate prostate brachytherapy (LDRPBT) is a curative prostate radiation therapy treatment that delivers a single fraction of radiation over a period of days. Prior studies have demonstrated the feasibility of fully convolutional networks to segment the prostate and surrounding OARs for LDRPBT dose-volume histogram analyses. However, performance evaluations have been limited to measures of global similarity between algorithm predictions and a reference. To date, the clinical use of automatic segmentation algorithms for LDRPBT has not been evaluated, to the authors' knowledge. The purpose of this work was to assess the performance of fully convolutional networks for prostate and OAR delineation on a prospectively identified cohort of patients who underwent LDRPBT by using clinically relevant metrics. Thirty patients underwent LDRPBT and were imaged with fully balanced steady-state free precession MRI after implantation. Custom automatic segmentation software was used to segment the prostate and four OARs. Dose-volume histogram analyses were performed by using both the original automatically generated contours and the physician-refined contours. Dosimetry parameters of the prostate, external urinary sphincter, and rectum were compared without and with the physician refinements. This study observed that physician refinements to the automatic contours did not significantly affect dosimetry parameters. Keywords: MRI, Neural Networks, Radiation Therapy, Radiation Therapy/Oncology, Genital/Reproductive, Prostate, Segmentation, Dosimetry Supplemental material is available for this article. © RSNA, 2022.

Computer-aided segmentation on MRI for prostate radiotherapy, part II: Comparing human and computer observer populations and the influence of annotator variability on algorithm variability.

BACKGROUND AND PURPOSE: Comparing deep learning (DL) algorithms to human interobserver variability, one of the largest sources of noise in human-performed annotations, is necessary to inform the clinical application, use, and quality assurance of DL for prostate radiotherapy. MATERIALS AND METHODS: One hundred fourteen DL algorithms were developed on 295 prostate MRIs to segment the prostate, external urinary sphincter (EUS), seminal vesicles (SV), rectum, and bladder. Fifty prostate MRIs of 25 patients undergoing MRI-based low-dose-rate prostate brachytherapy were acquired as an independent test set. Groups of DL algorithms were created based on the loss functions used to train them, and the spatial entropy (SE) of their predictions on the 50 test MRIs was computed. Five human observers contoured the 50 test MRIs, and SE maps of their contours were compared with those of the groups of the DL algorithms. Additionally, similarity metrics were computed between DL algorithm predictions and consensus annotations of the 5 human observers' contours of the 50 test MRIs. RESULTS: A DL algorithm yielded statistically significantly higher similarity metrics for the prostate than did the human observers (H) (prostate Matthew's correlation coefficient, DL vs. H: planning-0.931 vs. 0.903, p < 0.001; postimplant-0.925 vs. 0.892, p < 0.001); the same was true for the 4 organs at risk. The SE maps revealed that the DL algorithms and human annotators were most variable in similar anatomical regions: the prostate-EUS, prostate-SV, prostate-rectum, and prostate-bladder junctions. CONCLUSIONS: Annotation quality is an important consideration when developing, evaluating, and using DL algorithms clinically.

Computer-aided segmentation on MRI for prostate radiotherapy, Part I: Quantifying human interobserver variability of the prostate and organs at risk and its impact on radiation dosimetry.

BACKGROUND AND PURPOSE: Quantifying the interobserver variability (IoV) of prostate and periprostatic anatomy delineation on prostate MRI is necessary to inform its use for treatment planning, treatment delivery, and treatment quality assessment. MATERIALS AND METHODS: Twenty five prostate cancer patients underwent MRI-based low-dose-rate prostate brachytherapy (LDRPBT). The patients were scanned with a 3D T2-weighted sequence for treatment planning and a 3D T2/T1-weighted sequence for quality assessment. Seven observers involved with the LDRPBT workflow delineated the prostate, external urinary sphincter (EUS), seminal vesicles, rectum, and bladder on all 50 MRIs. IoV was assessed by measuring contour similarity metrics, differences in organ volumes, and differences in dosimetry parameters between unique observer pairs. Measurements from a group of 3 radiation oncologists (G1) were compared against those from a group consisting of the other 4 clinical observers (G2). RESULTS: IoV of the prostate was lower for G1 than G2 (Matthew's correlation coefficient [MCC], G1 vs. G2: planning-0.906 vs. 0.870, p < 0.001; postimplant-0.899 vs. 0.861, p < 0.001). IoV of the EUS was highest of all the organs for both groups, but was lower for G1 (MCC, G1 vs. G2: planning-0.659 vs. 0.402, p < 0.001; postimplant-0.684 vs. 0.398, p < 0.001). Large differences in prostate dosimetry parameters were observed (G1 maximum absolute prostate ΔD90: planning-76.223 Gy, postimplant-36.545 Gy; G1 maximum absolute prostate ΔV100: planning-13.927%, postimplant-8.860%). CONCLUSIONS: While MRI is optimal in the management of prostate cancer with radiation therapy, significant interobserver variability of the prostate and external urinary sphincter still exist.

p16 Represses DNA Damage Repair via a Novel Ubiquitin-Dependent Signaling Cascade.

Squamous cell carcinoma driven by human papillomavirus (HPV) is more sensitive to DNA-damaging therapies than its HPV-negative counterpart. Here, we show that p16, the clinically used surrogate for HPV positivity, renders cells more sensitive to radiotherapy via a ubiquitin-dependent signaling pathway, linking high levels of this protein to increased activity of the transcription factor SP1, increased HUWE1 transcription, and degradation of ubiquitin-specific protease 7 (USP7) and TRIP12. Activation of this pathway in HPV-positive disease led to decreased homologous recombination and improved response to radiotherapy, a phenomenon that can be recapitulated in HPV-negative disease using USP7 inhibitors in clinical development. This p16-driven axis induced sensitivity to PARP inhibition and potentially leads to "BRCAness" in head and neck squamous cell carcinoma (HNSCC) cells. Thus, these findings support a functional role for p16 in HPV-positive tumors in driving response to DNA damage, which can be exploited to improve outcomes in both patients with HPV-positive and HPV-negative HNSCC. SIGNIFICANCE: In HPV-positive tumors, a previously undiscovered pathway directly links p16 to DNA damage repair and sensitivity to radiotherapy via a clinically relevant and pharmacologically targetable ubiquitin-mediated degradation pathway.

Sample-size calculation for preclinical dose-response experiments using heterogeneous tumour models.

BACKGROUND: In preclinical radio-oncological research, local tumour control is considered the most relevant endpoint as it reflects the inactivation of cancer stem cells. Preclinical tumour-control assays may compare dose-response curves between different radiotherapy strategies, e.g., assessing additional targeted drugs and immunotherapeutic interventions, or between different radiation modalities. To mimic the biological heterogeneity of human tumour populations and to accommodate for approaches of personalized oncology, preclinical studies are increasingly performed combining larger panels of tumour models. For designing the study protocols and to obtain reliable results, prospective sample-size planning has to be developed that accounts for such heterogeneous cohorts. METHODS: A Monte-Carlo-based method was developed to estimate the sample size of a comparative 1:1 two-arm prospective tumour-control assay. Based on repeated logistic regression analysis, pre-defined dose levels, assumptions on the dose-response curves of the included tumour models and on the dose-modifying factors (DMF), the power is calculated for a given number of animals per dose group. RESULTS: Two applications are presented: (i) For a simple tumour-control assay with the head and neck squamous cell carcinoma (HNSCC) model FaDu, 10 animals would be required for each of 7 dose levels per arm to reveal a DMF of 1.25 with a power of 0.82 without drop out (total: 140 animals). (ii) In a more complex experiment combining six different lung tumour models to a heterogeneous population, 21 animals would be required for each of 11 dose levels per arm to reveal a DMF of 1.25 with a power of 0.81 without drop out (total: 462 animals). Analyzing the heterogeneous cohort reduces the required animal number by more than 50% compared to six individual tumour-control assays. CONCLUSION: An approach for estimating the required animal number for comparative tumour-control assays in a heterogeneous population is presented, allowing also the inclusion of different treatments as a personalized approach in the experimental arm. The software is publicly available and can be applied to plan comparisons of sigmoidal dose-response curves based on logistic regression.

Machine Segmentation of Pelvic Anatomy in MRI-Assisted Radiosurgery (MARS) for Prostate Cancer Brachytherapy.

PURPOSE: To investigate machine segmentation of pelvic anatomy in magnetic resonance imaging (MRI)-assisted radiosurgery (MARS) for prostate cancer using prostate brachytherapy MRIs acquired with different pulse sequences and image contrasts. METHODS AND MATERIALS: Two hundred 3-dimensional (3D) preimplant and postimplant prostate brachytherapy MRI scans were acquired with a T2-weighted sequence, a T2/T1-weighted sequence, or a T1-weighted sequence. One hundred twenty deep machine learning models were trained to segment the prostate, seminal vesicles, external urinary sphincter, rectum, and bladder using the MRI scans acquired with T2-weighted and T2/T1-weighted image contrast. The deep machine learning models consisted of 18 fully convolutional networks (FCNs) with different convolutional encoders. Both 2-dimensional and 3D U-Net FCNs were constructed for comparison. Six objective functions were investigated: cross-entropy, Jaccard distance, focal loss, and 3 variations of Tversky distance. The performance of the models was compared using similarity metrics, including pixel accuracy, Jaccard index, Dice similarity coefficient (DSC), 95% Hausdorff distance, relative volume difference, Matthews correlation coefficient, precision, recall, and average symmetrical surface distance. We selected the highest-performing architecture and investigated how the amount of training data, use of skip connections, and data augmentation affected segmentation performance. In addition, we investigated whether segmentation on T1-weighted MRI was possible with FCNs trained on only T2-weighted and T2/T1-weighted image contrast. RESULTS: Overall, an FCN with a DenseNet201 encoder trained via cross-entropy minimization yielded the highest combined segmentation performance. For the 53 3D test MRI scans acquired with T2-weighted or T2/T1-weighted image contrast, the DSCs of the prostate, external urinary sphincter, seminal vesicles, rectum, and bladder were 0.90 ± 0.04, 0.70 ± 0.15, 0.80 ± 0.12, 0.91 ± 0.06, and 0.96 ± 0.04, respectively, after model fine-tuning. For the 5 T1-weighted images, the DSCs of these organs were 0.82 ± 0.07, 0.17 ± 0.15, 0.46 ± 0.21, 0.87 ± 0.06, and 0.88 ± 0.05, respectively. CONCLUSIONS: Machine segmentation of the prostate and surrounding anatomy on 3D MRIs acquired with different pulse sequences for MARS low-dose-rate prostate brachytherapy is possible with a single FCN.

Risk Factors for Local Relapse and Inferior Disease-free Survival After Breast-conserving Management of Breast Cancer: Recursive Partitioning Analysis of 2161 Patients.

BACKGROUND: The purpose of this study was to analyze risk factors for ipsilateral in-breast relapse and inferior disease-free survival (DFS) after standard adjuvant whole-breast radiotherapy (± boost and systemic treatment) as part of a multimodal breast-conserving approach. PATIENTS AND METHODS: Decision trees were built through recursive partitioning analysis (RPA). The median follow-up for all 2161 patients was 114 months (9.5 years). RESULTS: Local relapse in the treated breast was uncommon (actuarial rates after 5 and 10 years were 2.7% and 5.8%, respectively). In RPA, the first split was related to age (52 years), with younger patients having a significantly higher risk of local relapse. The younger patients were stratified further by lymph node ratio (LNR). In patients older than 52 years, lack of endocrine treatment was associated with significantly higher risk. DFS was 80.7% at 10 years. The first split was caused by LNR, and the group with unfavorable LNR (> 0.20) could not be stratified further. Ten-year DFS in this group was as low as 50.6%. Patients with favorable LNR (0-0.20) could be stratified by additional risk factors, in particular primary tumor size. CONCLUSION: RPA is a suitable method to assign patients with early stage breast cancer to different risk groups, both regarding local relapse and DFS. Although age was a major risk factor for local relapse after breast-conserving management, LNR was associated with both endpoints. The systemic treatment approaches used in this study failed to provide satisfactory DFS in patients with LNR > 0.20 and 2 other subgroups.

Radiosensitization of Prostate Cancers In Vitro and In Vivo to Erbium-filtered Orthovoltage X-rays Using Actively Targeted Gold Nanoparticles.

Theoretical investigations suggest that gold nanoparticle (GNP)-mediated radiation dose enhancement and radiosensitization can be maximized when photons interact with gold, predominantly via photoelectric absorption. This makes ytterbium (Yb)-169, which emits photons with an average energy of 93 keV (just above the K-edge of gold), an ideal radioisotope for such purposes. This investigation tests the feasibility of tumor-specific prostate brachytherapy achievable with Yb-169 and actively targeted GNPs, using an external beam surrogate of Yb-169 created from an exotic filter material - erbium (Er) and a standard copper-filtered 250 kVp beam. The current in vitro study shows that treatment of prostate cancer cells with goserelin-conjugated gold nanorods (gGNRs) promotes gonadotropin releasing hormone receptor-mediated internalization and enhances radiosensitivity to both Er-filtered and standard 250 kVp beams, 14 and 10%, respectively. While the degree of GNP-mediated radiosensitization as seen from the in vitro study may be considered moderate, the current in vivo study shows that gGNR treatment plus Er-filtered x-ray irradiation is considerably more effective than radiation treatment alone (p < 0.0005), resulting in a striking reduction in tumor volume (50% smaller) 2 months following treatment. Overall, the current results provide strong evidence for the feasibility of tumor-specific prostate brachytherapy with Yb-169 and gGNRs.

Lower mean heart dose with deep inspiration breath hold-whole breast irradiation compared with brachytherapy-based accelerated partial breast irradiation for women with left-sided tumors.

PURPOSE: For left-sided breast cancer, radiation to the heart is a concern. We present a comparison of mean heart and coronary artery biologically effective dose (BED) between accelerated partial breast irradiation (APBI) and whole breast irradiation with deep inspiration breath-hold technique (DIBH-WBI). METHODS AND MATERIALS: A total of 100 patients with left-sided, early-stage breast cancer were identified. Fifty underwent single-entry catheter-based APBI and 50 underwent DIBH-WBI. The heart, left anterior descending/interventricular branch, left main, and right coronary artery were delineated. BEDs were calculated from APBI treatment plans (34 Gy in 3.4 Gy twice daily fractions) and for 4 separate plans generated for each DIBH-WBI patient: 50 Gy in 25 fractions (50/25), 50/25 + 10/5 boost, 40/15, and 40/15 + 10/5 boost. RESULTS: BED to the heart and coronary vessels were statistically significantly higher with APBI than with any of the DIBH-WBI dose/fractionation schedules. CONCLUSIONS: For women with left-sided early-stage breast cancer, DIBH-WBI resulted in statistically significantly lower mean BED to the heart and coronary vessels compared with APBI. This is likely due to increased physical separation between the heart and tumor bed afforded by the DIBH-WBI technique. Long-term assessment of late effects in these tissues will be required to determine whether these differences are clinically significant.

Articular cartilage scores in cranial cruciate ligament-deficient dogs with or without bucket handle tears of the medial meniscus.

OBJECTIVE: To compare articular cartilage scores in cranial cruciate ligament (CCL)-deficient dogs with or without concurrent bucket handle tears (BHT) of the medial meniscus. STUDY DESIGN: Retrospective case series. ANIMALS: Client-owned dogs treated with arthroscopy and tibial plateau leveling osteotomy or extracapsular repair for complete CCL rupture (290 stifles from 264 dogs). METHODS: Medical records and arthroscopic images were reviewed. Medial femoral condyle (MFC) and medial tibial plateau (MTP) cartilage was scored using the modified Outerbridge scale. Periarticular osteophytosis (PAO) and injury to the medial meniscus were recorded. Data were analyzed using Student's t-tests, Wilcoxon rank-sum test, and Fisher's exact test for changes in the stifle based on meniscal condition, body weight, and duration of lameness. RESULTS: PAO, MFC, and MTP articular cartilage scores were not significantly different in dogs with or without BHT. There were no significant differences in MFC or MTP scores when dogs were evaluated based on bodyweight and the presence or absence of a BHT. However, PAO formation was significantly increased in dogs weighing >13.6 kg and concurrent meniscal injury vs. dogs weighing <13.6 kg and concurrent meniscal injury (P < .001). Significantly more stifles with chronic lameness (40 of 89; 44.9%) had the highest PAO score of 2 reported compared to only 42 of 182 stifles (23.1%) with acute lameness (P < .001). CONCLUSION: The presence of a BHT of the medial meniscus was not associated with more severe arthroscopic articular cartilage lesions in the medial joint compartment at the time of surgery.

The Withers archive: Online availability of rod Wither's data.

The contents of the lab notebooks of H.R. Withers have been digitized and stored as 23 excel files, a total of approximately 45 megabytes. A procedure is described whereby those interested may gain access to the data.

The Limitations of Model-Based Experimental Design and Parameter Estimation in Sloppy Systems.

We explore the relationship among experimental design, parameter estimation, and systematic error in sloppy models. We show that the approximate nature of mathematical models poses challenges for experimental design in sloppy models. In many models of complex biological processes it is unknown what are the relevant physical mechanisms that must be included to explain system behaviors. As a consequence, models are often overly complex, with many practically unidentifiable parameters. Furthermore, which mechanisms are relevant/irrelevant vary among experiments. By selecting complementary experiments, experimental design may inadvertently make details that were ommitted from the model become relevant. When this occurs, the model will have a large systematic error and fail to give a good fit to the data. We use a simple hyper-model of model error to quantify a model's discrepancy and apply it to two models of complex biological processes (EGFR signaling and DNA repair) with optimally selected experiments. We find that although parameters may be accurately estimated, the discrepancy in the model renders it less predictive than it was in the sloppy regime where systematic error is small. We introduce the concept of a sloppy system-a sequence of models of increasing complexity that become sloppy in the limit of microscopic accuracy. We explore the limits of accurate parameter estimation in sloppy systems and argue that identifying underlying mechanisms controlling system behavior is better approached by considering a hierarchy of models of varying detail rather than focusing on parameter estimation in a single model.

HPV status, cancer stem cell marker expression, hypoxia gene signatures and tumour volume identify good prognosis subgroups in patients with HNSCC after primary radiochemotherapy: A multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).

OBJECTIVE: To investigate the impact of the tumour volume, HPV status, cancer stem cell (CSC) marker expression and hypoxia gene signatures, as potential markers of radiobiological mechanisms of radioresistance, in a contemporary cohort of patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received primary radiochemotherapy (RCTx). MATERIALS AND METHODS: For 158 patients with locally advanced HNSCC of the oral cavity, oropharynx or hypopharynx who were treated at six DKTK partner sites, the impact of tumour volume, HPV DNA, p16 overexpression, p53 expression, CSC marker expression and hypoxia-associated gene signatures on outcome of primary RCTx was retrospectively analyzed. The primary endpoint of this study was loco-regional control (LRC). RESULTS: Univariate Cox regression revealed a significant impact of tumour volume, p16 overexpression, and SLC3A2 and CD44 protein expression on LRC. The tumour hypoxia classification showed a significant impact only for small tumours. In multivariate analyses an independent correlation of tumour volume, SLC3A2 expression, and the 15-gene hypoxia signature with LRC was identified (CD44 protein n/a because of no event in the CD44-negative group). Logistic modelling showed that inclusion of CD44 protein expression and p16 overexpression significantly improved the performance to predict LRC at 2years compared to the model with tumour volume alone. CONCLUSIONS: Tumour volume, HPV status, CSC marker expression and hypoxia gene signatures are potential prognostic biomarkers for patients with locally advanced HNSCC, who were treated by primary RCTx. The study also supports that the individual tumour volumes should generally be included in biomarker studies and that panels of biomarkers are superior to individual parameters.

The Withers Archive: online availability of H. Rodney Withers' data.

We have collected lab notebooks from Rod Wither's many years of experimentation, from laboratories in Houston and Los Angeles, as well as from several of his collaborators in the USA and overseas. The contents have been digitized, and in this note we explain the mechanism that has been set up to make the 'Withers Archive' available online.

Computational Modeling of Micrometastatic Breast Cancer Radiation Dose Response.

PURPOSE: Prophylactic cranial irradiation (PCI) involves giving radiation to the entire brain with the goals of reducing the incidence of brain metastasis and improving overall survival. Experimentally, we have demonstrated that PCI prevents brain metastases in a breast cancer mouse model. We developed a computational model to expand on and aid in the interpretation of our experimental results. METHODS AND MATERIALS: MATLAB was used to develop a computational model of brain metastasis and PCI in mice. Model input parameters were optimized such that the model output would match the experimental number of metastases per mouse from the unirradiated group. An independent in vivo-limiting dilution experiment was performed to validate the model. The effect of whole brain irradiation at different measurement points after tumor cells were injected was evaluated in terms of the incidence, number of metastases, and tumor burden and was then compared with the corresponding experimental data. RESULTS: In the optimized model, the correlation between the number of metastases per mouse and the experimental fits was >95. Our attempt to validate the model with a limiting dilution assay produced 99.9% correlation with respect to the incidence of metastases. The model accurately predicted the effect of whole-brain irradiation given 3 weeks after cell injection but substantially underestimated its effect when delivered 5 days after cell injection. The model further demonstrated that delaying whole-brain irradiation until the development of gross disease introduces a dose threshold that must be reached before a reduction in incidence can be realized. CONCLUSIONS: Our computational model of mouse brain metastasis and PCI correlated strongly with our experiments with unirradiated mice. The results further suggest that early treatment of subclinical disease is more effective than irradiating established disease.

Low Cancer Stem Cell Marker Expression and Low Hypoxia Identify Good Prognosis Subgroups in HPV(-) HNSCC after Postoperative Radiochemotherapy: A Multicenter Study of the DKTK-ROG.

PURPOSE: To investigate the impact of hypoxia-induced gene expression and cancer stem cell (CSC) marker expression on outcome of postoperative cisplatin-based radiochemotherapy (PORT-C) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). EXPERIMENTAL DESIGN: Expression of the CSC markers CD44, MET, and SLC3A2, and hypoxia gene signatures were analyzed in the resected primary tumors using RT-PCR and nanoString technology in a multicenter retrospective cohort of 195 patients. CD44 protein expression was further analyzed in tissue microarrays. Primary endpoint was locoregional tumor control. RESULTS: Univariate analysis showed that hypoxia-induced gene expression was significantly associated with a high risk of locoregional recurrence using the 15-gene signature (P = 0.010) or the 26-gene signature (P = 0.002). In multivariate analyses, in patients with HPV16 DNA-negative but not with HPV16 DNA-positive tumors the effect of hypoxia-induced genes on locoregional control was apparent (15-gene signature: HR 4.54, P = 0.006; 26-gene signature: HR 10.27, P = 0.024). Furthermore, MET, SLC3A2, CD44, and CD44 protein showed an association with locoregional tumor control in multivariate analyses (MET: HR 3.71, P = 0.016; SLC3A2: HR 8.54, P = 0.037; CD44: HR 3.36, P = 0.054; CD44 protein n/a because of no event in the CD44-negative group) in the HPV16 DNA-negative subgroup. CONCLUSIONS: We have shown for the first time that high hypoxia-induced gene expression and high CSC marker expression levels correlate with tumor recurrence after PORT-C in patients with HPV16 DNA-negative HNSCC. After validation in a currently ongoing prospective trial, these parameters may help to further stratify patients for individualized treatment de-escalation or intensification strategies. Clin Cancer Res; 22(11); 2639-49. ©2016 AACR.

Ablative Radiotherapy Doses Lead to a Substantial Prolongation of Survival in Patients With Inoperable Intrahepatic Cholangiocarcinoma: A Retrospective Dose Response Analysis.

PURPOSE: Standard therapies for localized inoperable intrahepatic cholangiocarcinoma (IHCC) are ineffective. Advances in radiotherapy (RT) techniques and image guidance have enabled ablative doses to be delivered to large liver tumors. This study evaluated the effects of RT dose escalation in the treatment of IHCC. PATIENTS AND METHODS: Seventy-nine consecutive patients with inoperable IHCC were identified and treated with definitive RT from 2002 to 2014. At diagnosis, the median tumor size was 7.9 cm (range, 2.2 to 17 cm). Seventy patients (89%) received systemic chemotherapy before RT. RT doses were 35 to 100 Gy (median, 58.05 Gy) in three to 30 fractions for a median biologic equivalent dose (BED) of 80.5 Gy (range, 43.75 to 180 Gy). RESULTS: Median follow-up time for patients alive at time of analysis was 33 months (range, 11 to 93 months). Median overall survival (OS) time after diagnosis was 30 months; 3-year OS rate was 44%. Radiation dose was the single most important prognostic factor; higher doses correlated with an improved local control (LC) rate and OS. The 3-year OS rate for patients receiving BED greater than 80.5 Gy was 73% versus 38% for those receiving lower doses (P = .017); 3-year LC rate was significantly higher (78%) after a BED greater than 80.5 Gy than after lower doses (45%, P = .04). BED as a continuous variable significantly affected LC (P = .009) and OS (P = .004). There were no significant treatment-related toxicities. CONCLUSION: Delivery of higher doses of RT improves LC and OS in inoperable IHCC. A BED greater than 80.5 Gy seems to be an ablative dose of RT for large IHCCs, with long-term survival rates that compare favorably with resection.