Publications by authors named "John P Kirkpatrick"

108 Publications

Stereotactic Radiosurgery for Vestibular Schwannomas: Tumor Control Probability Analyses and Recommended Reporting Standards.

Int J Radiat Oncol Biol Phys 2020 Dec 26. Epub 2020 Dec 26.

Machine Learning Department, Moffitt Cancer Center, Tampa, Florida.

Purpose: We sought to investigate the tumor control probability (TCP) of vestibular schwannomas after single-fraction stereotactic radiosurgery (SRS) or hypofractionated SRS over 2 to 5 fractions (fSRS).

Methods And Materials: Studies (PubMed indexed from 1993-2017) were eligible for data extraction if they contained dosimetric details of SRS/fSRS correlated with local tumor control. The rate of tumor control at 5 years (or at 3 years if 5-year data were not available) were collated. Poisson modeling estimated the TCP per equivalent dose in 2 Gy per fraction (EQD2) and in 1, 3, and 5 fractions.

Results: Data were extracted from 35 publications containing a total of 5162 patients. TCP modeling was limited by the absence of analyzable data of <11 Gy in a single-fraction, variability in definition of "tumor control," and by lack of significant increase in TCP for doses >12 Gy. Using linear-quadratic-based dose conversion, the 3- to 5-year TCP was estimated at 95% at an EQD2 of 25 Gy, corresponding to 1-, 3-, and 5-fraction doses of 13.8 Gy, 19.2 Gy, and 21.5 Gy, respectively. Single-fraction doses of 10 Gy, 11 Gy, 12 Gy, and 13 Gy predicted a TCP of 85.0%, 88.4%, 91.2%, and 93.5%, respectively. For fSRS, 18 Gy in 3 fractions (EQD2 of 23.0 Gy) and 25 Gy in 5 fractions (EQD2 of 30.2 Gy) corresponded to TCP of 93.6% and 97.2%. Overall, the quality of dosimetric reporting was poor; recommended reporting guidelines are presented.

Conclusions: With current typical SRS doses of 12 Gy in 1 fraction, 18 Gy in 3 fractions, and 25 Gy in 5 fractions, 3- to 5-year TCP exceeds 91%. To improve pooled data analyses to optimize treatment outcomes for patients with vestibular schwannoma, future reports of SRS should include complete dosimetric details with well-defined tumor control and toxicity endpoints.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.019DOI Listing
December 2020

Patient outcomes and tumor control in single-fraction versus hypofractionated stereotactic body radiation therapy for spinal metastases.

J Neurosurg Spine 2020 Nov 6:1-10. Epub 2020 Nov 6.

Departments of1Neurosurgery and.

Objective: Stereotactic body radiation therapy (SBRT) offers efficient, noninvasive treatment of spinal neoplasms. Single-fraction (SF) high-dose SBRT has a relatively narrow therapeutic window, while hypofractionated delivery of SBRT may have an improved safety profile with similar efficacy. Because the optimal approach of delivery is unknown, the authors examined whether hypofractionated SBRT improves pain and/or functional outcomes and results in better tumor control compared with SF-SBRT.

Methods: This is a single-institution retrospective study of adult patients with spinal metastases treated with SF- or three-fraction (3F) SBRT from 2008 to 2019. Demographics and baseline characteristics, radiographic data, and posttreatment outcomes at a minimum follow-up of 3 months are reported.

Results: Of the 156 patients included in the study, 70 (44.9%) underwent SF-SBRT (median total dose 1700 cGy) and 86 (55.1%) underwent 3F-SBRT (median total dose 2100 cGy). At baseline, a higher proportion of patients in the 3F-SBRT group had a worse baseline profile, including severity of pain (p < 0.05), average use of pain medication (p < 0.001), and functional scores (p < 0.05) compared with the SF-SBRT cohort. At the 3-month follow-up, the 3F-SBRT cohort experienced a greater frequency of improvement in pain compared with the SF-SBRT group (p < 0.05). Furthermore, patients treated with 3F-SBRT demonstrated a higher frequency of improved Karnofsky Performance Scale (KPS) scores (p < 0.05) compared with those treated with SF-SBRT, with no significant difference in the frequency of improvement in modified Rankin Scale scores. Local tumor control did not differ significantly between the two cohorts.

Conclusions: Patients who received spinal 3F-SBRT more frequently achieved significant pain relief and an increased frequency of improvement in KPS compared with those treated with SF-SBRT. Local tumor control was similar in the two groups. Future work is needed to establish the relationship between fractionation schedule and clinical outcomes.
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http://dx.doi.org/10.3171/2020.6.SPINE20349DOI Listing
November 2020

Treatment Outcomes in Spinal Metastatic Disease With Indeterminate Stability.

Global Spine J 2020 Sep 25:2192568220956605. Epub 2020 Sep 25.

22957Duke University Medical Center, Durham, NC, USA.

Study Design: Retrospective cohort study.

Objective: The purpose of this study was to compare outcomes between different treatment modalities for metastatic disease with indeterminate instability (Spinal Instability Neoplastic Score [SINS] 7-12).

Methods: We retrospectively reviewed neurologically intact patients treated for spinal metastatic disease with a SINS of 7 to 12. The cohort was stratified by treatment approach: external beam radiation therapy alone (EBRT), surgery + EBRT (S+E), and cement augmentation + EBRT (K+E). Kaplan-Meier analysis was used to assess differences in length of survival (LOS) and ability to ambulate at time of death. Multivariate analysis was performed to assess adjusted LOS and ability to ambulate at time of death.

Results: The cohort included 211 patients, S+E (n = 57), EBRT (n = 128), and K+E (n = 27). In the S+E group, the median LOS was 430 days, which was statistically longer than the median LOS for the EBRT group (121 days) and the K+E group (169 days). In the S+E group, 52 patients (91.2%) and in the K+E group 24 patients (92.3%) retained the ability to ambulate at their time of death compared to 99 patients (77.3%) of the EBRT patients ( = .01). The overall rate of revision treatment at the spinal level initially treated was 17.5%, S+E (15.8%), EBRT (20.3%), and K+E (7.7%).

Conclusions: The length of survival, ability to maintain ambulatory ability, and revision treatment rates were all improved following surgical management and radiation therapy compared to radiation therapy alone. The authors' conclusion from these results are that patients with indeterminate spinal instability should be discussed in a multidisciplinary setting for the need of spinal stabilization in addition to radiation therapy.
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http://dx.doi.org/10.1177/2192568220956605DOI Listing
September 2020

Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient.

J Clin Oncol 2020 11 15;38(32):3773-3784. Epub 2020 Sep 15.

Miami Cancer Institute, Miami, FL.

Purpose: Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility.

Methods: A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively.

Results: Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation ( < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non-small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively.

Conclusion: Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).
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http://dx.doi.org/10.1200/JCO.20.01255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655019PMC
November 2020

Radiosurgery treatment planning using conformal arc informed volumetric modulated arc therapy.

Med Dosim 2021 Spring;46(1):3-12. Epub 2020 Aug 15.

Duke University, Durham, NC, USA; Duke University Medical Center, Durham, NC, USA.

Linac based radiosurgery to multiple metastases is commonly planned with volumetric modulated arc therapy (VMAT) as it effectively achieves high conformality to complex target arrangements. However, as the number of targets increases, VMAT can struggle to block between targets, which can lead to highly modulated and/or nonconformal multi-leaf collimator (MLC) trajectories that unnecessarily irradiation of healthy tissue. In this study we introduce, describe, and evaluate a treatment planning technique called Conformal Arc Informed VMAT (CAVMAT), which aims to reduce the dose to healthy tissue while generating highly conformal treatment plans. CAVMAT is a hybrid technique which combines the conformal MLC trajectories of dynamic conformal arcs with the MLC modulation and versatility of inverse optimization. CAVMAT has 3 main steps. First, targets are assigned to subgroups to maximize MLC blocking between targets. Second, arc weights are optimized to achieve the desired target dose, while minimizing MU variation between arcs. Third, the optimized conformal arc plan serves as the starting point for limited inverse optimization to improve dose conformity to each target. Twenty multifocal VMAT cases were replanned with CAVMAT with 20Gy applied to each target. The total volume receiving 2.5[cm], 6[cm], 12[cm], and 16[cm], conformity index, treatment delivery time, and the total MU were used to compare the VMAT and CAVMAT plans. In addition, CAVMAT was compared to a broad range of planning strategies from various institutions (108 linear accelerator based plans, 14 plans using other modalities) for a 5-target case utilized in a recent plan challenge. For the linear accelerator-based plans, a plan complexity metric based on aperture opening area and perimeter, total monitor units (MU), and MU for a given aperture opening was utilized in the plan challenge scoring algorithm to compare the submitted plans to CAVMAT. After re-planning the 20 VMAT cases, CAVMAT reduced the average V[cm] by 25.25 ± 19.23%, V[cm] by 13.68 ± 18.97%, V[cm] by 11.40 ± 19.44%, and V[cm] by 6.38 ± 19.11%. CAVMAT improved conformity by 3.81 ± 7.57%, while maintaining comparable target dose. MU for the CAVMAT plans increased by 24.35 ± 24.66%, leading to an increased treatment time of 2 minutes. For the plan challenge case, CAVMAT was 1 of 12 linac based plans that met all plan challenge scoring criteria. Compared to the average submitted VMAT plan, CAVMAT increased the VGy[%] of healthy tissue (Brain-PTV) by roughly 3.42%, but in doing so was able to reduce the VGy[%] by roughly 3.73%, while also reducing VGy[%] VGy[%], and VGy[%] The CAVMAT technique successfully eliminated insufficient MLC blocking between targets prior to the inverse optimization, leading to less complex treatment plans and improved tissue sparing. Tissue sparing, improved conformity, and decreased plan complexity at the cost of slight increase in treatment delivery time indicates CAVMAT to be a promising method to treat brain metastases.
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http://dx.doi.org/10.1016/j.meddos.2020.06.001DOI Listing
August 2020

Retrospective quality metrics review of stereotactic radiosurgery plans treating multiple targets using single-isocenter volumetric modulated arc therapy.

J Appl Clin Med Phys 2020 Jun 2;21(6):93-99. Epub 2020 Apr 2.

Department of Radiation Oncology, Duke University, Durham, NC, USA.

Purpose: To characterize key plan quality metrics in multi-target stereotactic radiosurgery (SRS) plans treated using single-isocenter volumetric modulated arc therapy (VMAT) in comparison to dynamic conformal arc (DCA) plans treating single target. To investigate the feasibility of quality improvement in VMAT planning based on previous planning knowledge.

Materials And Methods: 97 VMAT plans of multi-target and 156 DCA plans of single-target treated in 2017 at a single institution were reviewed. A total of 605 targets were treated with these SRS plans. The prescription dose was normalized to 20 Gy in all plans for this analysis. Two plan quality metrics, target conformity index (CI) and normal tissue volume receiving more than 12 Gy (V12Gy), were calculated for each target. The distribution of V12Gy per target was plotted as a function of the target volume. For multi-target VMAT plans, the number of targets being treated in the same plan and the distance between targets were calculated to evaluate their impact on V12Gy. VMAT plans that had a large deviation of V12Gy from the average level were re-optimized to determine the possibility of reducing the variation of V12Gy in VMAT planning.

Results: Conformity index of multi-target VMAT plans were lower than that of DCA plans while the mean values of 12 Gy were comparable. The V12Gy for a target in VMAT plan did not show apparent dependence on the total number of targets or the distance between targets. The distribution of V12Gy exhibited a larger variation in VMAT plans compared to DCA plans. Re-optimization of outlier plans reduced V12 Gy by 33.9% and resulted in the V12Gy distribution in VMAT plans more closely resembling that of DCA plans.

Conclusion: The benchmark data on key plan quality metrics were established for single-isocenter multi-target SRS planning. It is feasible to use this knowledge to guide VMAT planning and reduce high V12Gy outliers.
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http://dx.doi.org/10.1002/acm2.12869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324703PMC
June 2020

H, C, N chemical shift assignments of SHP2 SH2 domains in complex with PD-1 immune-tyrosine motifs.

Biomol NMR Assign 2020 10 1;14(2):179-188. Epub 2020 Apr 1.

Center for Biomolecular Drug Design and Institute of Organic Chemistry, Leibniz University Hannover, Schneiderberg 38, 30167, Hannover, Germany.

Inhibition of immune checkpoint receptor Programmed Death-1 (PD-1) via monoclonal antibodies is an established anticancer immunotherapeutic approach. This treatment has been largely successful; however, its high cost demands equally effective, more affordable alternatives. To date, the development of drugs targeting downstream players in the PD-1-dependent signaling pathway has been hampered by our poor understanding of the molecular details of the intermolecular interactions involved in the pathway. Activation of PD-1 leads to phosphorylation of two signaling motifs located in its cytoplasmic domain, the immune tyrosine inhibitory motif (ITIM) and immune tyrosine switch motif (ITSM), which recruit and activate protein tyrosine phosphatase SHP2. This interaction is mediated by the two Src homology 2 (SH2) domains of SHP2, termed N-SH2 and C-SH2, which recognize phosphotyrosines pY223 and pY248 of ITIM and ITSM, respectively. SHP2 then propagates the inhibitory signal, ultimately leading to suppression of T cell functionality. In order to facilitate mechanistic structural studies of this signaling pathway, we report the resonance assignments of the complexes formed by the signaling motifs of PD-1 and the SH2 domains of SHP2.
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http://dx.doi.org/10.1007/s12104-020-09941-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462904PMC
October 2020

Patterns of relapse after successful completion of initial therapy in primary central nervous system lymphoma: a case series.

J Neurooncol 2020 Apr 5;147(2):477-483. Epub 2020 Mar 5.

Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.

Purpose: Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin's lymphoma that involves the brain, spinal cord, or leptomeninges, without evidence of systemic disease. This rare disease accounts for ~ 3% of all primary central nervous system (CNS) tumors. Methotrexate-based regimens are the standard of care for this disease with overall survival rates ranging from 14 to 55 months. Relapse after apparent complete remission can occur. We sought to understand the outcomes of patients who relapsed.

Methods: This is an IRB-approved investigation of patients treated at our institution between 12/31/2004 and 10/12/2016. We retrospectively identified all cases of PCNSL as part of a database registry and evaluated these cases for demographic information, absence or presence of relapse, location of relapse, treatment regimens, and median relapse-free survival.

Results: This analysis identified 44 patients with a pathologically confirmed diagnosis of PCNSL. Mean age at diagnosis was 63.1 years (range 20-86, SD = 13.2 years). Of the 44 patients, 28 patients successfully completed an initial treatment regimen without recurrence or toxicity that required a change in therapy. Relapse occurred in 11 patients with the location of relapse being in the CNS only (n = 5), vitreous fluid only (n = 1), outside CNS only (n = 3), or a combination of CNS and outside of the CNS (n = 2). Sites of relapse outside of the CNS included testes (n = 1), lung (n = 1), adrenal gland (n = 1), kidney/adrenal gland (n = 1), and retroperitoneum (n = 1). Median relapse-free survival after successful completion of therapy was 6.7 years (95% CI 1.1, 12.6).

Conclusion: After successful initial treatment, PCNSL has a propensity to relapse, and this relapse can occur both inside and outside of the CNS. Vigilant monitoring of off-treatment patients with a history of PCNSL is necessary to guide early diagnosis of relapse and to initiate aggressive treatment.
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http://dx.doi.org/10.1007/s11060-020-03446-3DOI Listing
April 2020

Beyond an Updated Graded Prognostic Assessment (Breast GPA): A Prognostic Index and Trends in Treatment and Survival in Breast Cancer Brain Metastases From 1985 to Today.

Int J Radiat Oncol Biol Phys 2020 06 19;107(2):334-343. Epub 2020 Feb 19.

Miami Cancer Institute, Miami, Florida.

Purpose: Brain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts.

Methods And Materials: A multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively.

Results: Median survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01).

Conclusions: MS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.
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http://dx.doi.org/10.1016/j.ijrobp.2020.01.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276246PMC
June 2020

Radiation Therapy Practice Patterns for Brain Metastases in the United States in the Stereotactic Radiosurgery Era.

Adv Radiat Oncol 2020 Jan-Feb;5(1):43-52. Epub 2019 Jul 26.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Purpose: Utilization of stereotactic radiosurgery (SRS) for brain metastases (BM) has increased, prompting reassessment of whole brain radiation therapy (WBRT). A pattern of care analysis of SRS and WBRT dose-fractionations was performed in patients presenting with BM at the time of cancer diagnosis.

Methods And Materials: Adults with BM at cancer diagnosis between 2010 to 2015 and no prior malignancy were identified in the National Cancer Database. SRS was defined using published thresholds. Short (ShWBRT), standard (StWBRT), and extended (ExWBRT) dose-fractionations were defined as 4 to 9, 10 to 15, and >15 fractions. Radioresistant histology was defined as melanoma, renal cell carcinoma, sarcoma or spindle cell, or gastrointestinal primary.

Results: Of 4,087,967 adults with their first lifetime cancer, 90,388 (2.2%) had BM at initial diagnosis. Of these, 11,486 (12.7%) received SRS and 24,262 (26.8%) WBRT as first-course radiation therapy. The proportion of annual WBRT use decreased from 27.8% to 23.5% of newly diagnosed patients, and SRS increased from 8.7% to 17.9%. Common dose-fractionations were 30 Gy in 10 fractions (56.8%) for WBRT and 20 Gy in 1 fraction (13.0%) for SRS. On multivariate analysis, factors significantly associated with SRS versus WBRT included later year of diagnosis (2015 vs 2010, adjusted odds ratio [aOR] = 2.4), radioresistance (aOR = 2.0), academic facility (aOR = 1.9), highest income quartile (aOR = 1.6), chemotherapy administration (aOR = 1.4), and longer travel distance (>15 vs < 5 miles, aOR = 1.4). Linear regression revealed significant ExWBRT reductions (-22.4%/y, R = 0.97,  < .001) and no significant change for ShWBRT or StWBRT. Patients were significantly more likely to receive ShWBRT than StWBRT if not treated with chemotherapy (aOR = 3.5).

Conclusions: Utilization of WBRT, particularly ExWBRT, decreased while SRS utilization doubled as the first radiation therapy course in patients with BM at diagnosis. Patients with radioresistant histologies were more likely to receive SRS. Those not receiving chemotherapy, potentially owing to poor performance status, were less likely to receive SRS and more likely to receive ShWBRT.
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http://dx.doi.org/10.1016/j.adro.2019.07.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004940PMC
July 2019

Estrogen/progesterone receptor and HER2 discordance between primary tumor and brain metastases in breast cancer and its effect on treatment and survival.

Neuro Oncol 2020 09;22(9):1359-1367

Miami Cancer Institute, Miami, Florida, USA.

Background: Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM).

Methods: A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM.

Results: The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08).

Conclusions: Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly.

Key Points: 1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.
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http://dx.doi.org/10.1093/neuonc/noaa025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523450PMC
September 2020

Classifying Leptomeningeal Disease: An Essential Element in Managing Advanced Metastatic Disease in the Central Nervous System.

Int J Radiat Oncol Biol Phys 2020 03;106(3):587-588

Department of Radiation Oncology, Duke Center for Brain and Spine Metastasis, Duke University, Durham, North Carolina; Department of Neurosurgery, Duke Center for Brain and Spine Metastasis, Duke University, Durham, North Carolina. Electronic address:

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http://dx.doi.org/10.1016/j.ijrobp.2019.12.016DOI Listing
March 2020

Predicting intracranial progression following stereotactic radiosurgery for brain metastases: Implications for post SRS imaging.

J Radiosurg SBRT 2019 ;6(3):179-187

Department of Radiation Oncology, Duke University, Durham, NC, USA.

Purpose: Follow-up imaging after stereotactic radiosurgery (SRS) is crucial to identify salvageable brain metastases (BM) recurrence. As optimal imaging intervals are poorly understood, we sought to build a predictive model for time to intracranial progression.

Methods: Consecutive patients treated with SRS for BM at three institutions from January 1, 2002 to June 30, 2017 were retrospectively reviewed. We developed a model using stepwise regression that identified four prognostic factors and built a predictive nomogram.

Results: We identified 755 patients with primarily non-small cell lung, breast, and melanoma BMs. Factors such as number of BMs, histology, history of prior whole-brain radiation, and time interval from initial cancer diagnosis to metastases were prognostic for intracranial progression. Per our nomogram, risk of intracranial progression by 3 months post-SRS in the high-risk group was 21% compared to 11% in the low-risk group; at 6 months, it was 43% versus 27%.

Conclusion: We present a nomogram estimating time to BM progression following SRS to potentially personalize surveillance imaging.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774486PMC
January 2019

Current multidisciplinary management of brain metastases.

Cancer 2020 04 23;126(7):1390-1406. Epub 2020 Jan 23.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.

Brain metastasis (BM), the most common adult brain tumor, develops in 20% to 40% of patients with late-stage cancer and traditionally are associated with a poor prognosis. The management of patients with BM has become increasingly complex because of new and emerging systemic therapies and advancements in radiation oncology and neurosurgery. Current therapies include stereotactic radiosurgery, whole-brain radiation therapy, surgical resection, laser-interstitial thermal therapy, systemic cytotoxic chemotherapy, targeted agents, and immune-checkpoint inhibitors. Determining the optimal treatment for a specific patient has become increasingly individualized, emphasizing the need for multidisciplinary discussions of patients with BM. Recognizing and addressing the sequelae of BMs and their treatment while maintaining quality of life and neurocognition is especially important because survival for patients with BMs has improved. The authors present current and emerging treatment options for patients with BM and suggest approaches for managing sequelae and disease recurrence.
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http://dx.doi.org/10.1002/cncr.32714DOI Listing
April 2020

Recurrent Extradural Myxopapillary Ependymoma With Oligometastatic Spread.

Front Oncol 2019 28;9:1322. Epub 2019 Nov 28.

The Preston Robert Tisch Brain Tumor Center, Duke University Health System, Durham, NC, United States.

Myxopapillary ependymomas are a slow-growing, grade I type glial tumor in the lumbosacral region. More rarely, they can present as extradural, subcutaneous sacrococcygeal, or perisacral masses, and it is under these circumstances that they are more likely to spread. Here, we report the presentation of a sacrococcygeal mass in patient that was initially resected confirming extradural myxopapillary ependymoma. At initial resection, multiple small pulmonary nodules were detected. This mass recurred 2 years later at the resection site with an interval increase in the previously imaged pulmonary nodules. Resection of both the post-sacral mass and largest lung metastasis confirmed recurrent myxopapillary ependymoma with oligometastatic spread. Because these tumors are rare, with extradural presentation being even more infrequent, to this date there are no definitive therapeutic guidelines for initial treatment and continued surveillance. For myxopapillary ependymoma, current standard of care is first-line maximal surgical resection with or without postoperative radiotherapy depending on the extent of disease and extent of resection. However, there remains insufficient evidence on the role of radiotherapy to oligometastatic foci in providing any further survival benefit or extending time to recurrence. Thus, prospective studies assessing the role of upfront treatment of oligometastases with local resection and adjuvant radiotherapy are needed for improved understanding of extradural myxopapillary ependymoma.
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http://dx.doi.org/10.3389/fonc.2019.01322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892774PMC
November 2019

An investigation of machine learning methods in delta-radiomics feature analysis.

PLoS One 2019 13;14(12):e0226348. Epub 2019 Dec 13.

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, United States of America.

Purpose: This study aimed to investigate the effectiveness of using delta-radiomics to predict overall survival (OS) for patients with recurrent malignant gliomas treated by concurrent stereotactic radiosurgery and bevacizumab, and to investigate the effectiveness of machine learning methods for delta-radiomics feature selection and building classification models.

Methods: The pre-treatment, one-week post-treatment, and two-month post-treatment T1 and T2 fluid-attenuated inversion recovery (FLAIR) MRI were acquired. 61 radiomic features (intensity histogram-based, morphological, and texture features) were extracted from the gross tumor volume in each image. Delta-radiomics were calculated between the pre-treatment and post-treatment features. Univariate Cox regression and 3 multivariate machine learning methods (L1-regularized logistic regression [L1-LR], random forest [RF] or neural networks [NN]) were used to select a reduced number of features, and 7 machine learning methods (L1-LR, L2-LR, RF, NN, kernel support vector machine [KSVM], linear support vector machine [LSVM], or naïve bayes [NB]) was used to build classification models for predicting OS. The performances of the total 21 model combinations built based on single-time-point radiomics (pre-treatment, one-week post-treatment, and two-month post-treatment) and delta-radiomics were evaluated by the area under the receiver operating characteristic curve (AUC).

Results: For a small cohort of 12 patients, delta-radiomics resulted in significantly higher AUC than pre-treatment radiomics (p-value<0.01). One-week/two-month delta-features resulted in significantly higher AUC (p-value<0.01) than the one-week/two-month post-treatment features, respectively. 18/21 model combinations were with higher AUC from one-week delta-features than two-month delta-features. With one-week delta-features, RF feature selector + KSVM classifier and RF feature selector + NN classifier showed the highest AUC of 0.889.

Conclusions: The results indicated that delta-features could potentially provide better treatment assessment than single-time-point features. The treatment assessment is substantially affected by the time point for computing the delta-features and the combination of machine learning methods for feature selection and classification.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226348PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910670PMC
April 2020

The role of chemotherapy in the treatment of central neurocytoma.

CNS Oncol 2019 11 5;8(3):CNS41. Epub 2019 Nov 5.

Department of Neurosurgery, Duke University Hospital, Durham, NC 27710, USA.

Central neurocytoma (CN) is a rare WHO grade II central nervous system (CNS) tumor. This is an update on chemotherapeutic agents used in its treatment. An institutional review board-approved, chart review of patients seen at our institution resulted in a single case treated with chemotherapy and is herein included. We proceeded with a comprehensive literature review. We identified 18 citations, representing 39 cases of adult and pediatric CN treated with chemotherapy. With the addition of our single case, the total number of recurrent CN patients treated with temozolomide (TMZ) is nine. There exists marked heterogeneity in chemotherapy used to treat CN. TMZ is incorporated into treatment regimens in the setting of tumor recurrence: its role merits further study.
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http://dx.doi.org/10.2217/cns-2019-0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880304PMC
November 2019

Offer Hypofractionated SRS… If Her Performance Status Is Good.

Int J Radiat Oncol Biol Phys 2019 12 24;105(5):940-941. Epub 2019 Oct 24.

The Center for Brain and Spine Metastasis, Duke University Medical Center, Durham, North Carolina.

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http://dx.doi.org/10.1016/j.ijrobp.2018.07.001DOI Listing
December 2019

Management of Unruptured AVMs: The Pendulum Swings.

Int J Radiat Oncol Biol Phys 2019 11;105(4):687-689

Department of Radiation Oncology, Duke University, Durham, North Carolina; Department of Neurosurgery, Duke University, Durham, North Carolina. Electronic address:

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http://dx.doi.org/10.1016/j.ijrobp.2019.08.026DOI Listing
November 2019

Probing the dynamic stalk region of the ribosome using solution NMR.

Sci Rep 2019 09 19;9(1):13528. Epub 2019 Sep 19.

Institute of Structural and Molecular Biology, UCL and Birkbeck College London, Gower Street, London, WC1E 6BT, UK.

We describe an NMR approach based on the measurement of residual dipolar couplings (RDCs) to probe the structural and motional properties of the dynamic regions of the ribosome. Alignment of intact 70S ribosomes in filamentous bacteriophage enabled measurement of RDCs in the mobile C-terminal domain (CTD) of the stalk protein bL12. A structural refinement of this domain using the observed RDCs did not show large changes relative to the isolated protein in the absence of the ribosome, and we also found that alignment of the CTD was almost independent of the presence of the core ribosome particle, indicating that the inter-domain linker has significant flexibility. The nature of this linker was subsequently probed in more detail using a paramagnetic alignment strategy, which revealed partial propagation of alignment between neighbouring domains, providing direct experimental validation of a structural ensemble previously derived from SAXS and NMR relaxation measurements. Our results demonstrate the prospect of better characterising dynamical and functional regions of more challenging macromolecular machines and systems, for example ribosome-nascent chain complexes.
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http://dx.doi.org/10.1038/s41598-019-49190-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753160PMC
September 2019

Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).

Clin Transl Radiat Oncol 2019 Sep 27;18:39-45. Epub 2019 Jun 27.

Miami Cancer Institute, USA.

Background: Patients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985-2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database.

Methods: An IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA.

Results: Median survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0-1, 1.5-2, 2.5-3.0 and 3.5-4.0, respectively. >30% present in the worst prognostic group (GI-GPA of ≤1.0).

Conclusions: Brain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com.
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http://dx.doi.org/10.1016/j.ctro.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612649PMC
September 2019

The Evolving Modern Management of Brain Metastasis.

Clin Cancer Res 2019 11 18;25(22):6570-6580. Epub 2019 Jun 18.

Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

The incidence of brain metastases is increasing as cancer therapies improve and patients live longer, providing new challenges to the multidisciplinary teams that care for these patients. Brain metastatic cancer cells possess unique characteristics that allow them to penetrate the blood-brain barrier, colonize the brain parenchyma, and persist in the intracranial environment. In addition, brain metastases subvert the innate and adaptive immune system, permitting evasion of the antitumor immune response. Better understanding of the above mechanisms will allow for development and delivery of more effective therapies for brain metastases. In this review, we outline the molecular mechanisms underlying development, survival, and immunosuppression of brain metastases. We also discuss current and emerging treatment strategies, including surgery, radiation, disease-specific and mutation-targeted systemic therapy, and immunotherapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1624DOI Listing
November 2019

Survival and prognostic factors in patients with gastrointestinal cancers and brain metastases: have we made progress?

Transl Res 2019 06 27;208:63-72. Epub 2019 Feb 27.

Miami Cancer Institute.

The literature describing the prognosis of patients with gastrointestinal (GI) cancers and brain metastases (BM) is sparse. Our group previously published a prognostic index, the Graded Prognostic Assessment (GPA) for GI cancer patients with BM, based on 209 patients diagnosed from 1985-2005. The purpose of this analysis is to identify prognostic factors for GI cancer patients with newly diagnosed BM in a larger contemporary cohort. A multi-institutional retrospective IRB-approved database of 792 GI cancer patients with new BM diagnosed from 1/1/2006 to 12/31/2016 was created. Demographic data, clinical parameters, and treatment were correlated with survival and time from primary diagnosis to BM (TPDBM). Kaplan-Meier median survival (MS) estimates were calculated and compared with log-rank tests. The MS from time of first treatment for BM for the prior and current cohorts were 5 and 8 months, respectively (P < 0.001). Eight prognostic factors (age, stage, primary site, resection of primary tumor, Karnofsky Performance Status (KPS), extracranial metastases, number of BM and Hgb were found to be significant for survival, in contrast to only one (KPS) in the prior cohort. In this cohort, the most common primary sites were rectum (24%) and esophagus (23%). Median TPDBM was 22 months. Notably, 37% (267/716) presented with poor prognosis (GPA 0-1.0). Although little improvement in overall survival in this cohort has been achieved in recent decades, survival varies widely and multiple new prognostic factors were identified. Future work will translate these factors into a prognostic index to facilitate clinical decision-making and stratification of future clinical trials.
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http://dx.doi.org/10.1016/j.trsl.2019.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527460PMC
June 2019

The effect of setup uncertainty on optimal dosimetric margin in LINAC-based stereotactic radiosurgery with dynamic conformal arc technique.

J Radiosurg SBRT 2019 ;6(1):55-65

Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.

Purpose: To estimate the combined effect of setup uncertainty on optimal dosimetric margin by analyzing the dose distribution and biological effect in LINAC-based stereotactic radiosurgery (SRS) with dynamic conformal arc (DCA) technique.

Methods: SRS treatment plans were generated from CT scans of the Rando head phantom using four non-coplanar DCA's with total 480-degrees of arc. A single spherical planning target volume (PTV) of 4 different diameters was placed at the center of the phantom to simulate brain lesions. For each PTV, 5 treatment plans were created using identical dose calculation parameters, each with 5 different dosimetric margins. To simulate the effect of setup uncertainty, the isocenter for each plan was shifted to 13 different positions. A marginal dose of 20Gy in a single fraction with 6MV photon beam was prescribed to 49 different percentage isodose surfaces (%IDS). The plan quality was evaluated using Conformity Index (CI), Gradient Index (GI), EUD-based Tumor Control Probability (TCP), Normal Tissue Complication Probability (NTCP), and uncomplicated biological objective function (TCP x (1-NTCP) =p+).

Results: A +1mm dosimetric margin could result in a much higher p+ compared to 0mm and 1mm dosimetric margins and a smaller GI while achieving an equivalent p+ in a certain range of %IDS compared to +2mm and +3mm dosimetric margins. With 2mm setup error and +1mm dosimetric margin, the %IDS range optimized for each PTV is: around 80%IDS (10mm diameter); 63~70%IDS (20mm diameter); 66~79%IDS (30mm diameter).

Conclusion: This simulation study identified the preferred prescription %IDS for a given setup error and dosimetric margin to achieve an optimal dose distribution and favorable biological effect.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355454PMC
January 2019

Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool.

Neuro Oncol 2018 11;20(12):1652-1660

Miami Cancer Institute, Department of Radiation Oncology, Miami, Florida.

Background: Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985-2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors.

Methods: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively.

Results: The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0-1.0, 1.5-2.0, 2.5-3, and 3.5-4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively.

Conclusion: The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.
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http://dx.doi.org/10.1093/neuonc/noy099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231200PMC
November 2018

Effect of Targeted Therapies on Prognostic Factors, Patterns of Care, and Survival in Patients With Renal Cell Carcinoma and Brain Metastases.

Int J Radiat Oncol Biol Phys 2018 07 12;101(4):845-853. Epub 2018 Apr 12.

Miami Cancer Institute, Miami, Florida.

Purpose: To identify prognostic factors, define evolving patterns of care, and the effect of targeted therapies in a larger contemporary cohort of renal cell carcinoma (RCC) patients with new brain metastases (BM).

Methods And Materials: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new BM diagnosed from January 1, 2006, to December 31, 2015, was created. Clinical parameters and treatment were correlated with median survival and time from primary diagnosis to BM. Multivariable analyses were performed.

Results: The median survival for the prior/present cohorts was 9.6/12 months, respectively (P < .01). Four prognostic factors (Karnofsky performance status, extracranial metastases, number of BM, and hemoglobin b) were significant for survival after the diagnosis of BM. Of the 6 drug types studied, only cytokine use after BM was associated with improved survival. The use of whole-brain radiation therapy declined from 50% to 22%, and the use of stereotactic radiosurgery alone increased from 46% to 58%. Nonneurologic causes of death were twice as common as neurologic causes.

Conclusions: Additional prognostic factors refine prognostication in this larger contemporary cohort. Patterns of care have changed, and survival of RCC patients with BM has improved over time. The reasons for this improvement in survival remain unknown but may relate to more aggressive use of local brain metastasis therapy and a wider array of systemic treatment options for those patients with progressive extracranial tumor.
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http://dx.doi.org/10.1016/j.ijrobp.2018.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925530PMC
July 2018

Proton Therapy for Brain Metastases: A Question of Value.

Int J Radiat Oncol Biol Phys 2018 07 20;101(4):830-832. Epub 2018 Jun 20.

Department of Radiation Oncology, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina.

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http://dx.doi.org/10.1016/j.ijrobp.2018.05.005DOI Listing
July 2018