Aradhana Kaushal

An MRI-Compatible Robotic System With Hybrid Tracking for MRI-Guided Prostate Intervention

This paper reports the development, evaluation, and first clinical trials of the access to the prostate tissue (APT) II system-a scanner independent system for magnetic resonance imaging (MRI)-guided transrectal prostate interventions. The system utilizes novel manipulator mechanics employing a steerable needle channel and a novel six degree-of-freedom hybrid tracking method, comprising passive fiducial tracking for initial registration and subsequent incremental motion measurements. Targeting accuracy of the system in prostate phantom experiments and two clinical human-subject procedures is shown to compare favorably with existing systems using passive and active tracking methods. The portable design of the APT II system, using only standard MRI image sequences and minimal custom scanner interfacing, allows the system to be easily used on different MRI scanners.

The Role of Radiation Therapy in the Management of Sarcomas

Sarcomas represent a heterogeneous, challenging, and rare group of tumors that present many management challenges. In this article, the authors concentrate on the radiotherapeutic management of sarcomas occurring in the most common locations: the extremities, the trunk, and the retroperitoneum. An overview of the current radiotherapeutic management of soft tissue sarcoma is presented in addition to a discussion of how surgical management may affect radiotherapeutic management. Finally, the authors describe current controversies surrounding the appropriate management of sarcomas with radiotherapy and describe ongoing studies and future areas of research.

Radiotherapy for patients with the human immunodeficiency virus: are special precautions necessary?

Shortly after the onset of the acquired immunodeficiency syndrome (AIDS) epidemic in the 1980s, reports of radiation‐associated toxicity in patients with the human immunodeficiency virus (HIV) and AIDS began to appear in the medical literature. Although the majority of reports have focused on AIDS‐defining malignancies such as Kaposi sarcoma, greater‐than‐expected toxicity after a course of radiotherapy or chemoradiotherapy has also been documented in cancers not generally classified as being related to HIV. With improved antiretroviral therapies, HIV patients are living longer and have the potential to develop a variety of HIV‐associated and nonassociated malignancies that require treatment, including radiotherapy. This review reports the published data regarding the interactions of HIV, AIDS, and antiretroviral therapy with radiotherapy and implications for the management of malignancies in patients with HIV. Cancer 2010. Published 2009 by the American Cancer Society.

Active surveillance for prostate cancer: past, present and future.

Purpose of review This article reviews recent developments in the use of active surveillance for localized prostate cancer. Recent findings The treatment of localized prostate cancer continues to be a major challenge for urologic oncologists. Screening with prostate-specific antigen has resulted in increased numbers of low-risk prostate cancers being detected. Aggressive whole-gland therapy with surgery, or radiation therapy is associated with potentially life-altering treatment-related side effects such as urinary incontinence, bowel toxicity and erectile dysfunction. The goal of active surveillance is to avoid or delay the adverse events associated with prostate cancer therapy while still allowing for curative intervention in the future, if needed. Summary Active surveillance is a reasonable treatment option for many men with low-risk, and some men with intermediate-risk, prostate cancer. Additional research is needed to determine the optimal active surveillance inclusion criteria, monitoring schedule, and treatment triggers. It is hoped that advances in prostate imaging, biomarkers, and focal therapy will foster greater use of active surveillance in appropriately selected men to optimize quality-of-life without compromising cancer outcomes.

DNMT1 as a Molecular Target in a Multimodality-Resistant Phenotype in Tumor Cells

We have previously shown that hydrogen peroxide–resistant permanent (OC-14) cells are resistant to the cytotoxicity of several exogenous oxidative and anticancer agents including H2O2, etoposide, and cisplatin; and we refer to this process as an oxidative multimodality-resistant phenotype (MMRP). Furthermore, OC-14 cells contain increased activator protein 1 activity, and inhibition of activator protein 1 reversed the MMRP. In this study, we show that permanent Rat-1 cell lines genetically altered to overexpress c-Fos also displayed a similar MMRP to H2O2, etoposide, and cisplatin as OC-14 cells. Gene expression analysis of the OC-14 cells and c-Fos–overexpressing cells showed increased DNMT1 expression. Where OC-14 and c-Fos–overexpressing cells were exposed to 5-aza-2′-deoxycytidine, which inhibits DNMT activity, a significant but incomplete reversal of the MMRP was observed. Thus, it seems logical to suggest that DNMT1 might be at least one target in the MMRP. Rat-1 cells genetically altered to overexpress DNMT1 were also shown to be resistant to the cytotoxicity of H2O2, etoposide, and cisplatin. Finally, somatic HCT116 knockout cells that do not express either DNMT1 (DNMT1−/−) or DNMT3B (DNMT3B−/−) were shown to be more sensitive to the cytotoxicity of H2O2, etoposide, and cisplatin compared with control HCT116 cells. This work is the first example of a role for the epigenome in tumor cell resistance to the cytotoxicity of exogenous oxidative (H2O2) or systemic (etoposide and cisplatin) agents and highlights a potential role for DNMT1 as a potential molecular target in cancer therapy. (Mol Cancer Res 2008;6(2):243–9)

Upregulation of α-synuclein during localized radiation therapy signals the association of cancer-related fatigue with the activation of inflammatory and neuroprotective pathways

PURPOSE Neuroinflammatory mechanisms are associated with fatigue in neurodegenerative conditions such as Parkinsons. The symptoms in Parkinsons including fatigue are thought to be related to α-synuclein overexpression. This study investigated genomic correlates of fatigue experienced by men with prostate cancer receiving external beam radiation therapy (EBRT). PATIENTS AND METHODS Sixteen men with non-metastatic prostate cancer who were scheduled to receive EBRT were enrolled. Fatigue scores and blood were obtained at baseline (prior to EBRT, D0); one hour following initiation of EBRT (D1), day 7 (D7), day 14 (D14), midpoint (days 19-21, D21), completion (days 38-42, D42), and four weeks post-EBRT (days 68-72, D72). Gene expression profiling using microarray analysis was performed from peripheral blood and confirmatory qPCR and protein (ELISA) analyses verified the microarray results. Correlations between fatigue and gene/protein expressions were determined using a mixed model approach. RESULTS Microarray data showed significant, differential expression of 463 probesets following EBRT. SNCA had a 2.95-fold change at D21 from baseline. SNCA expression was confirmed by qPCR (p<0.001) and ELISA (p<0.001) over time during EBRT. Fatigue scores were significantly correlated with SNCA gene expression on D14 (r=0.55, p<0.05) and plasma α-synuclein concentrations on D42 of EBRT (r=0.54, p=0.04). CONCLUSION Fatigue experienced during EBRT may be mediated by α-synuclein overexpression. Alpha-synuclein may serve as a useful biomarker to understand the mechanisms and pathways related to the development of fatigue in this population.

Urine Analysis and Protein Networking Identify Met as a Marker of Metastatic Prostate Cancer

Purpose: Metastatic prostate cancer is a major cause of death of men in the United States. Expression of met, a receptor tyrosine kinase, has been associated with progression of prostate cancer. Experimental Design: To investigate met as a biomarker of disease progression, urinary met was evaluated via ELISA in men with localized (n = 75) and metastatic (n = 81) prostate cancer. Boxplot analysis was used to compare the distribution of met values between each group. We estimated a receiver operating characteristic curve and the associated area under the curve to summarize the diagnostic accuracy of met for distinguishing between localized and metastatic disease. Protein-protein interaction networking via yeast two-hybrid technology supplemented by Ingenuity Pathway Analysis and Human Interactome was used to elucidate proteins and pathways related to met that may contribute to progression of disease. Results: Met distribution was significantly different between the metastatic group and the group with localized prostate cancer and people with no evidence of cancer (P < 0.0001). The area under the curve for localized and metastatic disease was 0.90, with a 95% confidence interval of 0.84 to 0.95. Yeast two-hybrid technology, Ingenuity Pathway Analysis, and Human Interactome identified 89 proteins that interact with met, of which 40 have previously been associated with metastatic prostate cancer. Conclusion: Urinary met may provide a noninvasive biomarker indicative of metastatic prostate cancer and may be a central regulator of multiple pathways involved in prostate cancer progression.

Mitochondria-Related Gene Expression Changes Are Associated With Fatigue in Patients With Nonmetastatic Prostate Cancer Receiving External Beam Radiation Therapy

Background: Cancer-related fatigue (CRF) is associated with negative health outcomes and decreased health-related quality of life; however, few longitudinal studies have investigated molecular-genetic mechanisms of CRF. Objective: The objective of this study was to describe relationships between mitochondria-related gene expression changes and self-reported fatigue in prostate cancer patients receiving external beam radiation therapy (EBRT). Methods: A prospective, exploratory, and repeated-measures design was used. Self-report questionnaires and peripheral whole-blood samples were collected from 15 patients at 7 time points. Baseline data were compared against 15 healthy controls. The Human Mitochondria RT2 Profiler PCR Array was used to identify differential regulation of genes involved in mitochondrial biogenesis and function. Results: Compared with baseline, there were significant increases in fatigue scores (P = .02–.04) and changes in mitochondria-related gene expression (P = .001–.05) over time. Mean fatigue scores were 1.66 (SD, 1.66) at baseline, 3.06 (SD, 1.95) at EBRT midpoint, 2.98 (SD, 2.20) at EBRT completion, and 2.64 (SD, 2.56) at 30 days after EBRT. Over time, 11 genes related to mitochondrial function and structure were differentially expressed. Of these 11 genes, 3 (BCL2L1, FIS1, SLC25A37) were more than 2.5 fold up-regulated, and 8 (AIFM2, BCL2, IMMP2L, MIPEP, MSTO1, NEFL, SLC25A23, SLC25A4) were greater than 2-fold down-regulated. Furthermore, 8 genes (AIFM2, BCL2, FIS1, IMMP2L, MSTO1, SLC25A23, SLC25A37, SLC25A4) were significantly associated with the changes in fatigue scores. Conclusion: This study provides preliminary evidence that 8 mitochondrial function genes were significantly associated with fatigue in prostate cancer patients during EBRT. Implications for Practice: These findings identify possible pathways and early biomarkers for targeting novel interventions for CRF.

Parameters favorable to intraprostatic radiation dose escalation in men with localized prostate cancer.

PURPOSE To identify , within the framework of a current Phase I trial, whether factors related to intraprostatic cancer lesions (IPLs) or individual patients predict the feasibility of high-dose intraprostatic irradiation. METHODS AND MATERIALS Endorectal coil MRI scans of the prostate from 42 men were evaluated for dominant IPLs. The IPLs, prostate, and critical normal tissues were contoured. Intensity-modulated radiotherapy plans were generated with the goal of delivering 75.6 Gy in 1.8-Gy fractions to the prostate, with IPLs receiving a simultaneous integrated boost of 3.6 Gy per fraction to a total dose of 151.2 Gy, 200% of the prescribed dose and the highest dose cohort in our trial. Rectal and bladder dose constraints were consistent with those outlined in current Radiation Therapy Oncology Group protocols. RESULTS Dominant IPLs were identified in 24 patients (57.1%). Simultaneous integrated boosts (SIB) to 200% of the prescribed dose were achieved in 12 of the 24 patients without violating dose constraints. Both the distance between the IPL and rectum and the hip-to-hip patient width on planning CT scans were associated with the feasibility to plan an SIB (p = 0.002 and p = 0.0137, respectively). CONCLUSIONS On the basis of this small cohort, the distance between an intraprostatic lesion and the rectum most strongly predicted the ability to plan high-dose radiation to a dominant intraprostatic lesion. High-dose SIB planning seems possible for select intraprostatic lesions.

MRI-guided robotic prostate biopsy: a clinical accuracy validation

UNLABELLED Prostate cancer is a major health threat for men. For over five years, the U.S. National Cancer Institute has performed prostate biopsies with a magnetic resonance imaging (MRI)-guided robotic system. PURPOSE A retrospective evaluation methodology and analysis of the clinical accuracy of this system is reported. METHODS Using the pre and post-needle insertion image volumes, a registration algorithm that contains a two-step rigid registration followed by a deformable refinement was developed to capture prostate dislocation during the procedure. The method was validated by using three-dimensional contour overlays of the segmented prostates and the registrations were accurate up to 2 mm. RESULTS It was found that tissue deformation was less of a factor than organ displacement. Out of the 82 biopsies from 21 patients, the mean target displacement, needle placement error, and clinical biopsy error was 5.9 mm, 2.3 mm, and 4 mm, respectively. CONCLUSION The results suggest that motion compensation for organ displacement should be used to improve targeting accuracy.