Publications by authors named "Jean Nakamura"

53 Publications

Redistributing Central Target Dose Hot Spots for Hypofractionated Radiosurgery of Large Brain Tumors: A Proof-of-Principle Study.

Acta Neurochir Suppl 2021 ;128:101-106

Department of Radiation Oncology, University of California San Francisco (UCSF), San Francisco, CA, USA.

Objective: The present proof-of-principle study investigated radiobiological effects of redistributing central target dose hot spots across different treatment fractions during hypofractionated stereotactic radiosurgery (HSRS) of large intracranial tumors.

Methods: Redistribution of central target dose hot spots during HSRS was simulated, and its effects were evaluated in eight cases of brain metastases. To assess dose variations in the target across N number of treatment fractions, a generalized biologically effective dose (gBED) was formulated. The gBED enhancement ratio was defined as the ratio of gBED in the tested treatment plan (with central target dose hot spot redistributions across fractions) to gBED in the conventional treatment plan (without central target dose hot spot redistributions).

Results: At a median α value of 0.3/Gy, the tested treatment plans resulted in average gBED increases of 15.6 ± 3.5% and 8.3 ± 1.8% for α/β ratios of 2 and 10 Gy, respectively. In comparison with conventional treatment plans, the differences in the Paddick conformity index and gradient index did not exceed 2%.

Conclusion: Redistributing central target dose hot spots across different treatment fractions during HSRS may be considered promising for enhancing gBED in the target. It may be beneficial for management of large intracranial neoplasms; thus, it warrants further clinical testing.
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http://dx.doi.org/10.1007/978-3-030-69217-9_10DOI Listing
July 2021

Irradiation of mutant mouse models of spinal plexiform neurofibromas drives pathologic progression and decreases survival.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab063. Epub 2021 Apr 23.

Department of Radiation Oncology, School of Medicine, University of California, San Francisco, San Francisco, California, USA.

Background: Genetically susceptible individuals can develop malignancies after irradiation of normal tissues. In the context of therapeutic irradiation, it is not known whether irradiating benign neoplasms in susceptible individuals promotes neoplastic transformation and worse clinical outcomes. Individuals with Neurofibromatosis 1 (NF1) are susceptible to both radiation-induced second malignancies and spontaneous progression of plexiform neurofibromas (PNs) to malignant peripheral nerve sheath tumors (MPNSTs). The role of radiotherapy in the treatment of benign neoplasms such as PNs is unclear.

Methods: To test whether radiotherapy promotes neoplastic progression of PNs and reduces overall survival, we administered spinal irradiation (SI) to conditional knockout mouse models of NF1-associated PNs in 2 germline contexts: and . Both genotypes develop extensive null spinal PNs, modeling PNs in NF1 patients. A total of 101 mice were randomized to 0 Gy, 15 Gy (3 Gy × 5), or 30 Gy (3 Gy × 10) of spine-focused, fractionated SI and aged until signs of illness.

Results: SI decreased survival in both mice and mice, with the worst overall survival occurring in mice receiving 30 Gy. SI was also associated with increasing worrisome histologic features along the PN-MPNST continuum in PNs irradiated to higher radiation doses.

Conclusions: This preclinical study provides experimental evidence that irradiation of pre-existing PNs reduces survival and may shift PNs to higher grade neoplasms.
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http://dx.doi.org/10.1093/noajnl/vdab063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193912PMC
April 2021

Neuro-Oncology Practice Clinical Debate: Early treatment or observation for patients with newly diagnosed oligodendroglioma and small-volume residual disease.

Neurooncol Pract 2021 Feb 27;8(1):11-17. Epub 2020 Jun 27.

Department of Hematology and Medical Oncology, New York University, New York, NY, USA.

Advances in treatment of oligodendroglioma represent arguably the most significant recent development in the treatment of brain tumors, with multiple clinical trials demonstrating that median survival is approximately doubled in patients with World Health Organization grade II and III 1p/19q codeleted gliomas (ie, oligodendrogliomas) treated with procarbazine, lomustine, vincristine chemotherapy and radiation vs radiation alone. However, chemoradiotherapy itself is not without morbidity, including both short-term toxicities primarily related to chemotherapy and longer-term cognitive issues likely due to radiation. Patients and physicians both desire maximally effective therapy with minimal toxicity, and it remains unclear whether some patients with macroscopic residual disease after surgery can safely delay therapy, to avoid or delay toxicity, while simultaneously preserving the full benefits of treatment. In this article, experts in the field discuss the rationale for the approaches of up-front treatment with chemoradiotherapy and initial observation, respectively.
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http://dx.doi.org/10.1093/nop/npaa037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906263PMC
February 2021

Differentiating Radiation Necrosis from Brain Tumor Using Hyperpolarized Carbon-13 MR Metabolic Imaging.

Mol Imaging Biol 2021 06 13;23(3):417-426. Epub 2021 Jan 13.

Department of Radiation Oncology, University of California San Francisco, 505 Parnassus Ave, San Francisco, California, 94143, USA.

Purpose: Differentiation between radiation-induced necrosis and tumor recurrence is crucial to determine proper management strategies but continues to be one of the central challenges in neuro-oncology. We hypothesized that hyperpolarized C MRI, a unique technique to measure real-time in vivo metabolism, would distinguish radiation necrosis from tumor on the basis of cell-intrinsic metabolic differences. The purpose of this study was to explore the feasibility of using hyperpolarized [1-C]pyruvate for differentiating radiation necrosis from brain tumors.

Procedures: Radiation necrosis was initiated by employing a CT-guided 80-Gy single-dose irradiation of a half cerebrum in mice (n = 7). Intracerebral tumor was modeled with two orthotopic mouse models: GL261 glioma (n = 6) and Lewis lung carcinoma (LLC) metastasis (n = 7). C 3D MR spectroscopic imaging data were acquired following hyperpolarized [1-C]pyruvate injection approximately 89 and 14 days after treatment for irradiated and tumor-bearing mice, respectively. The ratio of lactate to pyruvate (Lac/Pyr), normalized lactate, and pyruvate in contrast-enhancing lesion was compared between the radiation-induced necrosis and brain tumors. Histopathological analysis was performed from resected brains.

Results: Conventional MRI exhibited typical radiographic features of radiation necrosis and brain tumor with large areas of contrast enhancement and T2 hyperintensity in all animals. Normalized lactate in radiation necrosis (0.10) was significantly lower than that in glioma (0.26, P = .004) and LLC metastatic tissue (0.25, P = .00007). Similarly, Lac/Pyr in radiation necrosis (0.18) was significantly lower than that in glioma (0.55, P = .00008) and LLC metastasis (0.46, P = .000008). These results were consistent with histological findings where tumor-bearing brains were highly cellular, while irradiated brains exhibited pathological markers consistent with reparative changes from radiation necrosis.

Conclusion: Hyperpolarized C MR metabolic imaging of pyruvate is a noninvasive imaging method that differentiates between radiation necrosis and brain tumors, providing a groundwork for further clinical investigation and translation for the improved management of patients with brain tumors.
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http://dx.doi.org/10.1007/s11307-020-01574-wDOI Listing
June 2021

A Prognostic Gene-Expression Signature and Risk Score for Meningioma Recurrence After Resection.

Neurosurgery 2020 12;88(1):202-210

Department of Radiation Oncology, University of California San Francisco, San Francisco, California.

Background: Prognostic markers for meningioma are needed to risk-stratify patients and guide postoperative surveillance and adjuvant therapy.

Objective: To identify a prognostic gene signature for meningioma recurrence and mortality after resection using targeted gene-expression analysis.

Methods: Targeted gene-expression analysis was used to interrogate a discovery cohort of 96 meningiomas and an independent validation cohort of 56 meningiomas with comprehensive clinical follow-up data from separate institutions. Bioinformatic analysis was used to identify prognostic genes and generate a gene-signature risk score between 0 and 1 for local recurrence.

Results: We identified a 36-gene signature of meningioma recurrence after resection that achieved an area under the curve of 0.86 in identifying tumors at risk for adverse clinical outcomes. The gene-signature risk score compared favorably to World Health Organization (WHO) grade in stratifying cases by local freedom from recurrence (LFFR, P < .001 vs .09, log-rank test), shorter time to failure (TTF, F-test, P < .0001), and overall survival (OS, P < .0001 vs .07) and was independently associated with worse LFFR (relative risk [RR] 1.56, 95% CI 1.30-1.90) and OS (RR 1.32, 95% CI 1.07-1.64), after adjusting for clinical covariates. When tested on an independent validation cohort, the gene-signature risk score remained associated with shorter TTF (F-test, P = .002), compared favorably to WHO grade in stratifying cases by OS (P = .003 vs P = .10), and was significantly associated with worse OS (RR 1.86, 95% CI 1.19-2.88) on multivariate analysis.

Conclusion: The prognostic meningioma gene-expression signature and risk score presented may be useful for identifying patients at risk for recurrence.
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http://dx.doi.org/10.1093/neuros/nyaa355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735867PMC
December 2020

Defining the ATPome reveals cross-optimization of metabolic pathways.

Nat Commun 2020 08 28;11(1):4319. Epub 2020 Aug 28.

Gladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA.

Disrupted energy metabolism drives cell dysfunction and disease, but approaches to increase or preserve ATP are lacking. To generate a comprehensive metabolic map of genes and pathways that regulate cellular ATP-the ATPome-we conducted a genome-wide CRISPR interference/activation screen integrated with an ATP biosensor. We show that ATP level is modulated by distinct mechanisms that promote energy production or inhibit consumption. In our system HK2 is the greatest ATP consumer, indicating energy failure may not be a general deficiency in producing ATP, but rather failure to recoup the ATP cost of glycolysis and diversion of glucose metabolites to the pentose phosphate pathway. We identify systems-level reciprocal inhibition between the HIF1 pathway and mitochondria; glycolysis-promoting enzymes inhibit respiration even when there is no glycolytic ATP production, and vice versa. Consequently, suppressing alternative metabolism modes paradoxically increases energy levels under substrate restriction. This work reveals mechanisms of metabolic control, and identifies therapeutic targets to correct energy failure.
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http://dx.doi.org/10.1038/s41467-020-18084-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455733PMC
August 2020

-Mutant Tumors Undergo Transcriptome and Kinome Remodeling after Inhibition of either mTOR or MEK.

Mol Cancer Ther 2020 Aug 26. Epub 2020 Aug 26.

Department of Radiation Oncology, University of California San Francisco, San Francisco, California.

Loss of the tumor suppressor leads to activation of RAS effector pathways, which are therapeutically targeted by inhibition of mTOR (mTORi) or MEK (MEKi). However, therapeutic inhibition of RAS effectors leads to the development of drug resistance and ultimately disease progression. To investigate molecular signatures in the context of loss and subsequent acquired drug resistance, we analyzed the exomes, transcriptomes, and kinomes of -mutant mouse tumor cell lines and derivatives of these lines that acquired resistance to either MEKi or mTORi. Biochemical comparisons of this unique panel of tumor cells, all of which arose in mice, indicate that loss of heterozygosity of as an initial genetic event does not confer a common biochemical signature or response to kinase inhibition. Although acquired drug resistance by -mutant tumor cells was accompanied by altered kinomes and irreversibly altered transcriptomes, functionally in multiple -mutant tumor cell lines, MEKi resistance was a stable phenotype, in contrast to mTORi resistance, which was reversible. Collectively, these findings demonstrate that -mutant tumors represent a heterogeneous group biochemically and undergo broader remodeling of kinome activity and gene expression in response to targeted kinase inhibition.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-1017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907257PMC
August 2020

Germline MUTYH Mutation in a Pediatric Cancer Survivor Developing a Secondary Malignancy.

J Pediatr Hematol Oncol 2020 10;42(7):e647-e654

Department of Radiation Oncology.

Radiotherapy-induced second malignant neoplasms (SMNs) are a severe late complication in pediatric cancer survivors. Germline mutations in tumor suppressor genes contribute to SMNs; however, the most relevant germline variants mediating susceptibility are not fully defined. The authors performed matched whole-exome sequencing analyses of germline and tumor DNA from 4 pediatric solid tumor survivors who subsequently developed radiation-associated SMNs. Pathogenic and predicted deleterious germline variants were identified for each patient and validated with Sanger sequencing. These germline variants were compared with germline variants in a cohort of 59 pediatric patients diagnosed with primary sarcomas. Pathway analysis was performed to test for similarities in the germline variant profiles between individuals diagnosed with SMNs or primary sarcomas. One index patient was found to have a pathogenic germline monoallelic mutation in the MUTYH gene, which encodes the base excision repair enzyme adenine DNA glycosylase. This specific germline mutation is associated with a form of familial adenomatous polyposis, a new diagnosis in the patient. Germline-level genetic similarity exists between SMN-developing patients and patients developing primary sarcomas, with relevant genes involved in signal transduction and DNA repair mechanisms. The authors identify a germline MUTYH mutation in a pediatric cancer survivor developing an SMN. Germline mutations involving specific pathways such as base excision repair may identify individuals at risk for developing SMNs. The composition of germline variants in individual patients may enable estimates of patient-specific risk for developing SMNs. The authors anticipate that further analyses of germline genomes and epigenomes will reveal diverse genes and mechanisms influencing cancer risk.
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http://dx.doi.org/10.1097/MPH.0000000000001668DOI Listing
October 2020

Stereotactic Radiosurgery to More Than 10 Brain Metastases: Evidence to Support the Role of Radiosurgery for Ideal Hippocampal Sparing in the Treatment of Multiple Brain Metastases.

World Neurosurg 2020 Mar 27;135:e174-e180. Epub 2019 Nov 27.

Department of Radiation Oncology, University of California San Francisco, San Francisco, California, USA. Electronic address:

Background: Brain metastases are a common occurrence, with literature supporting the treatment of a limited number of brain metastases with stereotactic radiosurgery (SRS), as opposed to whole brain radiotherapy (WBRT). Less well understood is the role of SRS in patients with ≥10 brain metastases.

Methods: Patients treated with SRS to ≥10 brain metastases without concurrent WBRT between March 1999 and December 2016 were reviewed. Analysis was performed for overall survival, treated lesion freedom from progression (FFP), freedom from new metastases (FFNMs), and adverse radiation effect. Hippocampal volumes were retrospectively generated in patients treated with up-front SRS for evaluation of dose volume metrics.

Results: A total of 143 patients were identified with 75 patients having up-front SRS and 68 patients being treated as salvage therapy after prior WBRT. The median number of lesions per patient was 13 (interquartile range [IQR], 11-17). Median total volume of treatment was 4.1 cm (IQR, 2.0-9.9 cm). The median 12-month FFP for up-front and salvage treatment was 96.8% (95% confidence interval [CI], 95.5-98.1) and 83.6% (95% CI, 79.9-87.5), respectively (P < 0.001). Twelve-month FFNMs for up-front and salvage SRS was 18.8% (95% CI, 10.9-32.3) versus 19.2% (95% CI, 9.7-37.8), respectively (P = 0.90). The mean hippocampal dose was 150 cGy (IQR, 100-202 cGy).

Conclusions: Excellent rates of local control can be achieved when treating patients with >10 intracranial metastases either in the up-front or salvage setting. Hippocampal sparing is readily achievable with expected high rates of new metastatic lesions in treated patients.
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http://dx.doi.org/10.1016/j.wneu.2019.11.089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152323PMC
March 2020

Reirradiation of recurrent high-grade glioma and development of prognostic scores for progression and survival.

Neurooncol Pract 2019 Sep 12;6(5):364-374. Epub 2019 Apr 12.

Department of Radiation Oncology, University of California San Francisco.

Background: Optimal techniques and patient selection for salvage reirradiation of high-grade glioma (HGG) are unclear. In this study, we identify prognostic factors for freedom from progression (FFP) and overall survival (OS) after reirradiation, risk factors for high-grade toxicity, and validate clinical prognostic scores.

Methods: A total of 116 patients evaluated between 2000 and 2018 received reirradiation for HGG (99 WHO grade IV, 17 WHO grade III). Median time to first progression after initial therapy was 10.6 months. Salvage therapies before reirradiation included surgery (31%) and systemic therapy (41%). Sixty-five patients (56%) received single-fraction stereotactic radiosurgery (SRS) as reirradiation. The median biologically effective dose (BED) was 47.25 Gy, and the median planning target volume (PTV) was 4.8 cc for SRS and 95.0 cc for non-SRS treatments. Systemic therapy was given concurrently to 52% and adjuvantly to 74% of patients.

Results: Median FFP was 4.9 months, and median OS was 11.0 months. Significant multivariable prognostic factors for FFP were performance status, time to initial progression, and BED; for OS they were age, time to initial progression, and PTV volume at recurrence. High-grade toxicity was correlated to PTV size at recurrence. Three-level prognostic scores were generated for FFP and OS, with cross-validated receiver operating characteristic area under the curve (AUC) of 0.640 and 0.687, respectively.

Conclusions: Clinical variables at the time of reirradiation for HGG can be used to prognosticate FFP and OS.
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http://dx.doi.org/10.1093/nop/npz017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753361PMC
September 2019

Subsequent Neoplasms After a Primary Tumor in Individuals With Neurofibromatosis Type 1.

J Clin Oncol 2019 11 18;37(32):3050-3058. Epub 2019 Sep 18.

The Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: Fundamental gaps in knowledge regarding the risk of subsequent neoplasms (SNs) in children with pathogenic neurofibromatosis type 1 (NF1) variants exposed to radiation and/or alkylator chemotherapy have limited the use of these agents.

Methods: We addressed these gaps by determining the SN risk in 167 NF1-affected versus 1,541 non-NF1-affected 5-year childhood cancer survivors from the Childhood Cancer Survivor Study and 176 nonoverlapping NF1-affected individuals with primary tumors from University of Alabama at Birmingham and Children's Hospital of Philadelphia exposed to radiation and/or chemotherapy. Proportional subdistribution hazards multivariable regression analysis was used to examine risk factors, adjusting for type and age at primary tumor diagnosis and therapeutic exposures.

Results: In the Childhood Cancer Survivor Study cohort, the 20-year cumulative incidence of SNs in NF1 childhood cancer survivors was 7.3%, compared with 2.9% in the non-NF1 childhood cancer survivors ( = .003), yielding a 2.4-fold higher risk of SN (95% CI, 1.3 to 4.3; = .005) in the NF1-affected individuals. In the University of Alabama at Birmingham and Children's Hospital of Philadelphia cohort, among NF1-affected individuals with a primary tumor, the risk of SNs was 2.8-fold higher in patients with irradiated NF1 (95% CI, 1.3 to 6.0; = .009). In contrast, the risk of SNs was not significantly elevated after exposure to alkylating agents (hazard ratio, 1.27; 95% CI, 0.3 to 3.0; = .9).

Conclusion: Children with NF1 who develop a primary tumor are at increased risk of SN when compared with non-NF1 childhood cancer survivors. Among NF1-affected children with a primary tumor, therapeutic radiation, but not alkylating agents, confer an increased risk of SNs. These findings can inform evidence-based clinical management of primary tumors in NF1-affected children.
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http://dx.doi.org/10.1200/JCO.19.00114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839906PMC
November 2019

Preoperative Dural Contact and Recurrence Risk After Surgical Cavity Stereotactic Radiosurgery for Brain Metastases: New Evidence in Support of Consensus Guidelines.

Adv Radiat Oncol 2019 Jul-Sep;4(3):458-465. Epub 2019 Mar 14.

Department of Radiation Oncology, San Francisco, California.

Purpose: The incidence of brain metastases is increasing as a result of more routine diagnostic imaging and improved extracranial systemic treatment strategies. As noted in recent consensus guidelines, postoperative stereotactic radiosurgery (SRS) to the resection cavity has lower rates of local control than whole brain radiation therapy but improved cognitive outcomes. Further analyses are needed to improve local control and minimize toxicity.

Methods And Materials: Patients receiving SRS to a resection cavity between 2006 and 2016 were retrospectively analyzed. Presurgical variables, including tumor location, diameter, dural/meningeal contact, and histology, were collected, as were SRS treatment parameters. Patients had routine follow-up with magnetic resonance imaging, and those noted to have local failure were further assessed for the recurrence location, distance from the target volume, and dosimetric characteristics.

Results: Overall, 82 patients and 85 resection cavities underwent postoperative SRS during the study period. Of these, 58 patients with 60 resection cavities with available follow-up magnetic resonance imaging scans were included in this analysis. With a median follow-up of 19.8 months, local recurrence occurred in 12 of the resection cavities for a 15% 1-year and 18% 2-year local recurrence rate. Pretreatment tumor volume contacted the dura/meninges in 100% of cavities with recurrence versus 67% of controlled cavities ( = .025). A total of 5 infield, 5 marginal, and 4 out-of-field recurrences were found, with a median distance to the centroid from the target volume of 3 mm. The addition of a 10-mm dural margin increased the target volume overlap with the recurrence contours for 10 of the 14 recurrences.

Conclusions: Dural contact was associated with an increased rate of recurrence for patients who received SRS to a surgical cavity, and the median distance of marginal recurrences from the target volume was 3 mm. These results provide evidence in support of recent consensus guidelines suggesting that additional dural margin on SRS volumes may benefit local control.
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http://dx.doi.org/10.1016/j.adro.2019.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639748PMC
March 2019

A robustness check procedure for hypofractionated Gamma Knife radiosurgery.

J Neurosurg 2018 12;129(Suppl1):140-146

Departments of2Radiation Oncology and.

OBJECTIVEInterfractional residual patient shifts are often observed during the delivery of hypofractionated brain radiosurgery. In this study, the authors developed a robustness treatment planning check procedure to assess the dosimetric effects of residual target shifts on hypofractionated Gamma Knife radiosurgery (GKRS).METHODSThe residual patient shifts were determined during the simulation process immediately after patient immobilization. To mimic incorporation of residual target shifts during treatment delivery, a quality assurance procedure was developed to sample and shift individual shots according to the residual uncertainties in the prescribed treatment plan. This procedure was tested and demonstrated for 10 hypofractionated GKRS cases.RESULTSThe maximum residual target shifts were less than 1 mm for the studied cases. When incorporating such shifts, the target coverage varied by 1.9% ± 2.2% (range 0.0%-7.1%) and selectivity varied by 3.6% ± 2.5% (range 1.1%-9.3%). Furthermore, when incorporating extra random shifts on the order of 0.5 mm, the target coverage decreased by as much as 7%, and nonisocentric variation in the dose distributions was noted for the studied cases.CONCLUSIONSA pretreatment robustness check procedure was developed and demonstrated for hypofractionated GKRS. Further studies are underway to implement this procedure to assess maximum tolerance levels for individual patient cases.
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http://dx.doi.org/10.3171/2018.7.GKS181581DOI Listing
December 2018

Brain metastasis growth on preradiosurgical magnetic resonance imaging.

Pract Radiat Oncol 2018 Nov - Dec;8(6):e369-e376. Epub 2018 Jun 7.

Department of Radiation Oncology, University of California, San Francisco, California.

Purpose: A previous analysis showed that brain metastases that are treated with frameless stereotactic radiation surgery (SRS) and planned with magnetic resonance imaging (MRI) >14 days before SRS had worse local control (LC). To evaluate if worse LC may be due to unaccounted interval metastasis growth and radiosurgical marginal miss, we quantified growth before SRS on preradiosurgical imaging.

Methods And Materials: We reviewed data from patients who were treated with fixed-frame SRS for brain metastases at our institution between 2010 and 2013 and had pretreatment diagnostic brain MRI and SRS-planning MRI scans available. Metastases were contoured on the pretreatment MRI scan and the day-of-treatment planning MRI scan for volumetric comparison. Growth rates were calculated. Serial volumetric contour expansions on the pretreatment MRI scans were used to determine the minimum margin necessary to encompass the entire metastasis on day of the SRS. LC was estimated by Kaplan-Meier method.

Results: Among 411 brain metastases in 165 patients, the time between pretreatment and treatment MRI was associated with metastasis growth (P < .001) with a mean growth rate of 0.02 ml/day (95% confidence interval, 0.01-0.03) and a 1.35-fold volume increase at 14 days. Time between MRI scans was associated with the amount of margin that was needed to target the entire brain metastasis volume on the day of the SRS (P < .001), as were volume of metastasis on the pre-treatment MRI (P < .001) and melanoma histology (P < .001). LC was not associated with growth rate among patients who underwent fixed-frame SRS.

Conclusions: Time between pretreatment MRI and SRS is associated with brain metastasis growth, but LC is not compromised when patients receive fixed-frame SRS with same-day MRI planning. Margins may be needed for metastases that are treated with frameless SRS to account for growth between the planning MRI and SRS delivery.

Summary: In this study, we quantify brain metastasis growth over time by taking advantage of the availability of 2 pretreatment magnetic resonance imaging scans taken at 2 time points among patients treated with frame-fixed radiation surgery. We found that metastasis growth is associated with time, initial metastasis size, melanoma histology, and concurrent chemotherapy. Performing serial margin expansions demonstrated factors that are associated with the amount of margin that is needed to target the entire metastasis on the day of radiation surgery.
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http://dx.doi.org/10.1016/j.prro.2018.06.004DOI Listing
January 2019

A high-throughput screen of real-time ATP levels in individual cells reveals mechanisms of energy failure.

PLoS Biol 2018 08 27;16(8):e2004624. Epub 2018 Aug 27.

Gladstone Institute of Neurological Disease, San Francisco, California, United States of America.

Insufficient or dysregulated energy metabolism may underlie diverse inherited and degenerative diseases, cancer, and even aging itself. ATP is the central energy carrier in cells, but critical pathways for regulating ATP levels are not systematically understood. We combined a pooled clustered regularly interspaced short palindromic repeats interference (CRISPRi) library enriched for mitochondrial genes, a fluorescent biosensor, and fluorescence-activated cell sorting (FACS) in a high-throughput genetic screen to assay ATP concentrations in live human cells. We identified genes not known to be involved in energy metabolism. Most mitochondrial ribosomal proteins are essential in maintaining ATP levels under respiratory conditions, and impaired respiration predicts poor growth. We also identified genes for which coenzyme Q10 (CoQ10) supplementation rescued ATP deficits caused by knockdown. These included CoQ10 biosynthetic genes associated with human disease and a subset of genes not linked to CoQ10 biosynthesis, indicating that increasing CoQ10 can preserve ATP in specific genetic contexts. This screening paradigm reveals mechanisms of metabolic control and genetic defects responsive to energy-based therapies.
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http://dx.doi.org/10.1371/journal.pbio.2004624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110572PMC
August 2018

Genomic characterization of chronic lymphocytic leukemia (CLL) in radiation-exposed Chornobyl cleanup workers.

Environ Health 2018 05 2;17(1):43. Epub 2018 May 2.

School of Medicine, University of California, San Francisco, San Francisco, CA, USA.

Background: Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population.

Methods: A detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively).

Results: Mutations in telomere-maintenance pathway genes POT1 and ATM were more frequent in UR-CLL compared to UN-CLL and W-CLL (both p < 0.05). No significant enrichment in copy-number abnormalities at del13q14, del11q, del17p or trisomy12 was identified in UR-CLL compared to other groups. Type of work performed in the Chornobyl zone, age at exposure and at diagnosis, calendar time, and Rai stage were significant predictors of total genetic lesions (all p < 0.05). Tumor telomere length was significantly longer in UR-CLL than in UN-CLL (p = 0.009) and was associated with the POT1 mutation and survival.

Conclusions: No significant enrichment in copy-number abnormalities at CLL-associated genes was identified in UR-CLL compared to other groups. The novel associations between radiation exposure, telomere maintenance and CLL prognosis identified in this unique case series provide suggestive, though limited data and merit further investigation.
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http://dx.doi.org/10.1186/s12940-018-0387-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930419PMC
May 2018

Mutational landscape of radiation-associated angiosarcoma of the breast.

Oncotarget 2018 Feb 19;9(11):10042-10053. Epub 2018 Jan 19.

Beaumont BioBank, Beaumont Health, Royal Oak, MI, USA.

Purpose: Radiation-associated breast angiosarcomas are a rare complication of radiation therapy for breast carcinoma. With relatively little is known about the genetic abnormalities present in these secondary tumors, we examined genomic variation in biospecimens from radiation-associated breast angiosarcomas.

Experimental Design: Patients were identified that had a previous breast cancer diagnosis, received radiation therapy, and developed angiosarcoma in the ipsilateral breast as the earlier cancer. Tumor regions were isolated from archival blocks using subsequent laser capture microdissection. Next generation sequencing was performed using a targeted panel of 160 cancer-related genes. Genomic variants were identified for mutation and trinucleotide-based mutational signature analysis.

Results: 44 variants in 34 genes were found in more than two thirds of the cases; this included 12 variants identified as potentially deleterious. Of particular note, the BRCA1 DNA damage response pathway was highly enriched with genetic variation. In a comparison to local recurrences, 14 variants in 11 genes were present in both the primary and recurrent lesions including variants in genes associated with the DNA damage response machinery. Furthermore, the mutational signature analysis shows that a previously defined IR signature is present in almost all of the current samples characterized by predominantly C→T substitutions.

Conclusions: While radiation-associated breast angiosarcomas are relatively uncommon, their prognosis is very poor. These data demonstrate a mutational pattern associated with genes involved in DNA repair. While important in revealing the biology behind these tumors, it may also suggest new treatment strategies that will prove successful.
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http://dx.doi.org/10.18632/oncotarget.24273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839370PMC
February 2018

A pooled mutational analysis identifies ionizing radiation-associated mutational signatures conserved between mouse and human malignancies.

Sci Rep 2017 08 9;7(1):7645. Epub 2017 Aug 9.

Department of Radiation Oncology, University of California, San Francisco, California, 94158, USA.

Single nucleotide variants (SNVs) identified in cancer genomes can be de-convolved using non-negative matrix factorization (NMF) into discrete trinucleotide-based mutational signatures indicative of specific cancer-causing processes. The stability of NMF-generated mutational signatures depends upon the numbers of variants available for analysis. In this work, we sought to assess whether data from well-controlled mouse models can compensate for scarce human data for some cancer types. High quality sequencing data from radiotherapy-induced cancers is particularly scarce and the mutational processes defining ionizing radiation (IR)-induced mutagenesis in vivo are poorly defined. Here, we combine sequencing data from mouse models of IR-induced malignancies and human IR-induced malignancies. To determine whether the signatures identified from IR-exposed subjects can be differentiated from other mutagenic signatures, we included data from an ultraviolet radiation (UV)-induced human skin cancer and from a mouse model of urethane-induced cancers. NMF distinguished all three mutagens and in the pooled analysis IR was associated with mutational signatures common to both species. These findings illustrate the utility of pooled analysis of mouse and human sequencing data.
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http://dx.doi.org/10.1038/s41598-017-07888-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550450PMC
August 2017

Somatic and Germline Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors.

Clin Cancer Res 2017 Apr 28;23(7):1852-1861. Epub 2016 Sep 28.

Department of Radiation Oncology, University of California, San Francisco, California.

Second malignant neoplasms (SMNs) are severe late complications that occur in pediatric cancer survivors exposed to radiotherapy and other genotoxic treatments. To characterize the mutational landscape of treatment-induced sarcomas and to identify candidate SMN-predisposing variants, we analyzed germline and SMN samples from pediatric cancer survivors. We performed whole-exome sequencing (WES) and RNA sequencing on radiation-induced sarcomas arising from two pediatric cancer survivors. To assess the frequency of germline variants in SMNs, Sanger sequencing was performed to analyze germline in 37 pediatric cancer survivors from the Childhood Cancer Survivor Study (CCSS) without any history of a familial cancer predisposition syndrome but known to have developed SMNs. WES revealed mutations involving p53's DNA-binding domain in both index cases, one of which was also present in the germline. The germline and somatic mutant variants were enriched in the transcriptomes for both sarcomas. Analysis of coding exons in germline specimens from the CCSS survivor cohort identified a G215C variant encoding an R72P amino acid substitution in 6 patients and a synonymous SNP A639G in 4 others, resulting in 10 of 37 evaluable patients (27%) harboring a germline variant. Currently, germline is not routinely assessed in patients with pediatric cancer. These data support the concept that identifying germline variants at the time a primary cancer is diagnosed may identify patients at high risk for SMN development, who could benefit from modified therapeutic strategies and/or intensive posttreatment monitoring. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570538PMC
April 2017

Indications and Efficacy of Gamma Knife Stereotactic Radiosurgery for Recurrent Glioblastoma: 2 Decades of Institutional Experience.

Neurosurgery 2017 Jan;80(1):129-139

Department of Neurological Surgery and.

Background: The role of stereotactic radiosurgery (SRS) for recurrent glioblastoma and the radionecrosis risk in this setting remain unclear.

Objective: To perform a large retrospective study to help inform proper indications, efficacy, and anticipated complications of SRS for recurrent glioblastoma.

Methods: We retrospectively analyzed patients who underwent Gamma Knife SRS between 1991 and 2013. We used the partitioning deletion/substitution/addition algorithm to identify potential predictor covariate cut points and Kaplan-Meier and proportional hazards modeling to identify factors associated with post-SRS and postdiagnosis survival.

Results: One hundred seventy-four glioblastoma patients (median age, 54.1 years) underwent SRS a median of 8.7 months after initial diagnosis. Seventy-five percent had 1 treatment target (range, 1-6), and median target volume and prescriptions were 7.0 cm 3 (range, 0.3-39.0 cm 3 ) and 16.0 Gy (range, 10-22 Gy), respectively. Median overall survival was 10.6 months after SRS and 19.1 months after diagnosis. Kaplan-Meier and multivariable modeling revealed that younger age at SRS, higher prescription dose, and longer interval between original surgery and SRS are significantly associated with improved post-SRS survival. Forty-six patients (26%) underwent salvage craniotomy after SRS, with 63% showing radionecrosis or mixed tumor/necrosis vs 35% showing purely recurrent tumor. The necrosis/mixed group had lower mean isodose prescription compared with the tumor group (16.2 vs 17.8 Gy; P = .003) and larger mean treatment volume (10.0 vs 5.4 cm 3 ; P = .009).

Conclusion: Gamma Knife may benefit a subset of focally recurrent patients, particularly those who are younger with smaller recurrences. Higher prescriptions are associated with improved post-SRS survival and do not seem to have greater risk of symptomatic treatment effect.
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http://dx.doi.org/10.1227/NEU.0000000000001344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5235998PMC
January 2017

Discovery of additional brain metastases on the day of stereotactic radiosurgery: risk factors and outcomes.

J Neurosurg 2017 Jun 1;126(6):1756-1763. Epub 2016 Jul 1.

Departments of 1 Radiation Oncology.

OBJECTIVE High-resolution double-dose gadolinium-enhanced Gamma Knife (GK) radiosurgery-planning MRI (GK MRI) on the day of GK treatment can detect additional brain metastases undiagnosed on the prior diagnostic MRI scan (dMRI), revealing increased intracranial disease burden on the day of radiosurgery, and potentially necessitating a reevaluation of appropriate management. The authors identified factors associated with detecting additional metastases on GK MRI and investigated the relationship between detection of additional metastases and postradiosurgery patient outcomes. METHODS The authors identified 326 patients who received GK radiosurgery at their institution from 2010 through 2013 and had a prior dMRI available for comparison of numbers of brain metastases. Factors predictive of additional brain metastases on GK MRI were investigated using logistic regression analysis. Overall survival was estimated by Kaplan-Meier method, and postradiosurgery distant intracranial failure was estimated by cumulative incidence measures. Multivariable Cox proportional hazards model and Fine-Gray regression modeling assessed potential risk factors of overall survival and distant intracranial failure, respectively. RESULTS The mean numbers of brain metastases (SD) on dMRI and GK MRI were 3.4 (4.2) and 5.8 (7.7), respectively, and additional brain metastases were found on GK MRI in 48.9% of patients. Frequencies of detecting additional metastases for patients with 1, 2, 3-4, and more than 4 brain metastases on dMRI were 29.5%, 47.9%, 55.9%, and 79.4%, respectively (p < 0.001). An index brain metastasis with a diameter greater than 1 cm on dMRI was inversely associated with detecting additional brain metastases, with an adjusted odds ratio of 0.57 (95% CI 0.4-0.9, p = 0.02). The median time between dMRI and GK MRI was 22 days (range 1-88 days), and time between scans was not associated with detecting additional metastases. Patients with additional brain metastases did not have larger total radiosurgery target volumes, and they rarely had an immediate change in management (abortion of radiosurgery or addition of whole-brain radiation therapy) due to detection of additional metastases. Patients with additional metastases had a higher incidence of distant intracranial failure than those without additional metastases (p = 0.004), with an adjusted subdistribution hazard ratio of 1.4 (95% CI 1.0-2.0, p = 0.04). Significantly worse overall survival was not detected for patients with additional brain metastases on GK MRI (log-rank p = 0.07), with the relative adjusted hazard ratio of 1.07, (95% CI 0.81-1.41, p = 0.65). CONCLUSIONS Detecting additional brain metastases on GK MRI is strongly associated with the number of brain metastases on dMRI and inversely associated with the size of the index brain metastasis. The discovery of additional brain metastases at time of GK radiosurgery is very unlikely to lead to aborting radiosurgery but is associated with a higher incidence of distant intracranial failure. However, there is not a significant difference in survival. ▪ CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort trial; evidence: Class IV.
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http://dx.doi.org/10.3171/2016.4.JNS152319DOI Listing
June 2017

Parameters influencing local control of meningiomas treated with radiosurgery.

J Neurooncol 2016 06 30;128(2):357-64. Epub 2016 Apr 30.

Department of Neurological Surgery, University of California San Francisco, 505 Parnassus Ave, Rm. M779, San Francisco, CA, 94143-0112, USA.

To identify parameters that influence local control after stereotactic radiosurgery (SRS) for meningiomas we retrospectively analyzed all meningiomas treated with Gamma Knife SRS at our institution from 1991 to 2007. Endpoints were measured from the date of SRS and estimated using the Kaplan-Meier method; subgroups were compared with log-rank tests. Sex, performance status, age, SRS setting, radiation dose, grade, volume and location were evaluated with univariate and multivariate Cox proportional hazards analyses. Of 280 patients with 438 tumors, 264 patients with clinical follow-up and 406 tumors with imaging follow-up were analyzed (median follow-up: 75.9 months). Thirty-seven percent of the tumors had no tissue diagnosis, 32 % were benign (grade I), 12 % atypical (grade II), and 19 % malignant (grade III). Five-year freedom from progression (FFP) was 97 % for presumed meningiomas, 87 % for grade I tumors, 56 % for grade II tumors, and 47 % for grade III tumors (p < 0.0001). Five-year FFP probabilities for upfront SRS versus SRS at recurrence after surgery versus SRS at recurrence after RT were 97, 86, and 38 %, respectively (p < 0.0001). Univariate analysis revealed that higher grade, larger target volume (median diameter: 2.4 cm) and SRS setting were associated with poorer FFP. Only target volume and SRS setting remained significant on multivariate analysis. Local control of presumed and grade I meningiomas is excellent with Gamma Knife SRS, but is suboptimal with high-grade tumors as well as for those treated at recurrence after RT or of large volume.
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http://dx.doi.org/10.1007/s11060-016-2121-1DOI Listing
June 2016

Assessment of image quality and dose calculation accuracy on kV CBCT, MV CBCT, and MV CT images for urgent palliative radiotherapy treatments.

J Appl Clin Med Phys 2016 03 8;17(2):279-290. Epub 2016 Mar 8.

University of California San Francisco.

A clinical workflow was developed for urgent palliative radiotherapy treatments that integrates patient simulation, planning, quality assurance, and treatment in one 30-minute session. This has been successfully tested and implemented clinically on a linac with MV CBCT capabilities. To make this approach available to all clin-ics equipped with common imaging systems, dose calculation accuracy based on treatment sites was assessed for other imaging units. We evaluated the feasibility of palliative treatment planning using on-board imaging with respect to image quality and technical challenges. The purpose was to test multiple systems using their commercial setup, disregarding any additional in-house development. kV CT, kV CBCT, MV CBCT, and MV CT images of water and anthropomorphic phantoms were acquired on five different imaging units (Philips MX8000 CT Scanner, and Varian TrueBeam, Elekta VersaHD, Siemens Artiste, and Accuray Tomotherapy linacs). Image quality (noise, contrast, uniformity, spatial resolution) was evaluated and compared across all machines. Using individual image value to density calibrations, dose calculation accuracies for simple treatment plans were assessed for the same phantom images. Finally, image artifacts on clinical patient images were evaluated and compared among the machines. Image contrast to visualize bony anatomy was sufficient on all machines. Despite a high noise level and low contrast, MV CT images provided the most accurate treatment plans relative to kV CT-based planning. Spatial resolution was poorest for MV CBCT, but did not limit the visualization of small anatomical structures. A comparison of treatment plans showed that monitor units calculated based on a prescription point were within 5% difference relative to kV CT-based plans for all machines and all studied treatment sites (brain, neck, and pelvis). Local dose differences > 5% were found near the phantom edges. The gamma index for 3%/3 mm criteria was ≥ 95% in most cases. Best dose calculation results were obtained when the treatment isocenter was near the image isocenter for all machines. A large field of view and immediate image export to the treatment planning system were essential for a smooth workflow and were not provided on all devices. Based on this phantom study, image quality of the studied kV CBCT, MV CBCT, and MV CT on-board imaging devices was sufficient for treatment planning in all tested cases. Treatment plans provided dose calculation accuracies within an acceptable range for simple, urgently planned palliative treatments. However, dose calculation accuracy was compromised towards the edges of an image. Feasibility for clinical implementation should be assessed separately and may be complicated by machine specific features. Image artifacts in patient images and the effect on dose calculation accuracy should be assessed in a separate, machine-specific study.
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http://dx.doi.org/10.1120/jacmp.v17i2.6040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874969PMC
March 2016

Investigating the clinical advantages of a robotic linac equipped with a multileaf collimator in the treatment of brain and prostate cancer patients.

J Appl Clin Med Phys 2015 09 8;16(5):284–295. Epub 2015 Sep 8.

University of California at San Francisco.

The purpose of this study was to evaluate the performance of a commercially avail-able CyberKnife system with a multileaf collimator (CK-MLC) for stereotactic body radiotherapy (SBRT) and standard fractionated intensity-modulated radiotherapy (IMRT) applications. Ten prostate and ten intracranial cases were planned for the CK-MLC. Half of these cases were compared with clinically approved SBRT plans generated for the CyberKnife with circular collimators, and the other half were compared with clinically approved standard fractionated IMRT plans generated for conventional linacs. The plans were compared on target coverage, conformity, homogeneity, dose to organs at risk (OAR), low dose to the surrounding tissue, total monitor units (MU), and treatment time. CK-MLC plans generated for the SBRT cases achieved more homogeneous dose to the target than the CK plans with the circular collimators, for equivalent coverage, conformity, and dose to OARs. Total monitor units were reduced by 40% to 70% and treatment time was reduced by half. The CK-MLC plans generated for the standard fractionated cases achieved prescription isodose lines between 86% and 93%, which was 2%-3% below the plans generated for conventional linacs. Compared to standard IMRT plans, the total MU were up to three times greater for the prostate (whole pelvis) plans and up to 1.4 times greater for the intracranial plans. Average treatment time was 25min for the whole pelvis plans and 19 min for the intracranial cases. The CK-MLC system provides significant improvements in treatment time and target homogeneity compared to the CK system with circular collimators, while main-taining high conformity and dose sparing to critical organs. Standard fractionated plans for large target volumes (> 100 cm3) were generated that achieved high prescription isodose levels. The CK-MLC system provides more efficient SRS and SBRT treatments and, in select clinical cases, might be a potential alternative for standard fractionated treatments.
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http://dx.doi.org/10.1120/jacmp.v16i5.5502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690182PMC
September 2015

Mutational Analysis of Ionizing Radiation Induced Neoplasms.

Cell Rep 2015 Sep 3;12(11):1915-26. Epub 2015 Sep 3.

Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

Ionizing radiation (IR) is a mutagen that promotes tumorigenesis in multiple exposure contexts. One severe consequence of IR is the development of second malignant neoplasms (SMNs), a radiotherapy-associated complication in survivors of cancers, particularly pediatric cancers. SMN genomes are poorly characterized, and the influence of genetic background on genotoxin-induced mutations has not been examined. Using our mouse models of SMNs, we performed whole exome sequencing of neoplasms induced by fractionated IR in wild-type and Nf1 mutant mice. Using non-negative matrix factorization, we identified mutational signatures that did not segregate by genetic background or histology. Copy-number analysis revealed recurrent chromosomal alterations and differences in copy number that were background dependent. Pathway analysis identified enrichment of non-synonymous variants in genes responsible for cell assembly and organization, cell morphology, and cell function and maintenance. In this model system, ionizing radiation and Nf1 heterozygosity each exerted distinct influences on the mutational landscape.
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http://dx.doi.org/10.1016/j.celrep.2015.08.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810600PMC
September 2015

Interval From Imaging to Treatment Delivery in the Radiation Surgery Age: How Long Is Too Long?

Int J Radiat Oncol Biol Phys 2015 Sep 7;93(1):126-32. Epub 2015 May 7.

Department of Radiation Oncology, University of California at San Francisco, San Francisco, California.

Purpose: The purpose of this study was to evaluate workflow and patient outcomes related to frameless stereotactic radiation surgery (SRS) for brain metastases.

Methods And Materials: We reviewed all treatment demographics, clinical outcomes, and workflow timing, including time from magnetic resonance imaging (MRI), computed tomography (CT) simulation, insurance authorization, and consultation to the start of SRS for brain metastases.

Results: A total of 82 patients with 151 brain metastases treated with SRS were evaluated. The median times from consultation, insurance authorization, CT simulation, and MRI for treatment planning were 15, 7, 6, and 11 days to SRS. Local freedom from progression (LFFP) was lower in metastases with MRI ≥ 14 days before treatment (P = .0003, log rank). The 6- and 12-month LFFP rate were 95% and 75% for metastasis with interval of <14 days from MRI to treatment compared to 56% and 34% for metastases with MRI ≥ 14 days before treatment. On multivariate analysis, LFFP remained significantly lower for lesions with MRI ≥ 14 days at SRS (P = .002, Cox proportional hazards; hazard ratio: 3.4, 95% confidence interval: 1.6-7.3).

Conclusions: Delay from MRI to SRS treatment delivery for brain metastases appears to reduce local control. Future studies should monitor the timing from imaging acquisition to treatment delivery. Our experience suggests that the time from MRI to treatment should be <14 days.
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http://dx.doi.org/10.1016/j.ijrobp.2015.05.001DOI Listing
September 2015

Monoallelic loss of the imprinted gene Grb10 promotes tumor formation in irradiated Nf1+/- mice.

PLoS Genet 2015 May 22;11(5):e1005235. Epub 2015 May 22.

Department of Radiation Oncology, University of California, San Francisco, San Francisco, California, United States of America.

Imprinted genes are expressed from only one parental allele and heterozygous loss involving the expressed allele is sufficient to produce complete loss of protein expression. Genetic alterations are common in tumorigenesis but the role of imprinted genes in this process is not well understood. In earlier work we mutagenized mice heterozygous for the Neurofibromatosis I tumor suppressor gene (NF1) to model radiotherapy-associated second malignant neoplasms that arise in irradiated NF1 patients. Expression analysis of tumor cell lines established from our mouse models identified Grb10 expression as widely absent. Grb10 is an imprinted gene and polymorphism analysis of cell lines and primary tumors demonstrates that the expressed allele is commonly lost in diverse Nf1 mutant tumors arising in our mouse models. We performed functional studies to test whether Grb10 restoration or loss alter fundamental features of the tumor growth. Restoring Grb10 in Nf1 mutant tumors decreases proliferation, decreases soft agar colony formation and downregulates Ras signaling. Conversely, Grb10 silencing in untransformed mouse embryo fibroblasts significantly increased cell proliferation and increased Ras-GTP levels. Expression of a constitutively activated MEK rescued tumor cells from Grb10-mediated reduction in colony formation. These studies reveal that Grb10 loss can occur during in vivo tumorigenesis, with a functional consequence in untransformed primary cells. In tumors, Grb10 loss independently promotes Ras pathway hyperactivation, which promotes hyperproliferation, an early feature of tumor development. In the context of a robust Nf1 mutant mouse model of cancer this work identifies a novel role for an imprinted gene in tumorigenesis.
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http://dx.doi.org/10.1371/journal.pgen.1005235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441450PMC
May 2015

Adverse radiation effect after stereotactic radiosurgery for brain metastases: incidence, time course, and risk factors.

J Neurosurg 2015 Aug 15;123(2):373-86. Epub 2015 May 15.

Departments of 1 Radiation Oncology and.

Object: The authors sought to determine the incidence, time course, and risk factors for overall adverse radiation effect (ARE) and symptomatic ARE after stereotactic radiosurgery (SRS) for brain metastases.

Methods: All cases of brain metastases treated from 1998 through 2009 with Gamma Knife SRS at UCSF were considered. Cases with less than 3 months of follow-up imaging, a gap of more than 8 months in imaging during the 1st year, or inadequate imaging availability were excluded. Brain scans and pathology reports were reviewed to ensure consistent scoring of dates of ARE, treatment failure, or both; in case of uncertainty, the cause of lesion worsening was scored as indeterminate. Cumulative incidence of ARE and failure were estimated with the Kaplan-Meier method with censoring at last imaging. Univariate and multivariate Cox proportional hazards analyses were performed.

Results: Among 435 patients and 2200 brain metastases evaluable, the median patient survival time was 17.4 months and the median lesion imaging follow-up was 9.9 months. Calculated on the basis of 2200 evaluable lesions, the rates of treatment failure, ARE, concurrent failure and ARE, and lesion worsening with indeterminate cause were 9.2%, 5.4%, 1.4%, and 4.1%, respectively. Among 118 cases of ARE, approximately 60% were symptomatic and 85% occurred 3-18 months after SRS (median 7.2 months). For 99 ARE cases managed without surgery or bevacizumab, the probabilities of improvement observed on imaging were 40%, 57%, and 76% at 6, 12, and 18 months after onset of ARE. The most important risk factors for ARE included prior SRS to the same lesion (with 20% 1-year risk of symptomatic ARE vs 3%, 4%, and 8% for no prior treatment, prior whole brain radiotherapy [WBRT], or concurrent WBRT) and any of these volume parameters: target, prescription isodose, 12-Gy, or 10-Gy volume. Excluding lesions treated with repeat SRS, the 1-year probabilities of ARE were < 1%, 1%, 3%, 10%, and 14% for maximum diameter 0.3-0.6 cm, 0.7-1.0 cm, 1.1-1.5 cm, 1.6-2.0 cm, and 2.1-5.1 cm, respectively. The 1-year probabilities of symptomatic ARE leveled off at 13%-14% for brain metastases maximum diameter > 2.1 cm, target volume > 1.2 cm(3), prescription isodose volume > 1.8 cm(3), 12-Gy volume > 3.3 cm(3), and 10-Gy volume > 4.3 cm(3), excluding lesions treated with repeat SRS. On both univariate and multivariate analysis, capecitabine, but not other systemic therapy within 1 month of SRS, appeared to increase ARE risk. For the multivariate analysis considering only metastases with target volume > 1.0 cm(3), risk factors for ARE included prior SRS, kidney primary tumor, connective tissue disorder, and capecitabine.

Conclusions: Although incidence of ARE after SRS was low overall, risk increased rapidly with size and volume, leveling off at a 1-year cumulative incidence of 13%-14%. This study describes the time course of ARE and provides risk estimates by various lesion characteristics and treatment parameters to aid in decision-making and patient counseling.
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http://dx.doi.org/10.3171/2014.10.JNS141610DOI Listing
August 2015
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