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1.  Mass spectrometry in cancer biomarker research: a case for immunodepletion of abundant blood-derived proteins from clinical tissue specimens 
Biomarkers in medicine  2014;8(2):269-286.
The discovery of clinically relevant cancer biomarkers using mass spectrometry (MS)-based proteomics has proven difficult, primarily because of the enormous dynamic range of blood-derived protein concentrations and the fact that the 22 most abundant blood-derived proteins constitute approximately 99% of the total plasma protein mass. Immunodepletion of clinical body fluid specimens (e.g., serum/plasma) for the removal of highly abundant proteins is a reasonable and reproducible solution. Often overlooked, clinical tissue specimens also contain a formidable amount of highly abundant blood-derived proteins present in tissue-embedded networks of blood/lymph capillaries and interstitial fluid. Hence, the dynamic range impediment to biomarker discovery remains a formidable obstacle, regardless of clinical sample type (solid tissue and/or body fluid). Thus, we optimized and applied simultaneous immunodepletion of blood-derived proteins from solid tissue and peripheral blood, using clear cell renal cell carcinoma as a model disease. Integrative analysis of data from this approach and genomic data obtained from the same type of tumor revealed concordant key pathways and protein targets germane to clear cell renal cell carcinoma. This includes the activation of the lipogenic pathway characterized by increased expression of adipophilin (PLIN2) along with 'cadherin switching', a phenomenon indicative of transcriptional reprogramming linked to renal epithelial dedifferentiation. We also applied immunodepletion of abundant blood-derived proteins to various tissue types (e.g., adipose tissue and breast tissue) showing unambiguously that the removal of abundant blood-derived proteins represents a powerful tool for the reproducible profiling of tissue proteomes. Herein, we show that the removal of abundant blood-derived proteins from solid tissue specimens is of equal importance to depletion of body fluids and recommend its routine use in the context of biological discovery and/or cancer biomarker research. Finally, this perspective presents the background, rationale and strategy for using tissue-directed high-resolution/accuracy MS-based shotgun proteomics to detect genuine tumor proteins in the peripheral blood of a patient diagnosed with nonmetastatic cancer, employing concurrent liquid chromatography–MS analysis of immunodepleted clinical tissue and blood specimens.
doi:10.2217/bmm.13.101
PMCID: PMC4201940  PMID: 24521024
blood; cancer biomarker discovery; clinical proteomics; clinical specimens; high-resolution/accurate LC-MS; immunoaffinity depletion; tissue
2.  MEK1/2 inhibition enhances the radiosensitivity of cancer cells by downregulating survival and growth signals mediated by EGFR ligands 
International Journal of Oncology  2013;42(6):2028-2036.
The inhibition of the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway through the suppression of mutated Ras or MAPK/extracellular signal-regulated kinase 1/2 (MEK1/2) has been shown to sensitize tumor cells to ionizing radiation (IR). The molecular mechanisms of this sensitization however, are not yet fully understood. In this study, we investigated the role of transforming growth factor-α (TGF-α) in the radiosensitizing effects of selumetinib, a selective inhibitor of MEK1/2. The expression of epidermal growth factor receptor (EGFR) ligands was assessed by ELISA in both Ras wild-type and Ras mutant cells that were exposed to radiation with or without selumetinib. The effects of selumetinib on the TGF-α/EGFR signaling cascade in response to radiation were examined by western blot analysis, clonogenic assay and by determing the yield of mitotic catastrophe. The treatment of cells with selumetinib reduced the basal and IR-induced secretion of TGF-α in both Ras wild-type and Ras mutant cell lines in vitro and in vivo. The reduction of TGF-α secretion was accompanied with a reduction in phosphorylated tumor necrosis factor-α converting enzyme (TACE) in the cells treated with selumetinib with or without IR. The treatment of cells with selumetinib with or without IR inhibited the phosphorylation of EGFR and check-point kinase 2 (Chk2), and reduced the expression of survivin. Supplementation with exogenous TGF-α partially rescued the selumetinib-treated cells from IR-induced cell death, restored EGFR and Chk2 phosphorylation and increased survivin expression. These data suggest that the inhibition of MEK1/2 with selumetinib may provide a mechanism to sensitize tumor cells to IR in a fashion that prevents the activation of the TGF-α autocrine loop following IR.
doi:10.3892/ijo.2013.1890
PMCID: PMC3699614  PMID: 23588995
radiation; transforming growth factor-α; AZD6244; selumetinib; Ras
3.  Role of Type II Pneumocyte Senescence in Radiation-Induced Lung Fibrosis 
Background
Radiation is a commonly delivered therapeutic modality for cancer. The causes underlying the chronic, progressive nature of radiation injury in the lung are poorly understood.
Methods
C57Bl/6NCr mice were exposed to thoracic irradiation (n = 3 per dose and time point for tissue collection). Microarray analysis of gene expression from irradiated murine lung was performed using one-way analysis of variance with post hoc Scheffe analysis. Senescence and type II airway epithelial cell (AECII) count were assayed in irradiated murine lung tissue (n = 3 per condition). Irradiated mice were treated with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase (NOX), and fibrosis was assessed by collagen assays. All statistical tests were two-tailed.
Results
Gene expression in lung tissue from mice irradiated to 17.5 Gy clustered with that of aged unirradiated mice. Only fibrogenic exposures led to AECII senescence (0 Gy: 0.66% +/− 0.67%; 5 Gy: 4.5% +/− 1.19%; 17.5 Gy: 18.7% +/− 3.05; P = .007) and depletion (0 Gy: 2.89 per alveolus +/− 0.26; 5 Gy: 2.41 +/− 0.19; 17.5 Gy: 1.6 +/− 0.14; P < .001) at 30 weeks. Treatment of irradiated mice with DPI for 16 weeks markedly reduced collagen accumulation (5×6 Gy: 57.26 μg/lung +/− 9.91; 5×6 Gy +/− DPI: 36.54μg/lung +/− 4.39; P = .03) and AECII senescence (5×6 Gy: 37.61% +/− 4.82%; 5×6 Gy +/− DPI: 12.38% +/− 2.78; P < .001).
Conclusions
These studies identify senescence as an important process in AECII in vivo and indicate that NOX is a critical mediator of radiation-induced AECII senescence and pulmonary fibrosis.
doi:10.1093/jnci/djt212
PMCID: PMC3787909  PMID: 24052614
4.  Peptidases released by necrotic cells control CD8+ T cell cross-priming  
The Journal of Clinical Investigation  2013;123(11):4755-4768.
Cross-priming of CD8+ T cells and generation of effector immune responses is pivotal for tumor immunity as well as for successful anticancer vaccination and therapy. Dead and dying cells produce signals that can influence Ag processing and presentation; however, there is conflicting evidence regarding the immunogenicity of necrotic cell death. We used a mouse model of sterile necrosis, in which mice were injected with sterile primary necrotic cells, to investigate a role of these cells in priming of CD8+ T cells. We discovered a molecular mechanism operating in Ag donor cells that regulates cross-priming of CD8+ T cells during primary sterile necrosis and thereby controls adaptive immune responses. We found that the cellular peptidases dipeptidyl peptidase 3 (DPP-3) and thimet oligopeptidase 1 (TOP-1), both of which are present in nonimmunogenic necrotic cells, eliminated proteasomal degradation products and blocked Ag cross-presentation. While sterile necrotic tumor cells failed to induce CD8+ T cell responses, their nonimmunogenicity could be reversed in vitro and in vivo by inactivation of DPP-3 and TOP-1. These results indicate that control of cross-priming and thereby immunogenicity of primary sterile necrosis relies on proteasome-dependent oligopeptide generation and functional status of peptidases in Ag donor cells.
doi:10.1172/JCI65698
PMCID: PMC3809774  PMID: 24216478
5.  Enhancement of 5- Fluorouracil-induced In Vitro and In Vivo Radiosensitization with MEK Inhibition 
Purpose
Gastrointestinal cancers frequently exhibit mutational activation of the Ras/MAPK pathway, which is implicated in resistance to ionizing radiation (IR) and chemotherapy. Concurrent radiotherapy and 5-fluorouracil (5-FU) based chemotherapy is commonly used for treatment of gastrointestinal malignancies. We previously reported radiosensitization with selumetinib, an inhibitor of MEK1/2. The purpose of the current study was to evaluate if selumetinib could enhance radiosensitivity induced by 5-FU.
Experimental Design
Clonogenic survival assays were performed with the HT29 (colorectal), HCT116 (colorectal) and MiaPaca-2 (pancreatic) cell lines using pre-IR treatment with selumetinib, 5-FU and 5-FU+selumetinib. Cell proliferation was determined using a tetrazolium conversion assay. Mitotic catastrophe and DNA repair were analyzed using immunocytochemistry. Flow cytometry was used to analyze cell cycle and apoptosis. Growth delay was used to determine effects of 5-FU+selumetinib on in vivo tumor radiosensitivity.
Results
Pre-IR treatment with 5-FU+selumetinib significantly decreased clonogenic survival compared to either agent alone. Dose modifying factors at a surviving fraction of 0.1 for 5-FU+selumetinib was 1.78, 1.52, and 1.3 for HT29, HCT116, and MiaPaca-2, respectively. Cell proliferation was decreased by treatment with selumetinib+5-FU as compared to single agent treatment regardless of treatment sequencing. Enhancement of 5-FU cytotoxicity and 5-FU mediated radiosensitization with selumetinib treatment was accompanied by an increase in mitotic catastrophe and apoptosis, and reductions in Stat3 phosphorylation and survivin expression. In vivo, an additive growth delay was observed with 5-FU+selumetinib+5Gy versus 5-FU+5Gy and selumetinib alone.
Conclusion
These data suggest that selumetinib can be used with 5-FU to augment radiation response.
doi:10.1158/1078-0432.CCR-11-0358
PMCID: PMC3149743  PMID: 21690569
selumetinib; AZD6244; 5-fluorouracil; radiosensitization; MEK1/2
6.  Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T Cell Transfer Immunotherapy 
Purpose
Most treatments for patients with metastatic melanoma have a low rate of complete regression and thus overall survival in these patients is poor. We have investigated the ability of adoptive cell transfer utilizing autologous, tumor infiltrating lymphocytes to mediate durable complete regressions in heavily pre-treated patients with metastatic melanoma.
Experimental Design
Ninety-three patients with measurable metastatic melanoma were treated with the adoptive transfer of autologous tumor-infiltrating lymphocytes administered in conjunction with interleukin-2 following a lymphodepleting preparative regimen on three sequential clinical trials. Ninety-five percent of these patients had progressive disease following a prior systemic treatment. Median potential followup was 62 months.
Results
Objective response rates by RECIST criteria in the three trials using lymphodepleting preparative regimens (chemotherapy alone or with 2Gy or 12Gy irradiation) were 49%, 52% and 72%. Twenty of the 93 patients (22%) achieved a complete tumor regression and 19 have ongoing complete regressions beyond three years The actuarial three and five year survivals for the entire group were 36% and 29% respectively but for the 20 complete responders were 100% and 93%. The likelihood of achieving a complete response was similar regardless of prior therapy. Factors associated with objective response included longer telomeres of the infused cells, the number of CD8+ CD27+ cells infused and the persistence of the infused cells in the circulation at one month (all p2<0.001).
Conclusions
Cell transfer therapy with autologous tumor infiltrating can mediate durable complete responses in patients with metastatic melanoma and has similar efficacy irrespective of prior treatment.
doi:10.1158/1078-0432.CCR-11-0116
PMCID: PMC3131487  PMID: 21498393
7.  Determination of cytokine protein levels in oral secretions in patients undergoing radiotherapy for head and neck malignancies 
Background
Cytokines may be elevated in tumor and normal tissues following irradiation. Cytokine expression in these tissues may predict for toxicity or tumor control. The purpose of this pilot study was to determine the feasibility of measuring local salivary cytokine levels using buccal sponges in patients receiving chemo-radiation for head and neck malignancies.
Patients and methods
11 patients with epithelial malignancies of the head and neck were recruiting to this study. All patients received radiotherapy to the head and neck region with doses ranging between 60 – 67.5 Gy. Chemotherapy was delivered concurrently with radiation in all patients. Salivary samples were obtained from high dose and low dose regions prior to treatment and at three intervals during treatment for assessment of cytokine levels (IL-4, IL-6, IL-8, IL-10, EGF, MCP-1, TNF-α, and VEGF).
Results
Cytokine levels were detectable in the salivary samples. Salivary cytokine levels of IL-4, IL-6, IL-8, EGF, MCP-1, TNF- α , and VEGF were higher in the high dose region compared to the low dose region at all time points (p < 0.05). A trend toward an increase in cytokine levels as radiation dose increased was observed for IL-6, IL-8, MCP-1, and TNF-α.
Conclusion
Assessment of salivary cytokine levels may provide a novel method to follow local cytokine levels during radiotherapy and may provide a mechanism to study cytokine levels in a regional manner.
doi:10.1186/1748-717X-7-64
PMCID: PMC3439271  PMID: 22537315
Saliva; Cytokine; Radiation; Milliplex
8.  CD8+ enriched “young” tumor infiltrating lymphocytes can mediate regression of metastatic melanoma 
Purpose
Tumor infiltrating lymphocytes (TIL) and interleukin (IL)-2 administered following lymphodepletion can cause the durable complete regression of bulky metastatic melanoma in patients refractory to approved treatments. However, the generation of a unique tumor-reactive TIL culture for each patient may be prohibitively difficult. We therefore investigated the clinical and immunological impact of unscreened, CD8+ enriched “young” TIL.
Experimental Design
Methods were developed for generating TIL that minimized the time in culture and eliminated the individualized tumor-reactivity screening step. Thirty-three patients were treated with these CD8+ enriched young TIL and IL-2 following non-myeloablative lymphodepletion (NMA). Twenty-three additional patients were treated with CD8+ enriched young TIL and IL-2 after lymphodepletion with NMA and 6Gy of total body irradiation (TBI).
Results
Young TIL cultures for therapy were successfully established from 83% of 122 consecutive melanoma patients. Nineteen of 33 patients (58%) treated with CD8+ enriched young TIL and NMA had an objective response (RECIST) including three complete responders. Eleven of 23 patients (48%) treated with TIL and 6Gy TBI had an objective response including two complete responders. At one month after TIL infusion the absolute CD8+ cell numbers in the periphery were highly correlated with response.
Conclusion
This study shows that a rapid and simplified method can be used to reliably generate CD8+ enriched young TIL for administration as an individualized therapy for advanced melanoma, and may allow this potentially effective treatment to be applied at other institutions and to reach additional patients.
doi:10.1158/1078-0432.CCR-10-1297
PMCID: PMC2978753  PMID: 20668005
adoptive immunotherapy; interleukin-2; lymphodepletion; personalized medicine; homeostasis
9.  Evaluation of the fullerene compound DF-1 as a radiation protector 
Background
Fullerene compounds are known to possess antioxidant properties, a common property of chemical radioprotectors. DF-1 is a dendrofullerene nanoparticle with antioxidant properties previously found to be radioprotective in a zebrafish model. The purpose of this study was to evaluate the radioprotective effects of DF-1 in a murine model of lethal total body irradiation and to assess for selective radioprotection of normal cells versus tumor cells.
Methods
In vitro radioresponse was evaluated with clonogenic assays with human tumor cells and fibroblast lines in the presence of varying concentrations of DF-1 or vehicle. DNA double strand break induction and repair was evaluated with immunocytochemistry for γH2AX. Lethal total body irradiation was delivered with 137Cs after intraperitoneal delivery of DF-1 or vehicle control. Bone marrow hypoxia was evaluated with piminidazole uptake assessed by flow cytometry.
Results
DF-1 provided modest radioprotection of human cancer cell lines and fibroblast cell lines when delivered prior to irradiation (dose modifying factor or 1.1). There was no evidence of selective protection of fibroblasts versus tumor cells. Cells treated with DF-1 at radioprotective doses were found to have fewer γH2AX foci at 1 and 6 hours after irradiation compared to vehicle treated controls. The LD50/30 for C57Bl6/Ncr mice treated with a single 300 mg/kg dose of DF-1 pre-irradiation was 10.09 Gy (95% CI 9.58-10.26) versus 8.29 Gy (95% CI, 8.21-8.32) for control mice. No protective effects were seen with a single 200 mg/kg dose. No increase in pimonidazole uptake was appreciated in bone marrow of mice treated with DF-1 compared to vehicle controls.
Conclusions
DF-1 has modest activity as a radiation protector in vivo. There was no evidence of selective protection from irradiation of normal versus tumor cells with DF-1.
doi:10.1186/1748-717X-5-34
PMCID: PMC2877563  PMID: 20459795
10.  Adoptive Cell Therapy for Patients With Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative Regimens 
Journal of Clinical Oncology  2008;26(32):5233-5239.
Purpose
The two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens.
Patients and Methods
We performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied.
Results
Although nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells.
Conclusion
Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies.
doi:10.1200/JCO.2008.16.5449
PMCID: PMC2652090  PMID: 18809613
11.  Clinical biomarkers of angiogenesis inhibition 
Cancer metastasis reviews  2008;27(3):415-434.
Introduction
An expanding understanding of the importance of angiogenesis in oncology and the development of numerous angiogenesis inhibitors are driving the search for biomarkers of angiogenesis. We review currently available candidate biomarkers and surrogate markers of anti-angiogenic agent effect.
Discussion
A number of invasive, minimally invasive, and non-invasive tools are described with their potential benefits and limitations. Diverse markers can evaluate tumor tissue or biological fluids, or specialized imaging modalities.
Conclusions
The inclusion of these markers into clinical trials may provide insight into appropriate dosing for desired biological effects, appropriate timing of additional therapy, prediction of individual response to an agent, insight into the interaction of chemotherapy and radiation following exposure to these agents, and perhaps most importantly, a better understanding of the complex nature of angiogenesis in human tumors. While many markers have potential for clinical use, it is not yet clear which marker or combination of markers will prove most useful.
doi:10.1007/s10555-008-9143-x
PMCID: PMC2676436  PMID: 18414993
Cancer; Angiogenesis; Biomarker; Imaging
12.  Adoptive Cell Therapy for Patients With Metastatic Melanoma: Evaluation of Intensive Myeloablative Chemoradiation Preparative Regimens 
Purpose
The two approved treatments for patients with metastatic melanoma, interleukin (IL)-2 and dacarbazine, mediate objective response rates of 12% to 15%. We previously reported that adoptive cell therapy (ACT) with autologous antitumor lymphocytes in lymphodepleted hosts mediated objective responses in 51% of 35 patients. Here, we update that study and evaluate the safety and efficacy of two increased-intensity myeloablative lymphodepleting regimens.
Patients and Methods
We performed two additional sequential trials of ACT with autologous tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma. Increasing intensity of host preparative lymphodepletion consisting of cyclophosphamide and fludarabine with either 2 (25 patients) or 12 Gy (25 patients) of total-body irradiation (TBI) was administered before cell transfer. Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) and survival were evaluated. Immunologic correlates of effective treatment were studied.
Results
Although nonmyeloablative chemotherapy alone showed an objective response rate of 49%, when 2 or 12 Gy of TBI was added, the response rates were 52% and 72% respectively. Responses were seen in all visceral sites including brain. There was one treatment-related death in the 93 patients. Host lymphodepletion was associated with increased serum levels of the lymphocyte homeostatic cytokines IL-7 and IL-15. Objective responses were correlated with the telomere length of the transferred cells.
Conclusion
Host lymphodepletion followed by autologous TIL transfer and IL-2 results in objective response rates of 50% to 70% in patients with metastatic melanoma refractory to standard therapies.
doi:10.1200/JCO.2008.16.5449
PMCID: PMC2652090  PMID: 18809613
13.  Post-collection, pre-measurement variables affecting VEGF levels in urine biospecimens 
Angiogenesis, the development and recruitment of new blood vessels, plays an important role in tumour growth and metastasis. Vascular endothelial growth factor (VEGF) is an important stimulator of angiogenesis. Circulating and urinary VEGF levels have been suggested as clinically useful predictors of tumour behaviour, and investigations into these associations are ongoing. Despite recent interest in measuring VEGF levels in patients, little is known about the factors that influence VEGF levels in biospecimens. To begin to address this question, urine samples were collected from patients with solid tumours undergoing radiotherapy and healthy volunteers. Four factors were examined for their effects on VEGF concentrations as measured by chemiluminescent immunoassay: time from sample collection to freezing, number of specimen freeze-thaw cycles, specimen storage tube type and the inclusion or exclusion of urinary sediment. The results of this study indicate that time to freeze up to 4 hrs, number of freeze-thaw cycles between one and five, and different types of polypropylene tubes did not have statistically significant effects on measured urinary VEGF levels. Urinary sediment had higher VEGF levels than supernatant in five of six samples from healthy patients. It is not clear whether there is an active agent in the sediment causing this increase or if the sediment particles themselves are affecting the accuracy of the assay. Therefore, we recommend centrifuging urine, isolating the supernatant, and freezing the sample in polypropylene microcentrifuge tubes or cryogenic vials within 4 hrs of collection. In addition, we recommend the use of samples within five freeze-thaw cycles.
doi:10.1111/j.1582-4934.2007.00135.x
PMCID: PMC2367114  PMID: 18366457
angiogenesis; VEGF; tumour markers; urine; biospecimens
14.  Increased intensity lymphodepletion and adoptive immunotherapy—how far can we go? 
Summary
In a recent clinical trial involving patients with metastatic melanoma, immunosuppressive conditioning with fludarabine and cyclophosphamide resulted in a 50% response rate and a robust long-term persistence of adoptively transferred T cells. Experimental findings indicate that lymphodepletion prior to adoptive transfer of tumor-specific T lymphocytes plays a key role in enhancing treatment efficacy by eliminating regulatory T cells and competing elements of the immune system (‘cytokine sinks’). Newly emerging animal data suggest that more profound lymphoablative conditioning with autologous hematopoetic stem-cell rescue might further enhance treatment results. Here we review recent advances in adoptive immunotherapy of solid tumors and discuss the rationale for lymphodepleting conditioning. We also address safety issues associated with translating experimental animal results of total lymphoid ablation into clinical practice.
Review criteria
The PubMed and MEDLINE databases were searched for articles published until April 2006. Electronic early-release publications were also included. Only articles published in English were considered. The search terms used included “adoptive cell transfer”, “lymphodepletion”, “lymphopenia”, “TBI”, “homeostatic proliferation”, “allogeneic transplant”, “syngeneic transplant”, “IPS” and “treatment related mortality”. Full articles were obtained and references were checked for additional material when appropriate. References were chosen based on the best clinical or laboratory evidence, especially if data had been corroborated by published work from other centers. Priority was given to studies in high-impact-factor journals when available.
doi:10.1038/ncponc0666
PMCID: PMC1773008  PMID: 17139318
adoptive cell transfer; immunodepletion; lymphodepletion; melanoma; T lymphocytes Top of page
15.  Early observed transient prostate-specific antigen elevations on a pilot study of external beam radiation therapy and fractionated MRI guided High Dose Rate brachytherapy boost 
Purpose
To report early observation of transient PSA elevations on this pilot study of external beam radiation therapy and magnetic resonance imaging (MRI) guided high dose rate (HDR) brachytherapy boost.
Materials and methods
Eleven patients with intermediate-risk and high-risk localized prostate cancer received MRI guided HDR brachytherapy (10.5 Gy each fraction) before and after a course of external beam radiotherapy (46 Gy). Two patients continued on hormones during follow-up and were censored for this analysis. Four patients discontinued hormone therapy after RT. Five patients did not receive hormones. PSA bounce is defined as a rise in PSA values with a subsequent fall below the nadir value or to below 20% of the maximum PSA level. Six previously published definitions of biochemical failure to distinguish true failure from were tested: definition 1, rise >0.2 ng/mL; definition 2, rise >0.4 ng/mL; definition 3, rise >35% of previous value; definition 4, ASTRO defined guidelines, definition 5 nadir + 2 ng/ml, and definition 6, nadir + 3 ng/ml.
Results
Median follow-up was 24 months (range 18–36 mo). During follow-up, the incidence of transient PSA elevation was: 55% for definition 1, 44% for definition 2, 55% for definition 3, 33% for definition 4, 11% for definition 5, and 11% for definition 6.
Conclusion
We observed a substantial incidence of transient elevations in PSA following combined external beam radiation and HDR brachytherapy for prostate cancer. Such elevations seem to be self-limited and should not trigger initiation of salvage therapies. No definition of failure was completely predictive.
doi:10.1186/1748-717X-1-28
PMCID: PMC1564026  PMID: 16914054

Results 1-15 (15)