Prognostic Significance of Immune Cell Infiltration in Muscle-invasive Bladder Cancer Treated with Definitive Chemoradiation: A Secondary Analysis of RTOG 0524 and RTOG 0712.

Chemoradiation therapy (CRT) is a treatment for muscle-invasive bladder cancer (MIBC). Using a novel transcriptomic profiling panel, we validated prognostic immune biomarkers to CRT using 70 pretreatment tumor samples from prospective trials of MIBC (NRG/RTOG 0524 and 0712). Disease-free survival (DFS) and overall survival (OS) were estimated via the Kaplan-Meier method and stratified by genes correlated with immune cell activation. Cox proportional-hazards models were used to assess group differences. Clustering of gene expression profiles revealed that the cluster with high immune cell content was associated with longer DFS (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.26-1.10; p = 0.071) and OS (HR 0.48, 95% CI 0.24-0.97; p = 0.040) than the cluster with low immune cell content. Higher expression of T-cell infiltration genes (CD8A and ICOS) was associated with longer DFS (HR 0.40, 95% CI 0.21-0.75; p = 0.005) and OS (HR 0.49, 95% CI 0.25-0.94; p = 0.033). Higher IDO1 expression (IFNγ signature) was also associated with longer DFS (HR 0.44, 95% CI 0.24-0.88; p = 0.021) and OS (HR 0.49, 95% CI 0.24-0.99; p = 0.048). These findings should be validated in prospective CRT trials that include biomarkers, particularly for trials incorporating immunotherapy for MIBC. PATIENT SUMMARY: We analyzed patient samples from two clinical trials (NRG/RTOG 0524 and 0712) of chemoradiation for muscle-invasive bladder cancer using a novel method to assess immune cells in the tumor microenvironment. Higher expression of genes associated with immune activation and high overall immune-cell content were associated with better disease-free survival and overall survival for patients treated with chemoradiation.

Long-Term Outcomes of a Phase I Trial of Weekly Docetaxel, Total Androgen Blockade, and Image Guided Intensity Modulated Radiation Therapy for Localized High-Risk Prostate Adenocarcinoma.

Purpose: Our purpose was to describe the long-term outcomes seen with the addition of concurrent weekly docetaxel to high-dose intensity modulated radiation (IMRT) to the prostate and androgen deprivation therapy in patients with high-risk nonmetastatic adenocarcinoma of the prostate. Methods and Materials: Nineteen patients with high-risk, localized prostate cancer were treated in a phase I trial with concurrent docetaxel at doses of 10 to 30 mg/m2, in a dose-escalated scheme, in addition to IMRT (77.4 Gy/43 fx) and neoadjuvant and concurrent combined androgen blockade (gonadotropin-releasing hormone agonist and antiandrogen). A gonadotropin-releasing hormone agonist was continued for an additional 24 months post radiation. Kaplan-Meier analysis was used to estimate the survival probabilities. Results: At a median follow-up of 10.5 years, 5-year and 10-year overall survival were found to be 89.5% and 68.4%, respectively. The median metastasis-free survival and progression-free survival were determined to be 11.3 years and 9.0 years, respectively. Conclusions: This regimen produced a 10-year overall survival of 68% with a 10-year metastasis-free survival of 58%. Grade >2 toxicity was minimal. These limited data suggest that the addition of concurrent weekly docetaxel to high-dose IMRT for high-risk prostate cancer warrants further investigation.

The times they are a-changin':Teaching and learning beyond COVID-19.

The COVID-19 pandemic has forced teachers to incorporate many changes to support student learning. In this paper, we present current research focusing on the impact of the changes brought by the pandemic on teachers. Specifically, we discuss the current state of teachers after working the frontline of the pandemic and changes that school leaders and policymakers should consider moving forward. These changes include virtual instruction options for specific groups of students, professional development and support for teachers implementing changes, and being cognizant of the workloads put on teachers. We believe these changes are critical to support student learning, but to also limit teacher attrition.

The Clinical Cell-Cycle Risk (CCR) Score Is Associated With Metastasis After Radiation Therapy and Provides Guidance on When to Forgo Combined Androgen Deprivation Therapy With Dose-Escalated Radiation.

PURPOSE: The clinical cell-cycle risk (CCR) score, which combines the University of California, San Francisco's Cancer of the Prostate Risk Assessment (CAPRA) and the cell cycle progression (CCP) molecular score, has been validated to be prognostic of disease progression for men with prostate cancer. This study evaluated the ability of the CCR score to prognosticate the risk of metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT). METHODS AND MATERIALS: This retrospective, multi-institutional cohort study included men with localized National Comprehensive Cancer Network (NCCN) intermediate-, high-, and very high-risk prostate cancer (N = 741). Patients were treated with dose-escalated RT with or without ADT. The primary outcome was time to metastasis. RESULTS: The CCR score prognosticated metastasis with a hazard ratio (HR) per unit score of 2.22 (95% confidence interval [CI], 1.71-2.89; P < .001). The CCR score better prognosticated metastasis than NCCN risk group (CCR, P < .001; NCCN, P = .46), CAPRA score (CCR, P = .002; CAPRA, P = .59), or CCP score (CCR, P < .001; CCP, P = .59) alone. In bivariable analyses, CCR score remained highly prognostic when accounting for ADT versus no ADT (HR, 2.18; 95% CI, 1.61-2.96; P < .001), ADT duration as a continuous variable (HR, 2.11; 95% CI, 1.59-2.79; P < .001), or ADT given at or below the recommended duration for each NCCN risk group (HR, 2.19; 95% CI, 1.69-2.86; P < .001). Men with CCR scores below or above the multimodality threshold (CCR score, 2.112) had a 10-year risk of metastasis of 3.7% and 21.24%, respectively. Men with below-threshold scores receiving RT alone had a 10-year risk of metastasis of 3.7%, and for men receiving RT plus ADT, the 10-year risk of metastasis was also 3.7%. CONCLUSIONS: The CCR score accurately and precisely prognosticates metastasis and adds clinically actionable information relative to guideline-recommended therapies based on NCCN risk in men undergoing dose-escalated RT with or without ADT. For men with scores below the multimodality threshold, adding ADT may not significantly reduce their 10-year risk of metastasis.

Favorable Trisomies and ETV6-RUNX1 Predict Cure in Low-Risk B-Cell Acute Lymphoblastic Leukemia: Results From Children's Oncology Group Trial AALL0331.

PURPOSE: Children's Oncology Group (COG) AALL0331 tested whether pegaspargase intensification on a low-intensity chemotherapy backbone would improve the continuous complete remission (CCR) rate in a low-risk subset of children with standard-risk B-acute lymphoblastic leukemia (ALL). METHODS: AALL0331 enrolled 5,377 patients with National Cancer Institute standard-risk B-ALL (age 1-9 years, WBC < 50,000/µL) between 2005 and 2010. Following a common three-drug induction, a cohort of 1,857 eligible patients participated in the low-risk ALL random assignment. Low-risk criteria included no extramedullary disease, < 5% marrow blasts by day 15, end-induction marrow minimal residual disease < 0.1%, and favorable cytogenetics (ETV6-RUNX1 fusion or simultaneous trisomies of chromosomes 4, 10, and 17). Random assignment was to standard COG low-intensity therapy (including two pegaspargase doses, one each during induction and delayed intensification) with or without four additional pegaspargase doses at 3-week intervals during consolidation and interim maintenance. The study was powered to detect a 4% improvement in 6-year CCR rate from 92% to 96%. RESULTS: The 6-year CCR and overall survival (OS) rates for the entire low-risk cohort were 94.7% ± 0.6% and 98.7% ± 0.3%, respectively. The CCR rates were similar between arms (intensified pegaspargase 95.3% ± 0.8% v standard 94.0% ± 0.8%; P = .13) with no difference in OS (98.1% ± 0.5% v 99.2% ± 0.3%; P = .99). Compared to a subset of standard-risk study patients given identical therapy who had the same early response characteristics but did not have favorable or unfavorable cytogenetics, outcomes were significantly superior for low-risk patients (CCR hazard ratio 1.95; P = .0004; OS hazard ratio 5.42; P < .0001). CONCLUSION: Standard COG therapy without intensified pegaspargase, which can easily be given as an outpatient with limited toxicity, cures nearly all children with B-ALL identified as low-risk by clinical, early response, and favorable cytogenetic criteria.

Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331.

PURPOSE: Children's Oncology Group (COG) AALL0331 tested whether intensified postinduction therapy that improves survival in children with high-risk B-cell acute lymphoblastic leukemia (ALL) would also improve outcomes for those with standard-risk (SR) ALL. PATIENTS AND METHODS: AALL0331 enrolled 5,377 patients between 2005 and 2010. All patients received a 3-drug induction with dexamethasone, vincristine, and pegaspargase (PEG) and were then classified as SR low, SR average, or SR high. Patients with SR-average disease were randomly assigned to receive either standard 4-week consolidation (SC) or 8-week intensified augmented Berlin-Frankfurt-Münster (BFM) consolidation (IC). Those with SR-high disease were nonrandomly assigned to the full COG-augmented BFM regimen, including 2 interim maintenance and delayed intensification phases. RESULTS: The 6-year event-free survival (EFS) rate for all patients enrolled in AALL0331 was 88.96% ± 0.46%, and overall survival (OS) was 95.54% ± 0.31%. For patients with SR-average disease, the 6-year continuous complete remission (CCR) and OS rates for SC versus IC were 87.8% ± 1.3% versus 89.1% ± 1.2% (P = .52) and 95.8% ± 0.8% versus 95.2% ± 0.8% (P = 1.0), respectively. Those with SR-average disease with end-induction minimal residual disease (MRD) of 0.01% to < 0.1% had an inferior outcome compared with those with lower MRD and no improvement with IC (6-year CCR: SC, 77.5% ± 4.8%; IC, 77.1% ± 4.8%; P = .71). At 6 years, the CCR and OS rates among 635 nonrandomly treated patients with SR-high disease were 85.55% ± 1.49% and 92.97% ± 1.08%, respectively. CONCLUSION: The 6-year OS rate for > 5,000 children with SR ALL enrolled in AALL0331 exceeded 95%. The addition of IC to treatment for patients with SR-average disease did not improve CCR or OS, even in patients with higher MRD, in whom it might have been predicted to provide more value. The EFS and OS rates are excellent for this group of patients with SR ALL, with particularly good outcomes for those with SR-high disease.

S-Glutathionylated Serine Proteinase Inhibitors as Biomarkers for Radiation Exposure in Prostate Cancer Patients.

In biological tissues, radiation causes the formation of reactive oxygen species (ROS), some of which lead to sequential oxidation of certain protein cysteine residues. Resultant cysteinyl radicals are subject to post-translational modification through S-glutathionylation. The present clinical trial was designed to determine if S-glutathionylated serine protease inhibitors (serpins) in blood could be used as biomarkers of exposure to radiation. 56 male prostate cancer patients treated with radiotherapy were enrolled in the trial and levels of S-glutathionylated serpins A1 and A3 were assessed by immunoblotting. Patients were classified into three groups: (1) external beam radiation therapy (EBRT); (2) brachytherapy (BT); (3) both EBRT and BT. Prior to treatment, baseline plasma levels of both unmodified and S-glutathionylated serpins were similar in each group. We identified elevated plasma levels of S-glutathionylated serpin A1 monomer, trimer and serpin A3 monomer in patient blood following radiation. Maximal increased levels of these S-glutathionylated serpins were correlated with increased duration of radiotherapy treatments. We conclude that it is practical to quantify patient plasma S-glutathionylated serpins and that these post-translationally modified proteins are candidate biomarkers for measuring radiation exposure. This provides a platform for use of such biomarkers in trials with the range of drugs that, like radiation, produce ROS.

Public Transit and School Choice in Philadelphia: Exploring Spatial Equity and Social Exclusion.

This paper explores the importance of considering transportation mode when calculating commute time for a child's school choice options. While proponents of school choice argue that students can attend any school that will provide them the best education, several have argued that commute time is as important for families as a school's characteristics. However, research to date models commute time using either distance as a proxy or minutes driving. In Philadelphia, a context where most people use public transportation to work and school, the authors argue that commute time to school must be calculated using this mode of transit. Using geospatial network analyses, the authors create choice sets for each neighborhood public high school. They first calculate the commute time between each zoned public high school and each public high school choice in the city by driving and by using public transportation. These two sets of commute times are then evaluated for the differences. The authors then calculate choice sets based on the average commute time in the city based on both modes of transportation. Finally, they compare the choice sets for each service area for spatial equity of public school quality. Findings indicate that the commute times between driving and public transportation are statistically different. Furthermore, public school choice sets within Philadelphia are spatially equitable, although the overall school quality needs improvement. The paper concludes with policy implications and recommendations for future research.

Report from the SWOG Radiation Oncology Committee: Research Objectives Workshop 2017.

The Radiation Therapy Committee of SWOG periodically evaluates its strategic plan in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2017 Strategic Planning Workshop included leaders in cancer basic sciences, molecular theragnostics, pharmaceutical and technology industries, clinical trial design, oncology practice, and statistical analysis. The committee discussed high-priority research areas, such as optimization of combined modality therapy, radiation oncology-specific drug design, identification of molecular profiles predictive of radiation-induced local or distant tumor responses, and methods for normal tissue-specific mitigation of radiation toxicity. The following concepts emerged as dominant questions ready for national testing: (i) what is the role of radiotherapy in the treatment of oligometastatic, oligorecurrent, and oligoprogressive disease? (ii) How can combined modality therapy be used to enhance systemic and local response? (iii) Can we validate and optimize liquid biopsy and other biomarkers (such as novel imaging) to supplement current response criteria to guide therapy and clinical trial design endpoints? (iv) How can we overcome deficiencies of randomized survival endpoint trials in an era of increasing molecular stratification factors? And (v) how can we mitigate treatment-related side effects and maximize quality of life in cancer survivors? The committee concluded that many aspects of these questions are ready for clinical evaluation and example protocol concepts are provided that could improve rates of cancer cure and quality of survival. Clin Cancer Res; 24(15); 3500-9. ©2018 AACR.

Pretreatment albumin may aid in patient selection for intrahepatic Y-90 microsphere transarterial radioembolization (TARE) for malignancies of the liver.

BACKGROUND: Hepatic malignancies are common including primary malignancies and metastases. Transarterial radioembolization (TARE) is an important treatment option. We reviewed safety and efficacy of (TARE) in our patients to identify factors that may impact treatment outcomes in a heterogeneous population. METHODS: All patients that received TARE at the Medical University of South Carolina from March 2006 through May of 2014 were included. Kaplan-Meier estimates on overall survival (OS) from date of first procedure are reported. Potential prognostic factors for OS were evaluated using log rank tests and Cox proportional hazards models. RESULTS: In the 114 patients that received TARE at our institution, median follow-up was 6.4 months (range, 0-86 months) with the following histologies: colorectal (CR) n=55, hepatocellular (HC) n=20, cholangiocarcinoma (CC) n=16, neuroendocrine (NE) n=12, breast (BR) n=6, other n=5. At least 1 line of prior systemic therapy was noted in 79% of patients. Median OS was significantly better with NE and BR histology, and in those with normal albumin levels. With an albumin >3.4 median OS was 10.3 months, but was only 3.1 months with an albumin <3 g/dL. Grade ≥2 toxicity was observed in 22 patients (19.3%) including 9 (7.9%) with Grade 3 and 1 (0.9%) with Grade 4 toxicity. CONCLUSIONS: TARE is a relatively safe and effective treatment for intrahepatic malignancies. Patients with NE and BR histology as well as those with better hepatic synthetic function were associated with significantly better survival. Our data suggest that patients with albumin below 3 g/dL may not derive significant benefit from TARE.

The impact of metabolic syndrome on outcome and response to neoadjuvant chemoradiation in locally advanced rectal cancer patients.

BACKGROUND AND OBJECTIVES: Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors shown to increase the risk of developing various malignancies, as well as diminish tumor response to conventional therapies. The effects of MetS and its individual components on therapeutic response and treatment-related outcomes were examined in patients with locally advanced rectal cancer (LARC). METHODS: Data was retrospectively collected on LARC patients treated with neoadjuvant chemoradiation (nCRT) and surgery. Medical records were reviewed for patient characteristics, staging, treatment plan, and outcomes. RESULTS: One hundred two patients were included in the study. Patients with HTN had a significantly decreased nCRT response and were four times more likely to experience a poor response to treatment compared to patients without HTN. Additionally, HTN was found to significantly increase the rate of surgical complications. Neither DM nor obesity exhibited any significant effect on therapeutic response or complication rates, either individually or in combination with another risk factor. CONCLUSION: This study demonstrates the importance of considering underlying MetS risk factors, especially HTN, when predicting tumor response in LARC patients undergoing nCRT followed by radical surgery. The results provide support for an increased focus on pre-treatment risk factor control to optimize cancer therapy outcomes.

The impact of surgical diversion before neoadjuvant therapy for rectal cancer.

Up-front fecal diversion can palliate emergent symptoms related to locally advanced rectal cancer (LARC) allowing patients to receive neoadjuvant chemoradiation therapy (nCRT). We analyzed outcomes of pretreatment-diverted LARC patients relative to nondiverted patients to define the impact of this management strategy. We retrospectively collected data on 103 LARC patients treated with nCRT and surgery. Medical records were reviewed for patient characteristics, staging, treatment plan, and outcomes. Thirteen LARC patients underwent pretreatment diversion for urgent symptoms and 90 LARC patients proceeded directly to nCRT. In all, 50 per cent of diverted patients presented with T4 tumor compared with 14 per cent in the nondiverted patients (P = 0.003). Diverted patients experienced a delay in time-to-treatment initiation of 12 days, although this difference was not statistically significant. Similar rates of chemoradiation and surgical toxicities were observed. Even though diverted patients demonstrated less pathologic response to nCRT compared with nondiverted patients (P = 0.04), there was no significant difference in overall survival. In conclusion, our study demonstrates the effectiveness of up-front fecal diversion at managing emergent obstructive symptoms related to advanced rectal cancer without additional complications, allowing patients to proceed with nCRT followed by radical surgery.

Phase 2 trial of induction gemcitabine, oxaliplatin, and cetuximab followed by selective capecitabine-based chemoradiation in patients with borderline resectable or unresectable locally advanced pancreatic cancer.

PURPOSE: To evaluate, in a phase 2 study, the safety and efficacy of induction gemcitabine, oxaliplatin, and cetuximab followed by selective capecitabine-based chemoradiation in patients with borderline resectable or unresectable locally advanced pancreatic cancer (BRPC or LAPC, respectively). METHODS AND MATERIALS: Patients received gemcitabine and oxaliplatin chemotherapy repeated every 14 days for 6 cycles, combined with weekly cetuximab. Patients were then restaged; "downstaged" patients with resectable disease underwent attempted resection. Remaining patients were treated with chemoradiation consisting of intensity modulated radiation therapy (54 Gy) and concurrent capecitabine; patients with borderline resectable disease or better at restaging underwent attempted resection. RESULTS: A total of 39 patients were enrolled, of whom 37 were evaluable. Protocol treatment was generally well tolerated. Median follow-up for all patients was 11.9 months. Overall, 29.7% of patients underwent R0 surgical resection (69.2% of patients with BRPC; 8.3% of patients with LAPC). Overall 6-month progression-free survival (PFS) was 62%, and median PFS was 10.4 months. Median overall survival (OS) was 11.8 months. In patients with LAPC, median OS was 9.3 months; in patients with BRPC, median OS was 24.1 months. In the group of patients who underwent R0 resection (all of which were R0 resections), median survival had not yet been reached at the time of analysis. CONCLUSIONS: This regimen was well tolerated in patients with BRPC or LAPC, and almost one-third of patients underwent R0 resection. Although OS for the entire cohort was comparable to that in historical controls, PFS and OS in patients with BRPC and/or who underwent R0 resection was markedly improved.

Phase I trial of weekly docetaxel, total androgen blockade, and image-guided intensity-modulated radiotherapy for localized high-risk prostate adenocarcinoma.

BACKGROUND: This was a phase I study to find the maximum tolerable dose (MTD) of weekly docetaxel combined with high-dose intensity-modulated radiotherapy (IMRT) and androgen deprivation therapy (ADT). PATIENTS AND METHODS: Men with localized high-risk prostate cancer (HRPC) were treated with weekly docetaxel at 10 to 30 mg/m(2) concurrent with IMRT of 77.4 Gy to the prostate and 45 Gy to the seminal vesicles. ADT consisted of a gonadotropin-releasing hormone agonist (GnRHa) and bicalutamide beginning 2 months before and during chemoradiation. GnRHa was continued for 24 months. RESULTS: Nineteen patients were enrolled. No dose-limiting toxicity (DLT) was seen with docetaxel doses up to 25 mg/m(2). At the 30 mg/m(2) level, 2 of 4 patients experienced DLTs of both grade 3 fatigue and dyspepsia. At 41 months' median follow-up, 2 patients had died--1 from metastatic prostate cancer and the other from heart failure. Two other patients experienced biochemical failure. One patient with bladder invasion at diagnosis experienced late grade 2 urinary hesitancy 9 months after completion of radiotherapy, requiring short-term intermittent catheterization. All patients had erectile dysfunction, but no late toxicities worse than grade 2 were identified. CONCLUSION: Weekly docetaxel may be combined with high-dose IMRT and long-term ADT up to a MTD of 25 mg/m(2). Acute toxicities and long-term side effects of this regimen were acceptable. Future studies evaluating the efficacy of docetaxel, ADT, and IMRT for localized HRPC should use a weekly dose of 25 mg/m(2) when limiting the irradiated volume to the prostate and seminal vesicles.

Adjuvant radiotherapy and lymph node status for pancreatic cancer: results of a study from the Surveillance, Epidemiology, and End Results (SEER) Registry Data.

OBJECTIVES: This study explores the relationship of lymph node ratio (LNR) and radiotherapy (RT) to overall survival (OS) for patients with resected pancreatic cancer. The impact of adjuvant RT, number of lymph nodes (LN) resected, positive LN resected, and disease extension was also evaluated. METHODS: The SEER database from 1998 to 2006 was reviewed, and 3314 patients with nonmetastatic carcinoma of the pancreas, surgical resection, examination of the regional LN, and a survival of >2 months were identified. Of these, 1597 patients received RT. Cox proportional hazards regression models and the logrank test were used to determine whether specific variables were related to OS. RESULTS: Median OS for patients having surgery alone was 14 months (1-y survival 58.1%, 2-y survival 33.6%) and for patients having adjuvant RT was 19 months (1-y survival 73.5%, 2-y survival 41.4%), P<0.001. For patients with LNR of 0%, OS was better compared with patients with any LN involvement, regardless of treatment group. Multivariable analysis found OS significantly related to LNR, total LN resected, positive resected LN, year of diagnosis, and regional extent of disease in patients without adjuvant RT. In patients who received adjuvant RT, OS significance was only persistent for LNR, the total LN resected, and positive resected LN. CONCLUSIONS: A higher LNR was indicative of worse OS in all patients. A strong association with improvement in OS was seen in patients having received adjuvant RT.

Slug expression inhibits calcitriol-mediated sensitivity to radiation in colorectal cancer.

Recently, a reciprocal relationship between calcitriol and epithelial-to-mesenchymal transition has been described. Therefore, we hypothesized that calcitriol (1α,25-dihydroxyvitamin D3) would enhance radiation sensitivity in colorectal cancer regulated by epithelial mesenchymal transition. Vitamin-D receptor, E-cadherin and vimentin protein as well as E-cadherin, Snail and Slug mRNA levels were assessed in a panel of human colorectal cancer cell lines at baseline and in response calcitriol. We defined cell lines as calcitriol sensitive based on demonstrating an enhanced epithelial phenotype with increased E-cadherin, reduced vimentin and decreased expression of Snail and Slug as well as decreased cellular migration in response to calcitriol. In calcitriol sensitive cells, including DLD-1 and HCT116, 24 h calcitriol pre-treatment enhanced the radiation sensitivity by 2.3- and 2.6-fold, respectively, at 4 Gy (P < 0.05). In contrast, SW620 cells with high baseline mesenchymal features including high Slug and vimentin expression with low E-cadherin expression demonstrated no significant radiation sensitizing response to calcitriol treatment. Similarly, transfection of Slug in the calcitriol sensitive colon cancer cell lines, DLD-1 and HCT 116, completely inhibited the radiation sensitizing effect of calcitriol. Collectively, we demonstrate that calcitriol can enhance the therapeutic effects of radiation in colon cancer cells and Slug expression mitigates this observed effect potentially representing an effective biomarker for calcitriol therapy.

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse.

Escape of prostate cancer (PCa) cells from ionizing radiation-induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.

Re-irradiation for salvage of prostate cancer failures after primary radiotherapy.

PURPOSE: To review the literature on use of radiation as a salvage option after local-only failure following initial treatment with radiation. METHODS: PubMed was searched from inception to June 2012 using terms designed to include relevant articles on salvage radiation as a treatment for local-only failures after radiation. RESULTS: Eighteen separate studies were found which demonstrated widely different patient populations, treatment methods, follow-up periods, and reporting. Only one phase II prospective study was found with no randomized controlled trials. Biochemical disease-free survival (bDFS) at four to 5 years ranged from 20 to 75%. Patient selection may have influenced these varying rates since some studies with lower bDFS had higher risk populations. Factors associated with improved bDFS included post-treatment prostate-specific antigen (PSA) nadir of <0.5 ng/mL, pre-salvage PSA <6, Gleason score ≤7, and PSA doubling time (PSADT) >10 months. Overall survival ranged from 54 to 94%, and disease-specific survival ranged from 74 to 100%. The crude rate of grade 3-4 genitourinary toxicities among all studies was 13% (range 0-47%), and the crude rate of grade 3-4 gastrointestinal toxicities was 5% (range 0-20%). Incontinence rates were low among reviewed studies at 4% (range 0-29%). CONCLUSIONS: Brachytherapy represents a reasonable salvage option for patients with local recurrence after initial radiotherapy for prostate cancer. However, rates of toxicities, as in other salvage treatments, can be fairly high, and the likelihood of death from prostate recurrence variable. Prospective studies are needed to better define the efficacy and toxicity of this treatment modality.

Vitamin D3 supplementation, low-risk prostate cancer, and health disparities.

Vitamin D promotes the differentiation of prostate cancer cells, raising the possibility that vitamin D deficiency over time may contribute to the progression from subclinical prostate cancer to clinical disease. Since low-risk prostate cancers are monitored over time in an effort to determine which progress into clinically important, more aggressive cancers, they provide an excellent model in which to study, over an extended period of time, the effects of enhancing vitamin D status and related changes in tumor progression. This is particularly relevant to African-American men, who exhibit a high prevalence of vitamin D deficiency as well as higher incidence of prostate cancer and higher mortality rates from prostate cancer than Caucasians. Our research team has recently completed an open-label clinical trial aimed at assessing the safety and potential efficacy of vitamin D3 supplementation at 4000 international units (IU) per day for one year in subjects diagnosed with early stage, low-risk prostate cancer. The results of this clinical study suggest that supplementation with vitamin D3 at 4000IU per day may benefit patients with early stage, low-risk prostate cancer on active surveillance, because of the improved outcome (a decreased number of positive cores at repeat biopsy) in more than half of the subjects enrolled in the trial. We also observed that, after one year of supplementation, there was no difference in circulating levels of vitamin D between African-American and Caucasian subjects who completed the study. These clinical results also suggest that robust and sustained vitamin D3 supplementation can reduce prostate cancer-related health disparities in African-American men and that these health disparities are at least in part the result of widespread hypovitaminosis D within the African-American population. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Comparison of radiation treatment delivery for pancreatic cancer: Linac intensity-modulated radiotherapy versus helical tomotherapy.

INTRODUCTION: Intensity-modulated radiotherapy (IMRT) has been shown to reduce dose to organs at risk (OAR) while adequately treating tumour volume. This study quantitatively compares the dosimetric differences from step-and-shoot IMRT compared with helical tomotherapy (HT) for pancreatic head cancer. METHODS: Twelve consecutive patients with non-metastatic, stage T3 or T4, unresectable pancreatic head cancer were planned for step-and-shoot IMRT as well as HT. Radiotherapy was planned to deliver 45.9 Gy to the clinical target volume in 30 fractions with an integrated boost to 54 Gy to the gross tumour volume (planning target volume 5400 including a 1-cm set-up margin). The uniformity index (UI) and conformity index (CI) were used to compare the quality of target coverage, while the quality index (QI) compared the dosimetric performance for OAR. RESULTS: Both methods were effective at covering the tumour with no significant difference in UI or CI. However, HT dosimetry exhibited superior sparing of OAR with significantly less stomach (mean QI(StomV30) = 0.84, P = 0.006) and small bowel dosing (mean small bowel QI(SBV30) = 0.84, P = 0.005). HT reduced dose to the kidney receiving the highest dose but the overall volume of kidney receiving 18 Gy was not significantly different between the two systems, indicating that HT spread the dose more uniformly through the kidneys. CONCLUSIONS: Target coverage is equivalent between the two systems; however, HT shows significantly better sparing of the stomach and small bowel. The decreased dose to OAR with HT is likely to improve the therapeutic ratio in the radiotherapy of pancreatic head cancers.