MGMT promoter methylation prediction based on multiparametric MRI via vision graph neural network.

Purpose: Glioblastoma (GBM) is aggressive and malignant. The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter in GBM tissue is considered an important biomarker for developing the most effective treatment plan. Although the standard method for assessing the MGMT promoter methylation status is via bisulfite modification and deoxyribonucleic acid (DNA) sequencing of biopsy or surgical specimens, a secondary automated method based on medical imaging may improve the efficiency and accuracy of those tests. Approach: We propose a deep vision graph neural network (ViG) using multiparametric magnetic resonance imaging (MRI) to predict the MGMT promoter methylation status noninvasively. Our model was compared to the RSNA radiogenomic classification winners. The dataset includes 583 usable patient cases. Combinations of MRI sequences were compared. Our multi-sequence fusion strategy was compared with those using single MR sequences. Results: Our best model [Fluid Attenuated Inversion Recovery (FLAIR), T1-weighted pre-contrast (T1w), T2-weighted (T2)] outperformed the winning models with a test area under the curve (AUC) of 0.628, an accuracy of 0.632, a precision of 0.646, a recall of 0.677, a specificity of 0.581, and an F1 score of 0.661. Compared to the winning models with single MR sequences, our ViG utilizing fused-MRI showed a significant improvement statistically in AUC scores, which are FLAIR (p=0.042), T1w (p=0.017), T1wCE (p=0.001), and T2 (p=0.018). Conclusions: Our model is superior to challenge champions. A graph representation of the medical images enabled good handling of complexity and irregularity. Our work provides an automatic secondary check pipeline to ensure the correctness of MGMT methylation status prediction.

Cascaded mutual enhancing networks for brain tumor subregion segmentation in multiparametric MRI.

Accurate segmentation of glioma and its subregions plays an important role in radiotherapy treatment planning. Due to a very populated multiparameter magnetic resonance imaging image, manual segmentation tasks can be very time-consuming, meticulous, and prone to subjective errors. Here, we propose a novel deep learning framework based on mutual enhancing networks to automatically segment brain tumor subregions. The proposed framework is suitable for the segmentation of brain tumor subregions owing to the contribution of Retina U-Net followed by the implementation of a mutual enhancing strategy between the classification localization map (CLM) module and segmentation module. Retina U-Net is trained to accurately identify view-of-interest and feature maps of the whole tumor (WT), which are then transferred to the CLM module and segmentation module. Subsequently, CLM generated by the CLM module is integrated with the segmentation module to bring forth a mutual enhancing strategy. In this way, our proposed framework first focuses on WT through Retina U-Net, and since WT consists of subregions, a mutual enhancing strategy then further aims to classify and segment subregions embedded within WT. We implemented and evaluated our proposed framework on the BraTS 2020 dataset consisting of 369 cases. We performed a 5-fold cross-validation on 200 datasets and a hold-out test on the remaining 169 cases. To demonstrate the effectiveness of our network design, we compared our method against the networks without Retina U-Net, mutual enhancing strategy, and a recently published Cascaded U-Net architecture. Results of all four methods were compared to the ground truth for segmentation and localization accuracies. Our method yielded significantly (P < 0.01) better values of dice-similarity-coefficient, center-of-mass-distance, and volume difference compared to all three competing methods across all tumor labels (necrosis and non-enhancing, edema, enhancing tumor, WT, tumor core) on both validation and hold-out dataset. Overall quantitative and statistical results of this work demonstrate the ability of our method to both accurately and automatically segment brain tumor subregions.

Automatic inverse treatment planning of Gamma Knife radiosurgery via deep reinforcement learning.

PURPOSE: Several inverse planning algorithms have been developed for Gamma Knife (GK) radiosurgery to determine a large number of plan parameters by solving an optimization problem, which typically consists of multiple objectives. The priorities among these objectives need to be repetitively adjusted to achieve a clinically good plan for each patient. This study aimed to achieve automatic and intelligent priority tuning by developing a deep reinforcement learning (DRL)-based method to model the tuning behaviors of human planners. METHODS: We built a priority-tuning policy network using deep convolutional neural networks. Its input was a vector composed of multiple plan metrics that were used in our institution for GK plan evaluation. The network can determine which tuning action to take based on the observed quality of the intermediate plan. We trained the network using an end-to-end DRL framework to approximate the optimal action-value function. A scoring function was designed to measure the plan quality to calculate the received reward of a tuning action. RESULTS: Vestibular schwannoma was chosen as the test bed in this study. The number of training, validation and testing cases were 5, 5, and 16, respectively. For these three datasets, the average scores of the initial plans obtained with the same initial priority set were 3.63 ± 1.34, 3.83 ± 0.86 and 4.20 ± 0.78, respectively, while they were improved to 5.28 ± 0.23, 4.97 ± 0.44 and 5.22 ± 0.26 through manual priority tuning by human expert planners. Our network achieved competitive results with 5.42 ± 0.11, 5.10 ± 0. 42, 5.28 ± 0.20, respectively. CONCLUSIONS: Our network can generate GK plans of comparable or slightly higher quality than the plans generated by human planners via manual priority tuning for vestibular schwannoma cases. The network can potentially be incorporated into the clinical workflow as planning assistance to improve GK planning efficiency and help to reduce plan quality variation caused by interplanner variability. We also hope that our method can reduce the workload of GK planners and allow them to spend more time on more challenging cases.

Regional Nodal Irradiation for Clinically Node-Positive Breast Cancer Patients With Pathologic Negative Nodes After Neoadjuvant Chemotherapy.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is increasingly used for operable breast cancer (BC). Appropriate radiation therapy (RT) fields (ie, whole breast [WB] ± regional nodal irradiation [RNI]) in patients who were clinically node positive (cN1) but convert to pathologically node negative (ypN0) after NAC are unknown and the subject of the accruing NSABP B-51 trial. We sought to compare outcomes between WB RT with or without RNI following breast conservation and sentinel lymph node biopsy (SLNB) alone in cN1, ypN0 women following NAC. PATIENTS AND METHODS: We identified all BC patients with cN1, ypN0 who underwent NAC followed by lumpectomy and SLNB between 2006 and 2015 in the National Cancer Database. RNI utilization was evaluated using Cochran-Armitage test. Overall survival between WB RT alone versus WB + RNI was compared using Kaplan-Meier with and without propensity score-based weighted adjustment and multivariable (MVA) Cox proportional hazards. RESULTS: From 2006 to 2015, RNI use increased from 48.13% to 62.13% (Pfor trend <.001). The 10-year survival for WB alone versus WB + RNI was 83.6% and 79.5%, respectively (P= .14). On MVA analysis, the addition of RNI compared to WB alone was not associated with a survival benefit (WB vs. WB + RNI: hazard ratio 0.80, 95% confidence interval, 0.58-1.11, P= .19). Results were unchanged after propensity score-based adjustment. CONCLUSION: For women with cN1 BC who convert to ypN0 following NAC and breast conserving surgery with SLNB alone, more extensive RNI may not provide a long-term survival benefit. Prospective validation via the NSABP B-51 trial will be essential.

Brain tumor segmentation using 3D Mask R-CNN for dynamic susceptibility contrast enhanced perfusion imaging.

The segmentation of neoplasms is an important part of radiotherapy treatment planning, monitoring disease progression, and predicting patient outcome. In the brain, functional magnetic resonance imaging (MRI) like dynamic susceptibility contrast enhanced (DSCE) or T1-weighted dynamic contrast enhanced (DCE) perfusion MRI are important tools for diagnosis. They play a crucial role in providing pre-operative assessment of tumor histology, grading, and biopsy guidance. However, the manual contouring of these neoplasms is tedious, expensive, time-consuming, and vulnerable to inter-observer variability. In this work, we propose a 3D mask region-based convolutional neural network (R-CNN) method to automatically segment brain tumors in DSCE MRI perfusion images. As our goal is to simultaneously localize and segment the tumor, our training process contained both a region-of-interest (ROI) localization and regression with voxel-wise segmentation. The combination of classification loss, ROI location and size regression loss, and segmentation loss were used to supervise the proposed network. We retrospectively investigated 21 patients' perfusion images, with between 50 and 70 perfusion time point volumes, a total of 1260 3D volumes. Tumor contours were automatically segmented by our proposed method and compared against other state-of-the-art methods and those delineated by physicians as the ground truth. The results of our method demonstrated good agreement with the ground truth contours. The average DSC, precision, recall, Hausdorff distance, mean surface distance (MSD), root MSD, and center of mass distance were 0.90 ± 0.04, 0.91 ± 0.04, 0.90 ± 0.06, 7.16 ± 5.78 mm, 0.45 ± 0.34 mm, 1.03 ± 0.72 mm, and 0.86 ± 0.91 mm, respectively. These results support the feasibility of our method in accurately localizing and segmenting brain tumors in DSCE perfusion MRI. Our 3D Mask R-CNN segmentation method in DSCE perfusion imaging has great promise for future clinical use.

A preliminary study on a multiresolution-level inverse planning approach for Gamma Knife radiosurgery.

PURPOSE: With many plan variables to determine, manual forward planning for Gamma Knife (GK) radiosurgery is very challenging. Inverse planning eases GK planning by determining the variables via solving an optimization problem. However, due to the vast search space, most inverse planning algorithms, including the one provided in Leksell GammaPlan (LGP) treatment planning system, have to predetermine the isocenter locations using some geometric methods and then optimize the shot shapes and durations at these preselected isocenters. This sequential planning scheme does not necessarily lead to optimal isocenter locations and hence globally optimal plans. In this study, we proposed a multiresolution-level (MRL) inverse planning approach, attempting to approach this large-scale GK optimization problem via an iterative method. METHODS: In our MRL approach, several rounds of optimizations were performed with a progressively increased resolution used for isocenter candidates. At each round, an optimization problem was solved to optimize the beam-on time for each collimator and sector at each isocenter candidate. The isocenters that obtained nonzero beam-on times at the previous round and their neighbors on a finer resolution were used as new isocenter candidates for the next round of optimization. After plan optimization, shot sequencing was performed to group the optimized sectors to deliverable composite shots. RESULTS: We have tested our MRL approach on six GK cases previously treated in our institution. For the five cases that have a single target, with similar target coverage obtained, our MRL inverse planning approach achieved better plan quality compared to manual forward planning and LGP inverse planning, with higher selectivity (0.73 ± 0.07 vs 0.72 ± 0.08 and 0.62 ± 0.10), lower gradient index (2.71 ± 0.25 vs 2.78 ± 0.24 and 3.00 ± 0.29), lower brainstem D0.1cc dose (6.10 ± 4.46 Gy vs 8.87 ± 4.82 Gy and 9.17 ± 3.80 Gy), and shorter total beam-on time (62.1 ± 22.9 min vs 83.6 ± 28.2 min and 70.7 ± 16.7 min). For the case that have six targets, compared with manual planning and LGP inverse planning, our MRL approach achieved higher selectivity (0.68 vs 0.57 and 0.47) and lower gradient index (3.77 vs 4.51 and 5.11). The beam-on time of our plan was slightly longer than manual planning and LGP inverse planning (206.4 min vs 204.7 min and 199.3 min). We have also performed sector duration optimization at the isocenters determined by manual planning or the LGP inverse planning, and the resulting plan qualities were found to be inferior to our MRL approach for all the six cases. CONCLUSIONS: This preliminary study has demonstrated the efficacy and feasibility of our MRL inverse planning approach for GK radiosurgery.

Lung Stereotactic Body Radiation Therapy and Concurrent Immunotherapy: A Multicenter Safety and Toxicity Analysis.

PURPOSE: Radical treatment of metastases with stereotactic body radiation therapy (SBRT) is commonly implemented in patients receiving concurrent immune checkpoint inhibition (ICI), despite limited safety and toxicity data. The purpose of this study was to evaluate the safety and tolerability of lung SBRT with concurrent ICI. METHODS AND MATERIALS: Records from a single academic institution were reviewed to identify patients treated with lung SBRT and concurrent (within 30 days) ICI; a contemporaneous cohort receiving lung SBRT alone was included for reference. Treatment-related adverse effects occurring within 30 days (acute) and 180 days (subacute) of SBRT were evaluated. RESULTS: Our study included 117 patients; 54 received SBRT with concurrent ICI (56 courses, 69 target lesions), and 63 received SBRT alone (68 courses, 79 lesions). Median follow-up was 9.2 months in the SBRT + ICI cohort. Among the patients, 67.9% received ICI monotherapy, 17.9% ICI/chemotherapy, and 14.3% ICI/ICI combinations; 25% received ICI between SBRT fractions, and 42.9% received ICI both before and after SBRT. The risk of grade 3 pneumonitis was higher in the SBRT + ICI versus SBRT alone cohort (10.7% vs 0%, P < .01) and any-grade pneumonitis was similar (33.9% vs 27.9%, SBRT + ICI vs SBRT, P = .47). The risk of any-grade pneumonitis appeared elevated with ICI/ICI combinations (62.5% vs 29.2%). Receipt of ICI, planning treatment volume, and lobes involved in SBRT were linked to high-grade pneumonitis. Subacute grade 3+ adverse effects occurred in 26.8% of SBRT + ICI and 2.9% of SBRT-alone patients. CONCLUSIONS: Overall, concurrent lung SBRT + ICI is safe. Given the clinically meaningful risk of pneumonitis, closer monitoring should be considered for SBRT + ICI patients, especially those receiving radiation therapy with ICI/ICI combinations.

Dosimetric Factors Related to Radiation Necrosis After 5-Fraction Radiosurgery for Patients With Resected Brain Metastases.

PURPOSE: Stereotactic radiosurgery (SRS) is increasingly used in the management of patients with resected brain metastases (rBMs). A significant complication of this therapy can be radiation necrosis (RN). Despite radiation therapy dose de-escalation and the delivery of several rather than a single dose fraction, rates of RN after SRS for rBMs remain high. We evaluated the dosimetric parameters associated with radiographic RN for rBMs. METHODS AND MATERIALS: From 2008 to 2016, 55 rBMs at a single institution that were treated postoperatively with 5-fraction linear accelerator-based SRS (25-35 Gy) with minimum 3 months follow-up were evaluated. For each lesion, variables recorded included radiation therapy dose to normal brain, location and magnitude of hotspots, clinical target volume (CTV), and margin size. Hotspot location was stratified as within the tumor bed alone (CTV) or within the planning target volume (PTV) expansion margin volume (PTV minus CTV). Cumulative incidence with competing risks was used to estimate rates of RN and local recurrence. Optimal cut-points predicting for RN for hotspot magnitude based on location were identified via maximization of the log-rank test statistic. RESULTS: Median age for all patients was 58.5 years. For all targets, the median CTV was 17.53 cm3, the median expansion margin to PTV was 2 mm, and the median max hotspot was 111%. At 1 year, cumulative incidence of radiographic RN was 18.2%. Univariate analysis showed that max hotspots with a hazard ratio of 3.28 (P = .045), hotspots within the PTV expansion margin with relative magnitudes of 105%, 110%, and 111%, and an absolute dose of 33.5 Gy predicted for RN (P = .029, P = .04, P = .038, and P = .0488, respectively), but hotspots within the CTV did not. CONCLUSIONS: To our knowledge, this is the first study that investigated dosimetric factors that predict for RN after 5-fraction hypofractionated SRS for rBM. Hotspot location and magnitude appear important for predicting RN risk, thus these parameters should be carefully considered during treatment planning.

Impact of Regional Nodal Irradiation and Hypofractionated Whole-Breast Radiation on Long-Term Breast Retraction and Poor Cosmetic Outcome in Breast Cancer Survivors.

PURPOSE: We performed a prospective longitudinal study to determine predictors of long-term breast asymmetry in breast cancer patients treated with breast-conserving surgery and whole-breast external-beam radiotherapy (XRT). PATIENTS AND METHODS: A total of 109 patients with stage 0 to III breast cancer treated with breast-conserving surgery followed by conventional (50 Gy plus boost) or hypofractionated (39.9 Gy with simultaneous integrated boost of 48 Gy) XRT were enrolled onto 2 studies of XRT-induced skin toxicity before (baseline), during, and 1 year after XRT. Using baseline and 1-year post-XRT photographs, breast asymmetry was objectively quantified by calculating the percentage breast retraction assessment (pBRA), with larger values indicating more asymmetry. Skin thickness ratio (STRA) values were calculated using ultrasound images. Univariate and multivariate analyses were conducted to determine the relationship among STRA-, patient-, tumor-, and treatment-related factors, and pBRA. RESULTS: Seventy-one patients (65%) had more breast asymmetry (positive change in pBRA) 1 year after XRT relative to baseline. Only pre-XRT STRA was associated with a higher pre-XRT baseline pBRA in multivariate analysis (P = .02). Larger breast volume, baseline pBRA, conventionally fractionated (vs. hypofractionated) XRT, supraclavicular nodal irradiation, and higher STRA at 1 year predicted for higher long-term pBRA in the multivariate model (all P < .05). Breast volume and supraclavicular nodal irradiation were associated with the largest changes in breast asymmetry (all P < .05). CONCLUSION: This prospective longitudinal study confirmed the known impact of breast volume, surgery, and XRT on breast asymmetry. We also found that supraclavicular nodal irradiation and conventionally fractionated XRT are associated with worse cosmetic outcome 1 year after XRT.

Full axillary lymph node dissection and increased breast epidermal thickness 1 year after radiation therapy for breast cancer.

BACKGROUND: We previously reported a prospective study showing axillary lymph node dissection (ALND) is associated with increased breast skin thickening during and 6 weeks post-radiation therapy (RT), and now report ALND's long-term impact at 1 year. METHODS: Among 66 women who received whole breast RT after lumpectomy, objective ultrasound measurements of epidermal thickness over four quadrants of the treated breast were measured at five time points: before RT, week 6 of RT, and 6 weeks, 6 months, and 1 year post-RT. Skin thickness ratio (STRA) was generated by normalizing for corresponding measurements of the contralateral breast. RESULTS: A total of 2,436 ultrasound images were obtained. Among 63 women with evaluable data at 1 year, mean STRA significantly increased at 6 months (absolute mean increase of 65%, SD 0.054), and remained elevated at 1 year post-RT (absolute mean increase of 44%, SD 0.048). In multivariable analysis, ALND compared to sentinel lymph node biopsy, longer interval between surgery and RT, increased baseline STRA, and Caucasian race predicted for more severe changes in STRA at 1 year compared to baseline (all P < .05). CONCLUSIONS: In the setting of whole breast RT, our findings suggest that ALND has long-term repercussions on breast skin thickening.

Targeted sequencing and intracranial outcomes of patients with lung adenocarcinoma brain metastases treated with radiotherapy.

BACKGROUND: Treatment for advanced lung adenocarcinoma (AC) has become increasingly personalized based on molecular results. However, for patients with AC brain metastases (BMs), intracranial outcomes based on molecular subtype and the frequency of molecular aberrations are less well defined. This study sought to report targeted next-generation sequencing results and investigate molecularly based outcomes for patients with AC-BMs treated with radiotherapy. METHODS: The records of 132 patients with AC-BMs treated at Emory University from September 2008 to August 2016 with successful next-generation sequencing were reviewed. Rates of local disease recurrence, distant brain failure (DBF), and salvage whole-brain radiotherapy (WBRT) were estimated using cumulative incidence with competing risk analysis. Univariate and multivariate analyses were performed. RESULTS: The most common aberrations included tumor protein 53 (TP53) (60%), KRAS (29%), epidermal growth factor receptor (EGFR) (20.5%), phosphatase and tensin homolog (PTEN) loss (15.5%), and MET amplification (13%). The majority of patients (62%) were treated with stereotactic radiosurgery alone. In these patients, KRAS mutation, anaplastic lymphoma kinase (ALK) rearrangement, and having ≥ 6 BMs were associated with an increased risk of salvage WBRT (P < .05). KRAS mutation remained significant for an increased risk of salvage WBRT when compared with EGFR/ALK/KRAS-negative patients (hazard ratio, 5.17; P < .05), despite a similar risk of DBF. PTEN loss was associated with increased risk of DBF (P < .05), whereas EGFR and ALK aberrations were associated with a decreased risk of local disease recurrence (P < .05). CONCLUSIONS: The results of the current study quantified the frequency of genetic aberrations in patients with AC-BMs and demonstrated their association with intracranial outcomes. In particular, a cohort of patients with KRAS mutations and ≥6 BMs were identified to be at high risk of requiring salvage WBRT after undergoing upfront stereotactic radiosurgery.

The role of postmastectomy radiotherapy in women with pathologic T3N0M0 breast cancer.

BACKGROUND: The authors determined the impact of postmastectomy radiotherapy (PMRT) on overall survival (OS) among patients with pT3N0M0 breast cancer in the National Cancer Data Base. METHODS: A total of 3437 patients with pT3N0M0 breast cancer who initially were treated with mastectomy between 2003 and 2011 were identified. Of these women, 1644 (47.8%) received PMRT (67% treated with chest wall RT alone and 33% treated with chest wall and regional lymph node irradiation). Univariable and multivariable analyses were conducted to identify characteristics associated with PMRT and OS. In addition, propensity score matching and interaction effect testing also were performed. RESULTS: PMRT was associated with age <40 years, private insurance coverage, treatment facility location within 10 miles of the patient's home zip code, Charlson-Deyo comorbidity score of 0, tumor size ≥7 cm, and treatment with chemotherapy or hormone therapy (all P<.05). PMRT was associated with improved 5-year OS (86.3% for patients treated with PMRT vs 66.4% for patients not treated with PMRT; P<.01). In addition to PMRT (hazard ratio, 0.72; 95% confidence interval, 0.59-0.87 [P<.01]), age ≤50 years, treatment at an academic/research program, Charlson-Deyo comorbidity score of 0, tumor size <7 cm, chemotherapy receipt, and hormone therapy receipt were associated with improved OS on multivariable analyses (all P<.05). Interaction testing found that PMRT improved OS independent of age, facility type, Charlson-Deyo comorbidity score, tumor grade and size, surgical margin status, and receipt of chemotherapy or hormone therapy (all P>.1). Finally, propensity score matching analysis confirmed the impact of PMRT on OS (P = .02). It is interesting to note that regional lymph node irradiation did not improve OS versus chest wall RT alone (P = .09). CONCLUSIONS: Among patients with pT3N0M0 breast cancer in the National Cancer Data Base, PMRT was found to be associated with improved OS regardless of surgical margin status, tumor size, and receipt of systemic therapy. Cancer 2017;123:2829-39. © 2017 American Cancer Society.

Benefit of adjuvant radiotherapy after breast-conserving therapy among elderly women with T1-T2N0 estrogen receptor-negative breast cancer.

BACKGROUND: The purpose of the current study was to evaluate the impact of radiotherapy (RT) among women aged ≥ 70 years with T1-2N0 estrogen receptor (ER)-negative breast cancer using Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked data. METHODS: The study included 3432 women, 2850 of whom received and 582 of whom did not receive RT after breast-conserving surgery. Outcomes were estimated by the cumulative incidence method and compared with the Gray test. The Fine and Gray subdistribution hazard regression models were used to assess the impact of RT and other variables. RESULTS: Women who received RT were more commonly aged <75 years (42% vs 16%), had T1 tumors (78% vs 65%), ductal carcinoma histology (91% vs 88%), a Charlson-Deyo Comorbidity Index of 0 (41% vs 25%), and had received chemotherapy (29% vs 12%). The 5-year cumulative incidence of mastectomy and breast cancer-specific death for patients who received versus those did not receive adjuvant RT was 4.9% and 8.3% versus 10.8% and 24.1%, respectively (P<.001). On multivariable analysis, the omission of RT was found to be an independent predictor of an increased risk of mastectomy (hazard ratio, 2.33; 95% confidence interval, 1.56-3.49). Among women aged ≥ 80 years or with T1N0 tumors, the mastectomy incidence with or without receipt of RT was 3.4% vs. 6.9%, and 5.3% vs 7.7%, respectively. CONCLUSIONS: The use of adjuvant RT after breast-conserving surgery in older women with T1-2N0 estrogen receptor-negative breast cancer is associated with a reduced incidence of future mastectomy and breast cancer death. The magnitude of benefit may be small for women aged ≥80 years or those with T1 tumors. Cancer 2016;122:3059-3068. © 2016 American Cancer Society.

Silencing CDK4 radiosensitizes breast cancer cells by promoting apoptosis.

BACKGROUND: The discovery of molecular markers associated with various breast cancer subtypes has greatly improved the treatment and outcome of breast cancer patients. Unfortunately, breast cancer cells acquire resistance to various therapies. Mounting evidence suggests that resistance is rooted in the deregulation of the G1 phase regulatory machinery. METHODS: To address whether deregulation of the G1 phase regulatory machinery contributes to radiotherapy resistance, the MCF10A immortalized human mammary epithelial cell line, ER-PR-Her2+ and ER-PR-Her2- breast cancer cell lines were irradiated. Colony formation assays measured radioresistance, while immunocytochemistry, Western blots, and flow cytometry measured the cell cycle, DNA replication, mitosis, apoptosis, and DNA breaks. RESULTS: Molecular markers common to all cell lines were overexpressed, including cyclin A1 and cyclin D1, which impinge on CDK2 and CDK4 activities, respectively. We addressed their potential role in radioresistance by generating cell lines stably expressing small hairpin RNAs (shRNA) against CDK2 and CDK4. None of the cell lines knocked down for CDK2 displayed radiosensitization. In contrast, all cell lines knocked down for CDK4 were significantly radiosensitized, and a CDK4/CDK6 inhibitor sensitized MDA-MB-468 to radiation induced apoptosis. Our data showed that silencing CDK4 significantly increases radiation induced cell apoptosis in cell lines without significantly altering cell cycle progression, or DNA repair after irradiation. Our results indicate lower levels of phospho-Bad at ser136 upon CDK4 silencing and ionizing radiation, which has been shown to signal apoptosis. CONCLUSION: Based on our data we conclude that knockdown of CDK4 activity sensitizes breast cancer cells to radiation by activating apoptosis pathways.

Matched cohort analysis of outcomes of definitive radiotherapy for prostate cancer in human immunodeficiency virus-positive patients.

PURPOSE: To compare the biochemical outcome and toxicity scores of men with human immunodeficiency virus (HIV) and prostate cancer with a matched control population with negative or unknown HIV status when treated with external-beam radiotherapy (EBRT). METHODS AND MATERIALS: A single-institution database of men with prostate cancer treated with EBRT from 1999 to 2009 was reviewed. Thirteen men with HIV were identified and matched to 2 control patients according to age, race, T stage, prostate-specific antigen level, Gleason score, RT dose, intensity-modulated RT vs. three-dimensional conformal RT, and whole-pelvis vs. prostate-only RT, for a total of 39 cases. The median follow-up time was 39 months (range, 3-110 months). RESULTS: The 4-year biochemical failure (BF)-free survival rate was 87% in the HIV-positive group vs. 89% in the controls (p = 0.94). Pre- and post-RT viral loads were found to be predictive of BF (p = 0.04 and p = 0.04, respectively). No men with HIV died, whereas 2 in the control group died of causes unrelated to prostate cancer. Acute and chronic genitourinary and gastrointestinal toxicity were less in the HIV-positive patients than in controls (p < 0.001, p < 0.001, p = 0.003, and p < 0.001, respectively). The HIV-positive men experienced an average decline in CD4 count of 193 cells/mm(3). CONCLUSIONS: Our findings suggest that men with HIV treated with EBRT have a similar risk of BF; however, high viral loads may contribute to an increased risk. This analysis supports that HIV-positive men with prostate cancer can be treated with definitive EBRT with similar disease control and toxicity outcomes as in the general population.

Does the addition of involved field radiotherapy to high-dose chemotherapy and stem cell transplantation improve outcomes for patients with relapsed/refractory Hodgkin lymphoma?

PURPOSE: To evaluate the value of adding involved field radiotherapy (IFRT) to patients with relapsed/refractory Hodgkin lymphoma (HL) undergoing high-dose chemotherapy (HDCT) and stem cell transplantation (SCT). METHODS AND MATERIALS: Ninety-two patients with relapsed/refractory HL undergoing HDCT and SCT from 1995 to 2008 were analyzed in a case-control design. Forty-six HL patients treated with IFRT within 2 months of SCT were matched to 46 HL patients who did not receive IFRT based on age, stage at relapse, timing of relapse, histology, and year of SCT. All were evaluated for response, survival, and toxicity with a median followup of 63.5 months. RESULTS: There was a trend for better disease control in patients receiving IFRT. Specifically, 10/46 IFRT patients (22%) relapsed/progressed after SCT compared with 17/46 control patients (37%). Of the failures after IFRT, 70% were inside the radiation field, all in sites of bulky disease. In patients with nonbulky disease, IFRT also resulted in significantly improved outcomes (failure rate 6% vs. 33%, respectively). When stratified by disease bulk, the use of IFRT was found to significantly improve DFS (p=0.032), but did not affect OS. In addition, IFRT and nonbulky disease were found to be positive prognostic indicators for DFS with hazard ratios of 0.357 (p=0.032) and 0.383 (p=0.034), respectively. Grade IV/V toxicities were significantly higher in the IFRT vs. non-IFRT group (28% vs. 2%; p<0.001), observed only in patients receiving a busulfan-based conditioning regimen. CONCLUSION: Patients with refractory or relapsed HL undergoing HDCT and SCT have a high risk of relapse in sites of prior disease involvement, especially in sites of bulky disease. The use of IFRT is associated with a lower risk of disease progression in these sites; however bulky disease sites are still difficult to control. Toxicity risk is significant, particularly when busulfan-based conditioning is combined with IFRT, and alternative chemotherapy conditioning regimens should be considered.

Value of PET restaging after chemotherapy for non-Hodgkin's lymphoma: implications for consolidation radiotherapy.

PURPOSE/OBJECTIVE: Patients treated for non-Hodgkin's Lymphoma (NHL) frequently are restaged for response using positron emission tomography (PET) scanning. This study investigates the role of subsequent consolidation radiation therapy (CRT) based on PET response to chemotherapy. MATERIALS/METHODS: An IRB-approved database was queried for patients who underwent PET scans after chemotherapy for NHL between 1995 and 2004; 77 patients were identified. To determine benefit of CRT, overall survival and local control were assessed with median follow-up of 39.8 months (range, 2-125 months). RESULTS: Median age of patients was 53 (range, 18-82 years). Multivariate analysis adjusted for age, indolent vs. aggressive histology, and time from chemotherapy to PET revealed PET positive scans (RR = 30.5; 95%CI = 5.9, 156.4), lack of RT (RR = 5.25; 95%CI = 1.26, 21.79), and Stage III/IV presentation (RR = 4.35; 95%CI = 1.03, 20) predicted increased likelihood of recurrence. Patients with positive PET scans after chemotherapy had significantly higher risk of relapse than those with negative scans (58.1% vs. 15.2%; p < 0.0001), although not everyone with positive scans recurred. Patients with positive PET scans receiving RT were not protected from relapse (63.2% relapse with RT, 50% relapse without RT; p = 0.71); in fact, over half the relapses in patients receiving RT for persistently positive PET scans were in-field. Crude 2 year OS was significantly different between PET positive and PET negative cohorts (p < 0.01). CONCLUSIONS: While RT may control relapse in PET negative patients, NHL patients who remain PET positive after chemotherapy are not well managed by RT alone.

Refractory or relapsed Hodgkin's disease and non-Hodgkin's lymphoma: optimizing involved-field radiotherapy in transplant patients.

UNLABELLED: This study assessed efficacy, optimal dosage and timing, and toxicity of involved-field radiotherapy used in conjunction with high-dose chemotherapy and stem cell transplantation for patients with refractory/relapsed Hodgkin's disease and non-Hodgkin's lymphoma. METHODS AND MATERIALS: 306 patients with refractory or relapsed Hodgkin's disease and non-Hodgkin's lymphoma were analyzed. Forty-one patients underwent involved-field radiotherapy in conjunction with high-dose chemotherapy and bone marrow or peripheral stem cell transplantation. Thirty-three patients received involved-field radiotherapy prior to stem cell transplantation directed at symptomatic and/or bulky sites; eight patients received involved-field radiotherapy after stem cell transplantation directed at sites of persistent disease. The other 265 patients with refractory/relapsed non-Hodgkin's lymphoma and Hodgkin's disease received high-dose chemotherapy/stem cell transplantation, but not involved-field radiotherapy. Data were analyzed using Cox proportional hazards regression to determine the risk of death among patients treated with stem cell transplantation compared with that among patients treated with stem cell transplantation and involved-field radiotherapy. RESULTS: There were 124 deaths during the follow-up period, including 17% of the patients treated with involved-field radiotherapy and 44.2% of the patients receiving chemotherapy without involved-field radiotherapy. Multivariate analysis found that patients who did not receive involved-field radiotherapy were 2.09 times more likely to die during the follow-up period than patients who received involved-field radiotherapy (P = 0.066; adjusted for age, stem cell transplantation type, stage I/II vs stage III/IV, refractory vs relapsed, and Hodgkin's disease vs non-Hodgkin's lymphoma). When patients were treated with involved-field radiotherapy prior to stem cell transplantation, 27 (79.4%) of the 34 patients achieved local control; when involved-field radiotherapy followed stem cell transplantation, 6 (85.7%) of the 7 patients experienced local control. Timing of involved-field radiotherapy prior to or following stem cell transplantation did not affect patient survival. Five of the 41 patients treated with involved-field radiotherapy developed toxicity subsequent to treatment. All but one of these patients had been treated with doses greater than 30 Gy. CONCLUSIONS: Although of borderline significance in this small sample, results of this study suggest that patients who receive involved-field radiotherapy in conjunction with stem cell transplantation may have increased survival when compared with patients who do not receive involved-field radiotherapy. Further follow-up of this cohort is necessary to confirm these findings.

Finger extensor variability in TMS parameters among chronic stroke patients.

BACKGROUND: This study determined the reliability of topographic motor cortical maps and MEP characteristics in the extensor digitorum communis (EDC) evoked by single-pulse TMS among patients with chronic stroke. METHODS: Each of ten patients was studied on three occasions. Measures included location of the EDC hotspot and center of gravity (COG), threshold of activation and average amplitude of the hotspot, number of active sites, map volume, and recruitment curve (RC) slope. RESULTS: Consistent intrahemispheric measurements were obtained for the three TMS mapping sessions for all measured variables. No statistically significant difference was observed between hemispheres for the number of active sites, COG distance or the RC slope. The magnitude and range of COG movement between sessions were similar to those reported previously with this muscle in able-bodied individuals. The average COG movement over three sessions in both hemispheres was 0.90 cm. The average COG movement in the affected hemisphere was 1.13 (+/- 0.08) cm, and 0.68 (+/- 0.04) cm) for the less affected hemisphere. However, significant interhemispheric variability was seen for the average MEP amplitude, normalized map volume, and resting motor threshold. CONCLUSION: The physiologic variability in some TMS measurements of EDC suggest that interpretation of TMS mapping data derived from hemiparetic patients in the chronic stage following stroke should be undertaken cautiously. Irrespective of the muscle, potential causes of variability should be resolved to accurately assess the impact of pharmacological or physical interventions on cortical organization as measured by TMS among patients with stroke.

Management of xerostomia related to radiotherapy for head and neck cancer.

Xerostomia is a permanent and devastating sequela of head and neck irradiation, and its consequences are numerous. Pharmaceutical therapy attempts to preserve or salvage salivary gland function through systemic administration of various protective compounds, most commonly amifostine (Ethyol) or pilocarpine. When these agents are ineffective or the side effects too bothersome, patients often resort to palliative care, for example, with tap water, saline, bicarbonate solutions, mouthwashes, or saliva substitutes. A promising surgical option is the Seikaly-Jha procedure, a method of preserving a single submandibular gland by surgically transferring it to the submental space before radiotherapy. Improved radiation techniques, including intensity-modulated radiotherapy and tomotherapy, allow more selective delivery of radiation to defined targets in the head and neck, preserving normal tissue and the salivary glands. Acupuncture may be another option for patients with xerostomia. All of these therapies need to be further studied to establish the most effective protocol to present to patients before radiotherapy has begun.