An interdisciplinary consensus on the management of brain metastases in patients with renal cell carcinoma.

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.

Comparison of setup accuracy and efficiency between the Klarity system and BodyFIX system for spine stereotactic body radiation therapy.

BACKGROUND: Spine stereotactic body radiation therapy (SBRT) uses highly conformal dose distributions and sharp dose gradients to cover targets in proximity to the spinal cord or cauda equina, which requires precise patient positioning and immobilization to deliver safe treatments. AIMS: Given some limitations with the BodyFIX system in our practice, we sought to evaluate the accuracy and efficiency of the Klarity SBRT patient immobilization system in comparison to the BodyFIX system. METHODS: Twenty-three patients with 26 metastatic spinal lesions (78 fractions) were enrolled in this prospective observational study with one of two systems - BodyFIX (n = 11) or Klarity (n = 12). All patients were initially set up to external marks and positioned to match bony anatomy on ExacTrac images. Table corrections given by ExacTrac during setup and intrafractional monitoring and deviations from pre- and posttreatment CBCT images were analyzed. RESULTS: For initial setup accuracy, the Klarity system showed larger differences between initial skin mark alignment and the first bony alignment on ExacTrac than BodyFIX, especially in the vertical (mean [SD] of 5.7 mm [4.1 mm] for Klarity vs. 1.9 mm [1.7 mm] for BodyFIX, p-value < 0.01) and lateral (5.4 mm [5.1 mm] for Klarity vs. 3.2 mm [3.2 mm] for BodyFIX, p-value 0.02) directions. For set-up stability, no significant differences (all p-values > 0.05) were observed in the maximum magnitude of positional deviations between the two systems. For setup efficiency, Klarity system achieved desired bony alignment with similar number of setup images and similar setup time (14.4 min vs. 15.8 min, p-value = 0.41). For geometric uncertainty, systematic and random errors were found to be slightly less with Klarity than with BodyFIX based on an analytical calculation. CONCLUSION: With image-guided correction of initial alignment by external marks, the Klarity system can provide accurate and efficient patient immobilization. It can be a promising alternative to the BodyFIX system for spine SBRT while providing potential workflow benefits depending on one's practice environment.

Additive Value of Magnetic Resonance Simulation Before Chemoradiation in Evaluating Treatment Response and Pseudoprogression in High-Grade Gliomas.

PURPOSE: A dedicated magnetic resonance imaging simulation (MRsim) for radiation treatment (RT) planning in patients with high-grade glioma (HGG) can detect early radiologic changes, including tumor progression after surgery and before standard of care chemoradiation. This study aimed to determine the effect of using postoperative magnetic resonance imaging (MRI) versus MRsim as the baseline for response assessment and reporting pseudoprogression on follow-up imaging at 1 month (FU1) after chemoradiation. METHODS AND MATERIALS: Histologically confirmed patients with HGG were planned for 6 weeks of RT in a prospective study for adaptive RT planning. All patients underwent postoperative MRI, MRsim, and follow-up MRI scans every 2 to 3 months. Tumor response was assessed by 3 independent blinded reviewers using Response Assessment in Neuro-Oncology criteria when baseline was either postoperative MRI or MRsim. Interobserver agreement was calculated using Light's kappa. RESULTS: Thirty patients (median age, 60.5 years; IQR, 54.5-66.3) were included. Median interval between surgery and RT was 34 days (IQR, 27-41). Response assessment at FU1 differed in 17 patients (57%) when the baseline was postoperative MRI versus MRsim, including true progression versus partial response or stable disease in 11 (37%) and stable disease versus partial response in 6 (20%) patients. True progression was reported in 19 patients (63.3%) on FU1 when the baseline was postoperative MRI versus 8 patients (26.7%) when the baseline was MRsim (P = .004). Pseudoprogression was observed at FU1 in 12 (40%) versus 4 (13%) patients, when the baseline was postoperative MRI versus MRsim (P = .019). Interobserver agreement between observers was moderate (κ = 0.579; P < .001). CONCLUSIONS: Our study demonstrates the value of acquiring an updated MR closer to RT in patients with HGG to improve response assessment, and accuracy in evaluation of pseudoprogression even at the early time point of first follow-up after RT. Earlier identification of patients with true progression would enable more timely salvage treatments including potential clinical trial enrollment to improve patient outcomes.

Outcomes and Pattern of Care for Spinal Myxopapillary Ependymoma in the Modern Era-A Population-Based Observational Study.

(1) Background: Myxopapillary ependymoma (MPE) is a rare tumor of the spine, typically slow-growing and low-grade. Optimal management strategies remain unclear due to limited evidence given the low incidence of the disease. (2) Methods: We analyzed data from 1197 patients with spinal MPE from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2020). Patient demographics, treatment modalities, and survival outcomes were examined using statistical analyses. (3) Results: Most patients were White (89.9%) with a median age at diagnosis of 42 years. Surgical resection was performed in 95% of cases. The estimated 10-year overall survival was 91.4%. Younger age (hazard ratio (HR) = 1.09, p < 0.001) and receipt of surgery (HR = 0.43, p = 0.007) were associated with improved survival. Surprisingly, male sex was associated with worse survival (HR = 1.86, p = 0.008) and a younger age at diagnosis compared to females. (4) Conclusions: This study, the largest of its kind, underscores the importance of surgical resection in managing spinal MPE. The unexpected association between male sex and worse survival warrants further investigation into potential sex-specific pathophysiological factors influencing prognosis. Despite limitations, our findings contribute valuable insights for guiding clinical management strategies for spinal MPE.

Response of treatment-naive brain metastases to stereotactic radiosurgery.

With improvements in survival for patients with metastatic cancer, long-term local control of brain metastases has become an increasingly important clinical priority. While consensus guidelines recommend surgery followed by stereotactic radiosurgery (SRS) for lesions >3 cm, smaller lesions (≤3 cm) treated with SRS alone elicit variable responses. To determine factors influencing this variable response to SRS, we analyzed outcomes of brain metastases ≤3 cm diameter in patients with no prior systemic therapy treated with frame-based single-fraction SRS. Following SRS, 259 out of 1733 (15%) treated lesions demonstrated MRI findings concerning for local treatment failure (LTF), of which 202 /1733 (12%) demonstrated LTF and 54/1733 (3%) had an adverse radiation effect. Multivariate analysis demonstrated tumor size (>1.5 cm) and melanoma histology were associated with higher LTF rates. Our results demonstrate that brain metastases ≤3 cm are not uniformly responsive to SRS and suggest that prospective studies to evaluate the effect of SRS alone or in combination with surgery on brain metastases ≤3 cm matched by tumor size and histology are warranted. These studies will help establish multi-disciplinary treatment guidelines that improve local control while minimizing radiation necrosis during treatment of brain metastasis ≤3 cm.

Advances in the management of spinal metastases: what the radiologist needs to know.

Spine is the most frequently involved site of osseous metastases. With improved disease-specific survival in patients with Stage IV cancer, durability of local disease control has become an important goal for treatment of spinal metastases. Herein, we review the multidisciplinary management of spine metastases, including conventional external beam radiation therapy, spine stereotactic radiosurgery, and minimally invasive and open surgical treatment options. We also present a simplified framework for management of spinal metastases used at The University of Texas MD Anderson Cancer Center, focusing on the important decision points where the radiologist can contribute.

Multidisciplinary management of spinal metastases: what the radiologist needs to know.

The modern management of spinal metastases requires a multidisciplinary approach that includes radiation oncologists, surgeons, medical oncologists, and diagnostic and interventional radiologists. The diagnostic radiologist can play an important role in the multidisciplinary team and help guide assessment of disease and selection of appropriate therapy. The assessment of spine metastases is best performed on MRI, but imaging from other modalities is often needed. We provide a review of the clinical and imaging features that are needed by the multidisciplinary team caring for patients with spine metastases and stress the importance of the spine radiologist taking responsibility for synthesizing imaging features across multiple modalities to provide a report that advances patient care.

Long term cost comparisons of radical cystectomy versus trimodal therapy for muscle-invasive bladder cancer.

BACKGROUND: Earlier studies on the cost of muscle-invasive bladder cancer treatments are limited to short-term costs of care. We determined the 2- and 5-year costs associated with trimodal therapy (TMT) vs. radical cystectomy (RC). METHODS: We performed a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Total Medicare costs at 2 and 5 years following RC vs. TMT were compared using inverse probability of treatment-weighted propensity score models. RESULTS: A total of 2,537 patients aged 66 to 85 years were diagnosed with clinical stage T2-4a muscle-invasive bladder cancer. Total median costs for patients that received no definitive treatment(s) were $73,780 and $88,275 at 2-and 5-years. Costs were significantly higher for TMT than RC at 2-years ($372,839 vs. $191,363, Median Difference $127,815, Hodges-Lehmann Estimate (H-L) 95% Confidence Interval (CI), $112,663-$142,966) and 5-years ($424,570 vs. $253,651, Median Difference $124,466, H-L 95% CI, $105,711-$143,221). TMT had higher outpatient costs than RC (2-years: $318,221 vs. $100,900; 5-years: $367,092 vs. $146,561) with significantly higher costs with radiology, medications, pathology/laboratory, and other professional services. RC had higher inpatient costs than TMT (2-years: $62,240 vs. $33,631, Median Difference $-29,174, H-L 95% CI, $-32,364-$-25,984; 5-years: $75,499 vs. $45,223, Median Difference $-29,843, H-L 95% CI, $-33,905-$-25,781). CONCLUSIONS AND RELEVANCE: The excess spending associated with trimodal therapy vs. radical cystectomy was largely driven by outpatient expenditures. The relatively high long-term trimodal therapy costs are prime targets for cost containment strategies to optimize future value-based care.

Use of the Toxicity Index in Evaluating Adverse Events in Anal Cancer Trials: Analysis of RTOG 9811 and RTOG 0529.

Novel toxicity metrics that account for all adverse event (AE) grades and the frequency of may enhance toxicity reporting in clinical trials. The Toxicity Index (TI) accounts for all AE grades and frequencies for categories of interest. We evaluate the feasibility of using the TI methodology in 2 prospective anal cancer trials and to evaluate whether more conformal radiation (using Intensity Modulated Radiation Therapy) results in improved toxicity as measured by the TI. Patients enrolled on NRG/RTOG 0529 or nonconformal RT enrolled on the 5-Fluorouracil/Mitomycin arm of NRG/RTOG 9811 were compared using the TI. Patients treated on NRG/RTOG 0529 had lower median TI compared with patients treated with nonconformal RT on NRG/RTOG 9811 for combined GI/GU/Heme/Derm events (3.935 vs 3.996, P=0.014). The TI methodology is a feasible method to assess all AEs of interest and may be useful as a composite metric for future efforts aimed at treatment de-escalation or escalation.

TMPRSS2/ERG fusion gene expression alters chemo- and radio-responsiveness in cell culture models of androgen independent prostate cancer.

PURPOSE/OBJECTIVES: The androgen regulated transmembrane serine protease (TMPRSS2) and ETS transcription factor (ERG) gene fusion is a strong prognostic factor for disease recurrence following prostatectomy. Expression of TMPRSS2/ETS-related gene (ERG) fusion gene transcripts is linked with tumor proliferation, invasion, and an aggressive phenotype. The aim of this study was to define the effect of TMPRSS2/ERG fusion gene expression on chemo- and radiosensitivity in prostate tumor cell lines. MATERIALS/METHODS: Clonogenic survival of PC3 and DU145 cells stably expressing TMPRSS2/ERG Types III and VI fusion genes was measured after X-irradiation (0-8 Gy) and Paclitaxel. Cell cycle changes and DNA double-strand break induction and repair were assessed. Differential gene expression was measured by microarray analysis. ERG signaling pathway interactions were studied using Ariadne Pathway Studio. RESULTS: Expression of the TMPRSS2/ERG fusions in PC3 cells increased radiation sensitivity and decreased paclitaxel sensitivity. Increased radiosensitivity was associated with persistent DNA breaks 24 hr post-irradiation, down-regulation of genes involved in DNA repair and mitosis and up-regulation of ETV, an ETS transcription factor. However, DU145 Types III and VI demonstrated a different sensitivity phenotype and gene expression changes. Pathway analysis of ERG signaling further illustrated the variation between the PC3 and DU145 cell lines containing TMPRSS2/ERG fusions. CONCLUSIONS: The effect of TMPRSS2/ERG gene fusions had differing effects on radiosensitivity and chemosensitivity depending on cell line and fusion type. Further work is needed with clinical samples to establish whether TMPRSS2/ERG gene fusions affect radio- and chemosensitivity in vivo.

Comparing Costs of Radical Versus Partial Cystectomy for Patients Diagnosed With Localized Muscle-Invasive Bladder Cancer: Understanding the Value of Surgical Care.

OBJECTIVE: To compare costs associated with radical versus partial cystectomy. Prior studies noted substantial costs associated with radical cystectomy, however, they lack surgical comparison to partial cystectomy. METHODS: A total of 2305 patients aged 66-85 years diagnosed with clinical stage T2-4a muscle-invasive bladder cancer from January 1, 2002 to December 31, 2011 were included. Total Medicare costs within 1 year of diagnosis following radical versus partial cystectomy were compared using inverse probability of treatment-weighted propensity score models. Cox regression and competing risks analysis were used to determine overall and cancer-specific survival, respectively. RESULTS: Median total costs were not significantly different for radical than partial cystectomy in 90 days ($73,907 vs $65,721; median difference $16,796, 95% CI $10,038-$23,558), 180 days ($113,288 vs $82,840; median difference $36,369, 95% CI $25,744-$47,392), and 365 days ($143,831 vs $107,359; median difference $34,628, 95% CI $17,819-$53,558), respectively. Hospitalization, surgery, pathology/laboratory, pharmacy, and skilled nursing facility costs contributed largely to costs associated with either treatment. Patients who underwent partial cystectomy had similar overall survival but had worse cancer-specific survival (Hazard Ratio 1.45, 95% Confidence Interval, 1.34-1.58, P < .001) than patients who underwent radical cystectomy. CONCLUSION: While treatments for bladder cancer are associated with substantial costs, we showed radical cystectomy had comparable total costs when compared to partial cystectomy among patients with muscle-invasive bladder cancer. However, partial cystectomy resulted in worse cancer-specific survival further supporting radical cystectomy as a high-value surgical procedure for muscle-invasive bladder cancer.

Long-Term Institutional Experience With Telemedicine Services for Radiation Oncology: A Potential Model for Long-Term Utilization.

PURPOSE: With the development of the coronavirus disease 2019 (COVID-19) pandemic, health care practices and radiation oncology departments have begun to incorporate telemedicine services to practice social distancing and minimize the chances of disease spread. Given the severity of this pandemic, it will likely fundamentally affect the use of these services for years to come. Our institution and radiation oncology department have used telemedicine services for many years; we would like to report on our departmental experience to guide other radiation oncology practices on its long-term use for clinical evaluation and patient care. METHODS AND MATERIALS: Our institution's telemedicine program provides clinical services for a number of remote locations and represents the largest telehealth network in the world, with over 300 sites and 60,000 patient encounters a year. RESULTS: Specifically for our radiation oncology department, over 200 patient encounters occur via telemedicine a year. Patients report great appreciation and satisfaction with these encounters, as they eliminate the time and energy needed for travel from long distances. It has resulted in improved efficiency and cost-effectiveness as well. CONCLUSIONS: Based on our institutional experience, our long-term vision for telemedicine (after COVID-19 pandemic has hopefully subsided) is as an excellent and cost-efficient tool to provide long-term follow-up for patients, especially for those who live far away in rural or underserved areas.

The Use of "QUAD Shot" in Anal Canal Squamous Cell Carcinoma: A Case Study With Review of the Literature.

CONTEXT: Patients with locoregional anal carcinoma who do not qualify for standard definitive chemoradiation are candidates for a short course of palliative hypofractionated radiotherapy such as QUAD Shot. METHODS: A 57-year-old man with massive locoregional squamous cell carcinoma of the anal canal was treated with QUAD Shot (14.8 Gy in four fractions over two consecutive days) repeated every four weeks for a total of two courses. RESULTS: He reported symptomatic relief following each course of radiation. In regard to his first QUAD Shot, his pain was 10/10 in severity at the time of admission and 4/10 at the time of discharge. In regard to his second QUAD Shot, his pain was 8/10 at the time of admission and 0/10 at the time of discharge. He did not experience any treatment-related toxicity. He passed away 15 weeks after the first course. CONCLUSION: QUAD Shot is both efficacious and safe for palliation in patients with anal carcinoma.

Comparison of Costs of Radical Cystectomy vs Trimodal Therapy for Patients With Localized Muscle-Invasive Bladder Cancer.

Importance: Earlier studies on the cost of muscle-invasive bladder cancer treatments lack granularity and are limited to 180 days. Objective: To compare the 1-year costs associated with trimodal therapy vs radical cystectomy, accounting for survival and intensity effects on total costs. Design, Setting, and Participants: This population-based cohort study used the US Surveillance, Epidemiology, and End Results-Medicare database and included 2963 patients aged 66 to 85 years who had received a diagnosis of clinical stage T2 to T4a muscle-invasive bladder cancer from January 1, 2002, through December 31, 2011. The data analysis was performed from March 5, 2018, through December 4, 2018. Main Outcomes and Measures: Total Medicare costs within 1 year of diagnosis following radical cystectomy vs trimodal therapy were compared using inverse probability of treatment-weighted propensity score models that included a 2-part estimator to account for intrinsic selection bias. Results: Of 2963 participants, 1030 (34.8%) were women, 2591 (87.4%) were white, 129 (4.4%) were African American, and 98 (3.3%) were Hispanic. Median costs were significantly higher for trimodal therapy than radical cystectomy in 90 days ($83 754 vs $68 692; median difference, $11 805; 95% CI, $7745-$15 864), 180 days ($187 162 vs $109 078; median difference, $62 370; 95% CI, $55 581-$69 160), and 365 days ($289 142 vs $148 757; median difference, $109 027; 95% CI, $98 692-$119 363), respectively. Outpatient care, radiology, medication expenses, and pathology/laboratory costs contributed largely to the higher costs associated with trimodal therapy. On inverse probability of treatment-weighted adjusted analyses, patients undergoing trimodal therapy had $136 935 (95% CI, $122 131-$152 115) higher mean costs compared with radical cystectomy 1 year after diagnosis. Conclusions and Relevance: Compared with radical cystectomy, trimodal therapy was associated with higher costs among patients with muscle-invasive bladder cancer. The differences in costs were largely attributed to medication and radiology expenses associated with trimodal therapy. Extrapolating cost figures resulted in a nationwide excess spending of $468 million for trimodal therapy compared with radical cystectomy for patients who received a diagnosis of bladder cancer in 2017.

Overview of accelerated partial breast irradiation.

Breast conserving therapy (BCT) has become an accepted option in the management of patients with early-stage breast cancer. However, studies have suggested that a lengthy course of adjuvant whole breast irradiation, as a component of BCT, may not always be necessary and that radiation therapy delivered only to the region of the tumor bed may be acceptable in appropriately selected patients. Several modalities are currently being explored as a means to deliver accelerated partial breast irradiation (APBI), including multicatheter interstitial brachytherapy, the MammoSite breast brachytherapy catheter (Cytyc Corporation, Marlborough, MA), and three-dimensional conformal external-beam radiation therapy. To date, phase 1/2 published data have demonstrated excellent local control rates and cosmesis. As additional data addressing the effectiveness of this treatment approach accumulate, a new standard of care may emerge. This review discusses data accumulated to date exploring the experience with all APBI modalities and presents future studies exploring this concept.

Comparing Survival Outcomes and Costs Associated With Radical Cystectomy and Trimodal Therapy for Older Adults With Muscle-Invasive Bladder Cancer.

Importance: Radical cystectomy is the guidelines-recommended treatment of muscle-invasive bladder cancer, but a resurgence of trimodal therapy has occurred. Limited comparative data are available on outcomes and costs attributable to these 2 treatments. Objective: To compare the survival outcomes and costs between trimodal therapy and radical cystectomy in older adults with muscle-invasive bladder cancer. Design, Setting, and Participants: This population-based cohort study used data from the Surveillance, Epidemiology, and End Results-Medicare linked database. A total of 3200 older adults (aged ≥66 years) with clinical stage T2 to T4a bladder cancer diagnosed from January 1, 2002, to December 31, 2011, and with claims data available through December 31, 2013, were included in the analysis. Patients who received radical cystectomy underwent either only surgery or surgery in combination with radiotherapy or chemotherapy. Patients who received trimodal therapy underwent transurethral resection of the bladder followed by radiotherapy and chemotherapy. Propensity score matching by sociodemographic and clinical characteristics was used. Data analysis was performed from August 1, 2017, to March 11, 2018. Main Outcomes and Measures: Overall survival and cancer-specific survival were evaluated using the Cox proportional hazards regression model and the Fine and Gray competing risk model. All Medicare health care costs for inpatient, outpatient, and physician services within 30, 90, and 180 days of treatment were compared. The total amount spent nationwide was estimated, using 180-day medical costs between treatments, by the total number of new cases of muscle-invasive bladder cancer in the United States in 2011. Results: Of the 3200 patients who met the inclusion criteria, 2048 (64.0%) were men and 1152 (36.0%) were women, with a mean (SD) age of 75.8 (6.0) years. After propensity score matching, 687 patients (21.5%) underwent trimodal therapy and 687 patients (21.5%) underwent radical cystectomy. Patients who underwent trimodal therapy had significantly decreased overall survival (hazard ratio [HR], 1.49; 95% CI, 1.31-1.69) and cancer-specific survival (HR, 1.55; 95% CI, 1.32-1.83). No differences in costs at 30 days were observed between trimodal therapy ($15 233 in 2002 vs $18 743 in 2011) and radical cystectomy ($17 990 in 2002 vs $21 738 in 2011). However, median total costs were significantly higher with trimodal therapy than with radical cystectomy at 90 days ($80 174 vs $69 181; median difference, $8964; Hodges-Lehmann 95% CI, $3848-$14 079) and at 180 days ($179 891 vs $107 017; median difference, $63 771; Hodges-Lehmann 95% CI, $55 512-$72 029). Extrapolating these figures to the total US population revealed $335 million in excess spending for trimodal therapy compared with the less costly radical cystectomy ($492 million) for patients who received a muscle-invasive bladder cancer diagnosis in 2011. Conclusions and Relevance: Trimodal therapy was associated with significantly decreased overall survival and cancer-specific survival as well as $335 million in excess spending in 2011. These findings have important health policy implications regarding the appropriate use of high value-based care among older adults with invasive bladder cancer who are candidates for either radical cystectomy or trimodal therapy.

Accelerated partial breast irradiation: Past, present, and future.

Accelerated partial breast irradiation (APBI) focuses higher doses of radiation during a shorter interval to the lumpectomy cavity, in the setting of breast conserving therapy for early stage breast cancer. The utilization of APBI has increased in the past decade because of the shorter treatment schedule and a growing body of outcome data showing positive cosmetic outcomes and high local control rates in selected patients undergoing breast conserving therapy. Technological advances in various APBI modalities, including intracavitary and interstitial brachytherapy, intraoperative radiation therapy, and external beam radiation therapy, have made APBI more accessible in the community. Results of early APBI trials served as the basis for the current consensus guidelines, and multiple prospective randomized clinical trials are currently ongoing. The pending long term results of these trials will help us identify optimal candidates that can benefit from ABPI. Here we provide an overview of the clinical and cosmetic outcomes of various APBI techniques and review the current guidelines for selecting suitable breast cancer patients. We also discuss the impact of APBI on the economics of cancer care and patient reported quality of life.

Regulation of cell-surface major histocompatibility complex class I expression by the endopeptidase EC3.4.24.15 (thimet oligopeptidase).

Endopeptidase EP24.15 (EC 3.4.24.15; thimet oligopeptidase), traditionally classified as a neuropeptide-processing enzyme, degrades well-known MHC I (major histocompatibility complex class I) peptides in cell extracts. In the present study, we determine the contribution of EP24.15 in vivo to the surface expression of MHC I on intact cells. CTLs (cytotoxic T-lymphocytes) recognize a vast array of peptides presented in the context of MHC I cell-surface molecules. Stable retroviral overexpression of EP24.15 induces a dramatic, long-term inhibition of surface MHC I. In contrast, overexpression of a mutant EP24.15, which is expressed, but is enzymically inactive, does not affect the surface MHC I expression level. We observed no difference in the effect of EP24.15 on the expression of different classes of MHC I. IFN-gamma (interferon-gamma) treatment re-established MHC I expression on these EP24.15-overexpressing cells, and also induced EP24.15 cytosolic protein expression and enzyme activity. To our knowledge, this is the first demonstration of cytokine-induced EP24.15 expression and activity. Conversely, stable retroviral silencing of endogenous EP24.15 by RNA interference induced a striking, long-term increase in surface MHC I. Subcellular fractionation and enzyme-activity experiments localized the vast majority of EP24.15 protein expression and function to the cytosol. Therefore we introduce a novel function of the cytosolic form of EP24.15. EP24.15 activity in the extracellular space is significant for neuropeptide processing, and in the present paper, we demonstrate that EP24.15 activity in the cytosol may be significant for regulation of MHC I cell-surface expression.

Cost analysis of adjuvant management strategies in early stage (stage I) testicular seminoma.

BACKGROUND: Acceptable post-orchiectomy adjuvant therapy strategies for stage I seminoma patients include surveillance, para-aortic radiation therapy (RT), dog-leg RT, and a single cycle of carboplatin. The required follow-up recommendations were amended by the National Comprehensive Cancer Network (NCCN) in 2012. Given a cause-specific survival of nearly 100%, a closer analysis of the reimbursement for each treatment strategy is warranted. METHODS: NCCN guidelines were used to design treatment plans for each acceptable adjuvant treatment strategy. Follow-up charges were generated for 10 years based on 2012 (version 1.2012; unchanged in current version 1.2013) and 2011 NCCN (version 2.2011) surveillance recommendations. The 2012 Medicare reimbursement rates were used to calculate each treatment strategy and incremental cost-effectiveness ratios to compare the treatment options. RESULTS: Under the current NCCN follow-up recommendations, the total reimbursements generated over 10 years of surveillance, para-aortic RT, dog-leg RT, and carboplatin were $10,643, $11,678, $9,662, and $10,405, respectively. This is compared with the reimbursements as per the 2011 NCCN recommendations: $20,986, $11,517, $9,394, and $20,365 respectively. Factoring the rates of relapse into a salvage model, observation was found to be more costly and less effective ($-1,831, $-7,318, $-7,010) in the adjuvant management of stage I seminoma patients. CONCLUSION: Based on incremental cost-effectiveness ratios, para-aortic RT, dog-leg RT, and carboplatin are cost-effective options for the treatment of stage I seminoma when compared with observation; however, surveillance could potentially spare as many as 80%-85% of men diagnosed with stage I seminoma from additional therapy after radical inguinal orchiectomy. Such cost and reimbursement analyses are becoming increasingly relevant, but are not meant to usurp sound clinical judgment. Further studies are required to validate these findings.

The role of neuropeptide processing enzymes in endocrine (prostate) cancer: EC 3.4.24.15 (EP24.15).

The zinc metalloendopeptidase EC3.4.24.15 [EP24.15, thimet oligopeptidase], a neuropeptide processing enzyme, is central to the formation and degradation of many bioactive peptides in the neural proteome, and is highly expressed in normal prostate. EP24.15 actions are increased in androgen-dependent prostate cancer compared to androgen-independent; augmented by androgen treatment, and inhibited by clinical GnRH analogs. The "neural" prostate includes: neuropeptides, cognate receptors and processing enzymes regulating signaling of peptide-mediated neural inputs.