Stereotactic Body Radiation Therapy and Concurrent Targeted Therapy for Lung Metastases in Pediatric Sarcoma.

Purpose: The purpose of this investigation was to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) for pulmonary metastases from pediatric sarcomas. Methods and Materials: This study was a single institutional retrospective chart review including patients younger than 21 years of age at diagnosis who had received SBRT for pulmonary metastasis from metastatic sarcoma. Our current electronic record system was queried for all eligible patients. Primary endpoint was tumor response as defined by Respone Evaluation Criteria in Solid Tumors 1.1 criteria. Secondarily, we analyzed factors that affected tumor response as well as toxicity of treatment. Median dose was 50 Gy ranging from 30 to 60 Gy in 5 fractions to the planning tumor volume. Results: There were 7 patients, ranging in age from 6 to 21 years with a total of 14 pulmonary lesions treated with SBRT. Median and mean follow-up times for the 7 patients were 10.6 months and 15.9 months, respectively. The complete response rate was 50%, partial response 21%, stable disease 21%, and progressive disease 7%. Four of the 7 patients were treated with concurrent systemic therapy, 3 of which were targeted oral therapies. Additionally, we observed that patients who were on targeted therapy such as regorafenib or pazopanib seemed to have better local control compared with patients without targeted therapy. Conclusions: With an overall response rate of 92%, SBRT provided a noninvasive effective palliative treatment option with few side effects in this small retrospective study of 7 patients. A larger prospective clinical trial is warranted to evaluate the role of SBRT in the treatment of unresectable metastatic pediatric sarcomas.

Gene Expression Patterns Associated with Survival in Glioblastoma.

The aim of this study was to investigate gene expression alterations associated with overall survival (OS) in glioblastoma (GBM). Using the Nanostring nCounter platform, we identified four genes (COL1A2, IGFBP3, NGFR, and WIF1) that achieved statistical significance when comparing GBM with non-neoplastic brain tissue. The four genes were included in a multivariate Cox Proportional Hazard model, along with age, extent of resection, and O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation, to create a unique glioblastoma prognostic index (GPI). The GPI score inversely correlated with survival: patient with a high GPI had a median OS of 7.5 months (18-month OS = 9.7%) whereas patients with a low GPI had a median OS of 20.1 months (18-month OS = 54.5%; log rank p-value = 0.004). The GPI score was then validated in 188 GBM patients from The Cancer Genome Atlas (TCGA) from a national data base; similarly, patients with a high GPI had a median OS of 10.5 months (18-month OS = 12.4%) versus 16.9 months (18-month OS = 41.5%) for low GPI (log rank p-value = 0.0003). We conclude that this novel mRNA-based prognostic index could be useful in classifying GBM patients into risk groups and refine prognosis estimates to better inform treatment decisions or stratification into clinical trials.

Molecular mechanisms of sensitivity and resistance to radiotherapy.

The molecular mechanisms underlying sensitivity and resistance to radiotherapy is an area of active investigation and discovery as its clinical applications have the potential to improve cancer patients' outcomes. In addition to the traditional pathways of radiation biology, our knowledge now includes molecular pathways of radiation sensitivity and resistance which have provided insights into potential targets for enhancing radiotherapy efficacy. Sensitivity to radiotherapy is influenced by the intricate interplay of various molecular mechanisms involved in DNA damage repair, apoptosis, cellular senescence, and epigenetics. Translationally, there have been several successful applications of this new knowledge into the clinic, such as biomarkers for improved response to chemo-radiation. New therapies to modify radiation response, such as the poly (ADP-ribose) polymerase (PARP) inhibitors, derived from research on DNA repair pathways leading to radiotherapy resistance, are being used clinically. In addition, p53-mediated pathways are critical for DNA damage related apoptosis, cellular senescence, and cell cycle arrest. As the understanding of genetic markers, molecular profiling, molecular imaging, and functional assays improve, these advances once translated clinically, will help propel modern radiation therapy towards more precise and individualized practices.

Dodecafluoropentane Emulsion as a Radiosensitizer in Glioblastoma Multiforme.

Purpose: Glioblastoma multiforme (GBM) is a hypoxic tumor resistant to radiotherapy. The purpose of this study was to assess the safety and efficacy of a novel oxygen therapeutic, dodecafluoropentane emulsion (DDFPe), in chemoradiation treatment of GBM. Experimental Design: In this multicenter phase Ib/II dose-escalation study, patients were administered DDFPe via intravenous infusion (0.05, 0.10, or 0.17 mL/kg) while breathing supplemental oxygen prior to each 2 Gy fraction of radiotherapy (30 fractions over 6 weeks). Patients also received standard-of-care chemotherapy [temozolomide (TMZ)]. Serial MRI scans were taken to monitor disease response. Adverse events were recorded and graded. TOLD (tissue oxygenation level-dependent) contrast MRI was obtained to validate modulation of tumor hypoxia. Results: Eleven patients were enrolled. DDFPe combined with radiotherapy and TMZ was well tolerated in most patients. Two patients developed delayed grade 3 radiation necrosis during dose escalation, one each at 0.1 and 0.17 mL/kg of DDFPe. Subsequent patients were treated at the 0.1 mL/kg dose level. Kaplan-Meier analysis showed a median overall survival of 19.4 months and a median progression-free survival of 9.6 months, which compares favorably to historical controls. Among 6 patients evaluable for TOLD MRI, a statistically significant reduction in tumor T1 was observed after DDFPe treatment. Conclusions: This trial, although small, showed that the use of DDFPe as a radiosensitizer in patients with GBM was generally safe and may provide a survival benefit. This is also the first time than TOLD MRI has shown reversal of tumor hypoxia in a clinical trial in patients. The recommended dose for phase II evaluation is 0.1 mL/kg DDFPe.Trial Registration: NCT02189109. Significance: This study shows that DDFPe can be safely administered to patients, and it is the first-in-human study to show reversal of hypoxia in GBM as measured by TOLD MRI. This strategy is being used in a larger phase II/III trial which will hopefully show a survival benefit by adding DDFPe during the course of fractionated radiation and concurrent chemotherapy.

Brachytherapy for Central Serous Chorioretinopathy.

Brachytherapy is widely used for the treatment of choroidal melanoma and has recently been explored for the treatment of wet age-related macular degeneration. We propose the use of low dose radiation via episcleral brachytherapy in refractory cases of central serous chorioretinopathy (CSCR). The pathogenesis of CSCR involves dilatation and hyperpermeability of large choroidal vessels. Low dose radiation can induce intimal proliferation in large choroidal vessels and decrease their hyperpermeability. Concerns about the use of brachytherapy in CSCR include damage to the choriocapillaris or the retinal vessels. This can be addressed with the use of a specialized device through which a very precise and appropriate dose can be delivered. The dose of the radiation delivered decreases exponentially at a depth of approximately 0.5-1.5 mm from the devise-sclera interface. Considering an increased choroidal thickness in cases of CSCR, delivery of a safe dose can be assured.

Feasibility and Efficacy of Partially Replacing Post-Transplantation Cyclophosphamide with Bendamustine in Pediatric and Young Adult Patients Undergoing Haploidentical Bone Marrow Transplantation.

Post-transplantation cyclophosphamide (PT-CY) is the most widely applied graft-versus-host disease (GVHD) prophylaxis regimen in T-cell replete haploidentical bone marrow transplantation (haplo-BMT). Although PT-CY has met with great success in the haplo-BMT arena by suppressing GVHD, patients without acute GVHD have high relapse rates. One strategy to reduce relapse rates being explored by others is a dosage reduction of PT-CY. We have taken a different approach in evaluating whether partially replacing PT-CY with post-transplantation bendamustine (PT-BEN) would be advantageous, an idea based on our preclinical research identifying several beneficial immunomodulatory properties of BEN. We therefore initiated and completed a Phase Ia trial to evaluate the progressive substitution of PT-CY with PT-BEN (ClinicalTrials.gov identifier NCT02996773). We compared outcomes between 13 patients with high-risk hematologic malignancies who received PT-CY/BEN and 31 contemporaneous haplo-BMT recipients treated with the same myeloablative conditioning regimens but receiving only PT-CY. We found that partial replacement of PT-CY with PT-BEN (PT-CY/BEN) on day +4 was well tolerated and associated with significantly earlier trilineage engraftment. We also report favorable trends toward significant improvements on univariate and multivariate analyses with PT-CY/BEN compared with PT-CY with respect to rates of chronic GVHD (hazard ratio [HR], .08; 95% confidence interval [CI], .005 to 1.11; P = .06), and GVHD-free relapse-free survival (GRFS) (HR, .22; 95% CI, .05 to .86; P = .039). Our human trial has now transitioned to Phase Ib, which will further evaluate the safety and potential benefits of PT-CY/BEN. Herein we also expand our pediatric, adolescent, and young adult experience to 31 patients, demonstrating overall survival, progression-free survival, and GRFS at 3 years of 85.6%, 76.1%, and 58.2%, respectively, in a largely racial/ethnic minority cohort. PT-CY/BEN appears to be a promising treatment option that requires further evaluation.

Innovations in radiotherapy and advances in immunotherapy for the treatment of brain metastases.

Radiotherapy for brain metastases has evolved tremendously over the past four decades, allowing for improved intracranial control of disease with reduced neurotoxicity. The main technological advance was provided by volumetric modulated arc therapy (VMAT), a computer-controlled delivery method that has opened the door for single-isocenter multi-metastases stereotactic radiosurgery (SRS) and hippocampal avoidance whole brain radiation therapy (HA-WBRT). Other notable advances have occurred in the combination of immune checkpoint inhibitors (ICI) and radiosurgery. When these two modalities are combined in the proper sequence (within 30 days from each other), it provides promising results in the treatment of intracranial metastases from melanoma. There is emerging evidence of a synergistic interaction between ICI and SRS, providing better intracranial tumor control and lengthening the survival of patients afflicted by this common complication of cancer.

Introduction to novel developments in radio-imaging and radiotherapy.

Radiation therapy has long been known to be a very effective form of therapy in relieving symptoms and prolonging the life of patients with brain metastases. Novel developments in this field have allowed oncologists to improve on older forms of radiation therapy; these recent advances in radiotherapeutic techniques (stereotactic radiosurgery and hippocampal-avoidant whole brain radiation therapy) allow sparing of the healthy brain from receiving unnecessary radiation while delivering effective treatment to the metastases, thus improving the quality of life for surviving patients. Furthermore, multiple clinical trials have documented the increased loco-regional control in the brain when radiosurgery is interdigitated with immune check point inhibitors for treatment of melanoma brain metastases. Mild hyperthermia has been used for decades as an adjuvant to radiotherapy in the treatment of radiation resistant cancers; lately, however, thermal therapies, such as hyperthermia, cryoablation, radiofrequency ablation and high intensity focused ultrasound are being investigated to provide a new ablative approach to cancer while thermoacoustic imaging and thermometry have recently been proposed as new techniques for monitoring tissue temperature in the breast during ablation treatment. In addition, other hybrid techniques have emerged that combine ultrasounds with other forms of energy such as light to provide a more accurate diagnosis and enhance the efficacy of therapy for early and late stage cancers.

Expression Levels of RAD51 Inversely Correlate with Survival of Glioblastoma Patients.

Treatment failures of glioblastoma (GBM) occur within high-dose radiation fields. We hypothesized that this is due to increased capacity for DNA damage repair in GBM. We identified 24 adult GBM patients treated with maximal safe resection followed by radiation with concurrent and adjuvant temozolomide. The mRNA from patients was quantified using NanoString Technologies' nCounter platform and compared with 12 non-neoplastic temporal lobe tissue samples as a control. Differential expression analysis identified seven DNA repair genes significantly upregulated in GBM tissues relative to controls (>4-fold difference, adjusted p values < 0.001). Among these seven genes, Cox proportional hazards models identified RAD51 to be associated with an increased risk of death (HR = 3.49; p = 0.03). Kaplan-Meier (KM) analysis showed that patients with high RAD51 expression had significantly shorter OS compared to low levels (median OS of 10.6 mo. vs 20.1 mo.; log-rank p = 0.03). Our findings were validated in a larger external dataset of 162 patients using publicly available gene expression data quantified by the same NanoString technology (median OS of 13.8 mo. vs. 17.4 mo; log-rank p = 0.006). Within this uniformly treated GBM population, RAD51, in the homologous recombination pathway, was overexpressed (vs. normal brain) and inversely correlated with OS. High RAD51 expression may be a prognostic biomarker and a therapeutic target in GBM.

T-Cell Replete Myeloablative Haploidentical Bone Marrow Transplantation Is an Effective Option for Pediatric and Young Adult Patients With High-Risk Hematologic Malignancies.

Twenty-one pediatric and young adult patients (1.1-24.7 years) with hematologic malignancies underwent myeloablative T-cell replete haploidentical bone marrow transplant (haplo-BMT) between October 2015 to December 2019. Fifty-seven percent of the patients were ethnic or racial minorities. Thirteen patients had B-cell precursor acute lymphoblastic leukemia (B-ALL) with 10 receiving 1,200 cGy fractionated total body irradiation with fludarabine while the remaining 11 patients had targeted dose-busulfan, fludarabine, melphalan conditioning. Graft-vs.-host disease (GvHD) prophylaxis consisted of post-transplant cyclophosphamide (15 patients) or cyclophosphamide and bendamustine (six patients), with all patients receiving tacrolimus and mycophenolate mofetil. Twelve patients were in first or second remission at time of transplant with five in >2nd remission and four with measurable disease. Three patients had failed prior transplants and three CAR-T cell therapies. Only one patient developed primary graft failure but engrafted promptly after a second conditioned T-replete peripheral blood stem cell transplant from the same donor. An absolute neutrophil count of 0.5 × 109/L was achieved at a median time of 16 days post-BMT while platelet engraftment occurred at a median of 30 days. The cumulative incidence of grades III to IV acute GvHD and chronic GvHD was 15.2 and 18.1%, respectively. With a median follow-up of 25.1 months the relapse rate is 17.6% with an overall survival of 84.0% and a progression-free survival of 74.3%. The chronic graft-vs.-host-free relapse-free survival (CRFS) is 58.5% while acute and chronic graft-vs.-host-free relapse-free survival (GRFS) is 50.1%. Myeloablative conditioned T-replete haploidentical BMT is a viable alternative to matched unrelated transplantation for children and young adults with high-risk hematologic malignancies.

Hippocampal Avoidance During Whole-Brain Radiotherapy Plus Memantine for Patients With Brain Metastases: Phase III Trial NRG Oncology CC001.

PURPOSE: Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS: This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS: Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [P = .049] and 16.4% v 33.3% [P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue (P = .04), less difficulty with remembering things (P = .01), and less difficulty with speaking (P = .049) and using imputed data, less interference of neurologic symptoms in daily activities (P = .008) and fewer cognitive symptoms (P = .01). CONCLUSION: HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

Targeting PD-L1 After Adjuvant Radiation in Subtotally Resected Primary Pineal Melanoma: A Case Report and Literature Review.

Primary melanoma of the pineal gland is a rare disease entity with an overall poor prognosis. Limited data exist to appropriately guide treatment decisions. Historical case reports have showed some success using a combination of surgical resection, radiotherapy, and chemotherapy, but long-term survival has been exceedingly rare. This report presents a female patient with a primary pineal melanoma who underwent subtotal resection followed by adjuvant focal radiation to the residual tumor. Immunohistochemistry identified a strong positivity for PD-L1 (70%). After radiation, systemic therapy with pembrolizumab was initiated with the plan to treat until progression. She has now completed 33 cycles of pembrolizumab without interruptions, complications, or disease progression. At the time of writing, the patient has had an excellent clinical outcome, with a durable near-complete response of >138 weeks. To our knowledge, this is the first patient with a pineal melanoma to be managed by targeting PD-L1. Furthermore, she has achieved the second longest overall survival and the longest progression-free survival reported in the literature.

The Impact of Low-Dose Cranial Boost on the Long-Term Outcomes of Adult Patients with High-Risk Acute Lymphoblastic Leukemia Undergoing Total Body Irradiation and Allogeneic Hematopoietic Stem Cell Transplantation.

PURPOSE: Total body irradiation (TBI) is an integral part of the conditioning regimen for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic, hematopoietic, cell transplantation (allo-HCT). There are conflicting data in the literature regarding the utility of a cranial irradiation boost in high-risk adult ALL without evidence of preexisting central nervous system (CNS) involvement. This study investigates the posttransplant clinical outcomes of patients with high-risk adult ALL undergoing TBI conditioning for allo-HCT with or without a whole-brain boost, without overt CNS involvement at the time of diagnosis. METHODS AND MATERIALS: A retrospective cohort study was conducted using a medical record analysis. We identified 58 patients who were treated between January 1998 and December 2016, and met our preset inclusion criteria of adults (age >18 years old) who carried a pathologically confirmed diagnosis of CNS-negative, high-risk ALL, who underwent hematopoietic stem cell transplantation with TBI conditioning. A multivariate analysis of correlation between patient outcomes and collected categorical variables was assessed with stepwise Cox logistic regression. Survival analyses were assessed using the Kaplan-Meier technique with a log-rank test. RESULTS: With a median follow-up time of 5.3 years, there was a statistically significant improvement in actuarial 7-year CNS relapse-free survival (100% vs 76.4%; P = .043) in favor of patients undergoing a cranial boost. There was no statistically significant improvement in 7-year progression-free survival (78.3% vs 62.5%; P = .076) or overall survival (49.4% vs 43.5%; P = .921) with versus without a cranial boost. On multivariate analysis, the presence of a cranial boost was the only identified variable with an independent relationship to CNS relapse-free survival. CONCLUSIONS: Adult patients with high-risk, CNS-negative ALL were found to have a statistically significant improvement in CNS relapse-free survival and a trend toward improved progression-free survival with the inclusion of a cranial boost with TBI pretransplant conditioning. Our data indicate that further investigation into the use of cranial boost in this patient population is warranted.

The role of radiation therapy in the treatment of metastatic cancer.

Radiation therapy continues to play an important role in the management of cancer. In this review, we discuss the use of radiation therapy to target and control micrometastatic disease (adjuvant use of radiation), or using stereotactic radiation therapy to address small volumes of gross disease, such as oligometastases, and finally the use of radiation therapy in the era of immunotherapy. Radiation therapy is commonly used to treat nodal basins suspected of harboring microscopic disease. More recently, computer and technical innovations have allowed radiation oncologists to treat small volumes of gross disease within the brain and also in the body with great success, adding to the cancer armamentarium. This modality of cancer treatment that began shortly after the discovery of X-rays by William Roentgen continues to evolve and finds new clinical applications which minimize toxicity while increasing effectiveness. The newly discovered interactions of high dose/fraction radiation (stereotactic radiosurgery) with immune check point inhibitors in melanoma is the latest example of how synergism can be achieved between two different modalities thus increasing the therapeutic ratio to control metastatic cancer.

Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide/Bendamustine in Pediatric and Young Adult Patients with Hematologic Malignancies.

More than half of patients undergoing hematopoietic cell transplantation at our institution are ethnic or racial minorities, making the search for matched unrelated donors more challenging. Since the introduction of haploidentical bone marrow transplant (haplo-BMT) into our pediatric BMT program in 2015, 69.2% of recipients have been minorities. Herein, we describe our experience with the first 13 pediatric and young adult patients with hematologic malignancies who have undergone T cell-replete haplo-BMT after myeloablative conditioning (MAC) at our institution. We have previously documented that in experimental haplo-BMT, post-transplant bendamustine (PT-BEN) is at least as effective as post-transplant cyclophosphamide (PT-CY) against graft-versus-host disease (GVHD) and elicits superior graft-versus-leukemia (GVL) effects. We report on, for the first time in humans, 4 patients treated with PT-CY and PT-BEN after haplo-BMT as part of our ongoing institutional phase I/II study (NCT02996773). The remaining 9 patients reviewed in this report received PT-CY. Our findings indicate that MAC haplo-BMT is well tolerated by children and young adults with advanced hematologic malignancies with no observed nonrelapse mortality or grades III to IV GVHD. All patients who underwent haplo-BMT remain alive and disease-free with a median follow-up of 15.6 months (range, 1.5 to 31.2). Preliminary findings from our ongoing clinical trial demonstrate that partial substitution of PT-BEN for PT-CY is feasible and safe after haplo-BMT as an immune modulatory strategy to alleviate GVHD and potentially more effectively preserve GVL.

Interval Change in Diffusion and Perfusion MRI Parameters for the Assessment of Pseudoprogression in Cerebral Metastases Treated With Stereotactic Radiation.

OBJECTIVE: Apparent increases in the size of cerebral metastases after stereotactic radiosurgery (SRS) can be caused by pseudoprogression or true disease progression, which poses a diagnostic challenge at conventional MRI. The purpose of this study was to assess whether interval change in DWI and perfusion MRI parameters can differentiate pseudoprogression from progressive disease after treatment with SRS. MATERIALS AND METHODS: Patients with apparent growth of cerebral metastases after SRS treatment who underwent pre- and post-SRS DWI, dynamic susceptibility contrast (DSC)-MRI, and perfusion dynamic contrast-enhanced (DCE)-MRI were retrospectively evaluated. Final assignment of pseudoprogression or progressive disease was determined at 6-month follow-up imaging using the Response Assessment in Neuro-Oncology Brain Metastases criteria. Mean values of apparent diffusion coefficient (ADC), DCE-MRI-derived volume transfer constant (Ktrans), and DSC-MRI-derived relative cerebral blood volume (CBV) from pre- and post-SRS MRI scans were compared between groups using univariate and regression analysis. Fisher exact test was used to compare interval change of imaging biomarkers. RESULTS: Of 102 cerebral metastases evaluated, 32 lesions in 29 patients met our inclusion criteria. The mean duration of follow-up was 7.2 months (range, 6-14 months). Twenty-two lesions were determined as pseudoprogression, and 10 lesions were determined as progressive disease using the Response Assessment in Neuro-Oncology Brain Metastases criteria at 6-month follow-up MRI. The interval change pattern of our imaging parameters matched the expected patterns of treatment response for ADC (23/32 lesions; 72%; p = 0.055; odds ratio, 5.1), Ktrans (24/32 lesions; 75%; p = 0.006; odds ratio, 19.2), and relative CBV (27/32 lesions; 84%; p = 0.001; odds ratio, 25.3). CONCLUSION: Pseudoprogression can be distinguished from disease progression in cerebral metastases treated with SRS via an interval decrease in relative CBV and Ktrans values.

Multiparametric MRI for Differentiation of Radiation Necrosis From Recurrent Tumor in Patients With Treated Glioblastoma.

OBJECTIVE: Differentiation of radiation necrosis (RN) from recurrent tumor (RT) in treated patients with glioblastoma remains a diagnostic challenge. The purpose of this study is to evaluate the diagnostic performance of multiparametric MRI in distinguishing RN from RT in patients with glioblastoma, with the use of a combination of MR perfusion and diffusion parameters. MATERIALS AND METHODS: Patients with glioblastoma who had a new enhancing mass develop after completing standard treatment were retrospectively evaluated. Apparent diffusion coefficient (ADC), volume transfer constant (Ktrans), and relative cerebral blood volume (rCBV) values were calculated from the MR images on which the enhancing lesions first appeared. Repeated measure of analysis, logistic regression, and ROC analysis were performed. RESULTS: Of a total of 70 patients evaluated, 46 (34 with RT and 12 with RN) met our inclusion criteria. Patients with RT had significantly higher mean rCBV (p < 0.001) and Ktrans (p = 0.006) values and lower ADC values (p = 0.004), compared with patients with RN. The overall diagnostic accuracy was 85.8% for rCBV, 75.5% for Ktrans, and 71.3% for ADC values. The logistic regression model showed a significant contribution of rCBV (p = 0.024) and Ktrans (p = 0.040) as independent imaging classifiers for differentiation of RT from RN. Combined use of rCBV and Ktrans at threshold values of 2.2 and 0.08 min-1, respectively, improved the overall diagnostic accuracy to 92.8%. CONCLUSION: In patients with treated glioblastoma, rCBV outperforms ADC and Ktrans as a single imaging classifier to predict recurrent tumor versus radiation necrosis; however, the combination of rCBV and Ktrans may be used to improve overall diagnostic accuracy.

Improved time to disease progression in the brain in patients with melanoma brain metastases treated with concurrent delivery of radiosurgery and ipilimumab.

Background: To identify the optimal sequencing and timing of immunotherapy (IT) and stereotactic radiosurgery (SRS) for melanoma brain metastases (MBMs). Methods: The elapsed days between IT and SRS were correlated with local control (LC), regional brain control (RBC), time to CNS progression (TTPCNS), overall survival (OS), and radiation necrosis (RN). Logistic regression and Cox proportional models were used for statistical analysis. Results: Twenty-five patients with 58 MBMs underwent SRS and IT. Median follow-up was 22.7 mo (3.1-77.9 mo). A median of 2 SRS treatments of 21 Gy (range 16-24 Gy) and 4 cycles of Ipilimumab were delivered. SRS was delivered Before, After or Concurrently with IT in 9, 5, and 11 patients, respectively; 8/25 received SRS ≤30 d of IT and 17/25 were >30 d of IT. Median OS was 35.8 mo, 1- and 2-y OS was 83% and 64%, respectively, and LC was 94.8%. By timing, RBC and TTPCNS were significantly improved when SRS was delivered ≤30 d of IT (75% vs 23.5%, p = 0.03 and median not reached vs 5.7 mo, p = 0.02, respectively). By groups, Concurrent delivery improved TTPCNS (p = 0.04). The rate of RN was 20.7% (12/58 lesions) and RN was associated with improved OS (HR 0.21, p = 0.01). Conclusions: High OS was found for MBM treated with SRS and IT compared to historical reports. A significant association for improved RBC and TTPCNS was found when SRS was delivered concurrently and within 30 d of IT. Occurrence of RN was higher than SRS alone series but significantly associated with improved OS.

Does ultrasound measurement improve the accuracy of electronic brachytherapy in the treatment of superficial non-melanomatous skin cancer?

PURPOSE: Electronic brachytherapy (eBT) is a form of contact radiation therapy used for thin superficial non-melanomatous skin cancers (NMSCs). An accurate measurement of diameter and depth is important for eBT treatment planning. Therefore, we compared clinical measurements by an experienced physician to measurements obtained using ultrasound (US), an objective imaging modality, in order to determine if clinical measurements were accurate enough for adequate NMSC treatment. MATERIAL AND METHODS: Eighteen patients with 20 biopsy-proven NMSCs first had a clinical examination and then an US evaluation prior to starting eBT. One physician provided a clinical measurement for diameter and depth based on physical examination during radiation oncology consultation. The patients then had an US evaluation with a 14 or 18 MHz US unit, to determine both the diameter and depth measurements; eBT dose prescription was done using the US derived measurements. The clinical measurements and US measurements were compared using a t-test. RESULTS: Seventeen lesions were basal cell carcinoma and 3 lesions were squamous cell carcinoma. The most common location was the nose (10 lesions). The difference between the clinical and the US derived measurements for the second largest diameter was found to be statistically significant (p = 0.03), while the difference for the largest diameter of the lesions was not (p = 0.24). More importantly, the depth measurements obtained with US were also found to be significantly different from the clinical estimates (p = 0.02). All patients have had a complete response to therapy with a median follow-up of 24 months. CONCLUSIONS: Statistically different measurements were obtained in 2 of 3 parameters used in choosing applicator size and prescription depth using an US assessment. The data presented suggests that US is a more objective modality than clinical judgment for determining superficial NMSC diameter and prescription depth for personalized eBT planning.

Radiotherapeutic management of vestibular schwannomas using size- and location-adapted fractionation regimens to maximize the therapeutic ratio.

BACKGROUND: We evaluated and compared the radiographic and clinical outcomes of patients with vestibular schwannomas treated with single fraction stereotactic radiosurgery (SRS), 5 fractions of hypofractionated stereotactic radiation therapy (hSRT), or 25 to 30 fractions of conventionally fractionated stereotactic radiation therapy (cfSRT). METHODS AND MATERIALS: Fifty-six patients treated with LINAC-based SRS (median, 12.5 Gy), hSRT (25 Gy), or cfSRT (median, 54 Gy) were retrospectively reviewed. Fractionation was based on the size of the tumor, proximity to the brainstem, and potential risk of neurological sequelae. Median follow-up time was 55.2 months. RESULTS: The pretreatment median tumor diameter was significantly smaller for SRS (1.14 cm) compared with hSRT (1.7 cm) (P = .03) and cfSRT (2.0 cm) (P < .001). The overall local tumor control was 96.4%: 100% SRS, 100% hSRT, and 90% cfSRT (P = .19). Tumor regression was observed in 53.3% of SRS, 76.2% of hSRT, and 90% of cfSRT (P = .05). There was less transient expansion of tumors treated with cfSRT (5%) than with SRS (53.3%) or hSRT (28.6%) (P = .005). The median time to regression was 13.8 months for SRS, 14.2 months for hSRT, and 5.5 months for cfSRT (P = .34). There was a 3.6% incidence of grade 3 trigeminal neuropathy, but there was no grade 3 facial neuropathy. CONCLUSIONS: All 3 regimens demonstrated similar excellent local control with minimal toxicity; however, the ability of hSRT to treat larger tumors with comparable outcomes to SRS and greater patient convenience when compared with cfSRT suggest that hSRT may offer the optimal treatment approach.