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PURPOSE The Bone Metastases Ensemble Trees for Survival Decision Support Platform (BMETS-DSP) provides patient-specific survival predictions and evidence-based recommendations to guide multidisciplinary management for symptomatic bone metastases. We assessed the clinical utility of the BMETS-DSP through a pilot prepost design in a simulated clinical environment. METHODS Ten Radiation Oncology physicians reviewed 55 patient cases at two time points: without and then with the use of BMETS-DSP. Assessment included 12-month survival estimate, confidence in and likelihood of sharing estimates with patients, and recommendations for open surgery, systemic therapy, hospice referral, and radiotherapy (RT) regimen. Paired statistics compared pre- versus post-DSP outcomes. Reported statistical significance is P < .05. RESULTS Pre- versus post-DSP, overestimation of true minus estimated survival time was significantly reduced (mean difference –2.1 [standard deviation 4.1] v –1 month [standard deviation 3.5]). Prediction accuracy was significantly improved at cut points of < 3 (72 v 79%), ≤ 6 (64 v 71%), and ≥ 12 months (70 v 81%). Median ratings of confidence in and likelihood of sharing prognosis significantly increased. Significantly greater concordance was seen in matching use of 1-fraction RT with the true survival < 3 months (70 v 76%) and < 10-fraction RT with the true survival < 12 months (55 v 62%) and appropriate use of open surgery (47% v 53%), without significant changes in selection of hospice referral or systemic therapy. CONCLUSION This pilot study demonstrates that BMETS-DSP significantly improved physician survival estimation accuracy, prognostic confidence, likelihood of sharing prognosis, and use of prognosis-appropriate RT regimens in the care of symptomatic bone metastases, supporting future multi-institutional validation of the platform.

Glioblastoma recurrence between initial resection and standard-of-care adjuvant chemoradiotherapy (CRT) is a negative prognostic factor in an already highly aggressive disease. Re-resection with GammaTileⓇ(GT Medical Technologies Inc., Tempe, AZ) placement affords expedited adjuvant radiation to mitigate the likelihood of such growth. Here, we report a glioblastoma patient who underwent re-resection and GammaTileⓇ (GT) placement within two months of the initial gross total resection due to regrowth that reached the size of the original presenting tumor. The patient subsequently received concurrent temozolomide and 60 Gy external beam to regions outside of the brachytherapy range, fulfilling the generally accepted Stupp regimen. The patient tolerated the treatment without complication. The dosimetrics and implications of the case presentation are reviewed.

PURPOSE: Adjacent tissues-in-beam (TIB) may receive substantial incidental doses within standard tangent fields during hypofractioned whole breast irradiation (HF-WBI). To characterize the impact of dose to TIB, we analyzed dosimetric parameters of TIB and associated acute toxicity. MATERIALS AND METHODS: Plans prescribed to 40.5 Gy/15 fractions from 4/2016-1/2018 were evaluated. Structures of interest were contoured: (1) TIB: all tissues encompassed by plan 30% isodose lines, (2) breast, (3) non-breast TIB (nTIB): TIB minus contoured breast. Volumes of TIB, breast, and nTIB receiving 100%–107% of prescription dose (V100-V107) were calculated. Twelve patient- and physician-reported acute toxicities were prospectively collected weekly. Correlations between volumetric and dosimetric parameters were assessed. Uni- and multivariable logistic regressions evaluated toxicity grade changes as a function of TIB, breast, and nTIB V100-V107 (in cm(3)). RESULTS: We evaluated 137 plans. Breast volume was positively correlated with nTIB and nTIB V100 (rho = 0.52, rho = 0.30, respectively, both p 2 cm(3) were noted in 14% of breast and 21% of nTIB volumes. On multivariable analyses, increasing breast and nTIB V100 significantly raised odds of grade 2+ dermatitis and burning/twinging pain, respectively; increasing nTIB V105 elevated odds of hyperpigmentation and burning pain; and increasing nTIB V107 raised odds of burning pain. Threshold volumes for >6-fold odds of developing burning pain were TIB V105 > 100 cm(3) and V107 > 5 cm(3). CONCLUSIONS: For HF-WBI, doses to nTIB over the prescription predicted acute toxicities independent of breast doses. These data support inclusion of TIB as a region of interest in treatment planning and protocol design

Alterations in peripheral blood cell populations, including myeloid cell subsets and lymphocytes, have been associated with poor prognostic outcomes in patients with glioblastoma (GBM). To date, evaluation of these populations has largely been on freeze-thawed samples at a limited number of time points. The purpose of our study is to identify the frequency and activation status of tumor-supportive myeloid and lymphocyte subsets during the course of standard adjuvant therapy in patients with GBM in fresh peripheral blood samples. We hypothesize that dysfunctional myeloid and lymphocyte populations expand during standard care temozolomide (TMZ)/radiation therapy (RT). We prospectively enrolled 16 patients with a new diagnosis of GBM that underwent maximal safe surgical resection. Twelve received standard adjuvant therapy consisting of six weeks of TMZ/RT. Four received alternative therapies: one experimental chemotherapeutic/three alternative radiation schemes. Peripheral blood was obtained seven times over the course of adjuvant therapy: prior to starting adjuvant therapy, five during treatment, and once one month after completion of therapy. Eleven patients completed all seven time points. Peripheral blood samples were analyzed by flow cytometry, focusing on immune checkpoints and critical markers of activation of systemic immunity. Available preliminary data demonstrate a median increase of 2.1% (-21.2–27.4%) in the frequency (%fx) of myeloid-derived suppressor cells (MDSC) after commencement of adjuvant therapy at time point 2 (TP2), compared to baseline. To date, 7/16 patients are alive and without evidence of recurrent disease on imaging. The majority of these patients had a decrease in %fx of MDSC at TP2, after starting adjuvant therapy, compared to baseline. The %fx of CD8+ T cells was greatest at TP7 (range: 21.7%-67.0%), one month after TMZ/RT, for most patients. PD-1 and FOXP3 expression by lymphocytes was variable across time points, suggesting the importance of additional factors which will be explored through future analyses. These early findings suggest that the immune response changes throughout the course of TMZ/RT. An understanding of these changes in the peripheral blood, termed immunodynamics in the context of our studies, may be valuable future tool to aid in optimizing immunity in patients with GBM.

INTRODUCTION Neurofibromatosis type 1 (NF1) is a rare tumor suppressor syndrome that predisposes to nervous system tumors. The optimal treatment of gliomas in adults with NF1 is uncertain. Specifically, little is known about the effectiveness or toxicity of radiation therapy (RT) in this population although it is standard of care for progressive low grade glioma (LGG) or high grade glioma (HGG) in general. We evaluated the tolerability of RT and time to progression (TTP) after completion of RT in people with NF1 diagnosed with glioma in adulthood. METHODS Charts were reviewed for patients with a confirmed NF1 syndrome, LGG or HGG, > 18 years old, receiving RT and followed at Johns Hopkins University between 2009–2019. Secondary outcomes were overall survival (OS) from diagnosis and RT associated toxicity. Progression was defined radiographically; toxicity was graded by CTCAE. RESULTS Eight people (6 males) with median age of 36.5 years (range, 20–63) received RT at median of 56.7Gy either at the time of diagnosis (N=4) or at recurrence (N=4). Three patients (37.5%) had LGG; five (62.5%) had HGG. Tumor locations were brainstem (6) and temporal lobe (2). All patients received concurrent chemotherapy with RT; temozolomide (7) or bevacizumab (1). At median follow-up of 28.3 months (0.9–90.2) from RT completion, 5/8 patients had progression. Of those who progressed, median TTP was 12.7 months (2.5–26.6). The longest period of disease control was 28.9 months. One and two-year OS rates were 87% and 32%, respectively. RT associated toxicities were within the expected range. CONCLUSIONS Overall disease control after RT was variable, with some examples of extraordinary duration of disease control, and RT toxicities were within expected range. Collaborative efforts to examine a larger cohort of adults with NF1 associated gliomas are needed to define optimal care, but these observations suggest RT is a feasible modality.

Radiotherapy is cytotoxic to tumor cells and is therefore a critical component of therapy for many malignancies, including glioblastoma (GBM). We now appreciate the value of the immunomodulatory effects of radiation that may be important to overall therapeutic success in some patients with this primary brain tumor. Although potentially beneficial immune-stimulating properties of radiotherapy treatment have been the focus of recent study, this modality is actually at the same time associated with the depletion of lymphocytes, which are crucial to the defense against neoplastic development and progression. In this review, we describe the association of systemic lymphopenia with poor tumor outcome, present evidence that radiotherapy is an important contributing cause of lymphodepletion, describe the systemic immune context of tumor and brain injury that contributes to immunosuppression, describe other contributing factors to lymphopenia including concomitant medications and treatments, and speculate about the role of the normal physiologic response to brain injury in the immunosuppressive dynamics of GBM. Radiotherapy is one significant and potentially actionable iatrogenic suppressor of immune response that may be limiting the success of therapy in GBM and other tumor types. Altered strategies for radiotherapy more permissive of a vigorous antineoplastic immune response may improve outcome for malignancy.

Background: Improvements in systemic therapy continue to increase survival for patients with brain metastases. Updated dosimetric models are required to optimize long-term safety of stereotactic radiosurgery (SRS) for this indication. Methods: Patients at a single institution receiving SRS from December 2011 to December 2014 were retrospectively reviewed. Patients with radiographic progression of at least one lesion, and with at least 6 months of follow-up from the start of SRS were included. Grade 3 necrosis was defined as requiring surgical intervention. This data were combined with two additional published datasets to construct logistic models describing necrosis risk as a function of dose and volume. Results: From our institution, 294 brain metastases across 57 patients in 139 treatment plans met inclusion criteria. Primary histologies included non-small cell lung cancer (n = 19), melanoma (n = 13), breast carcinoma (n = 9), renal cell carcinoma (n = 7), and other (n = 9). Median follow-up from SRS of first cranial metastasis was 21.7 months (range: 6.3–56.6) and median overall survival was 25.6 months (range: 6.5–56.6). There were eight cases of Grade 1–2 and two cases of Grade 3 necrosis. As a useful clinical reference point, 20 cc of total brain receiving a single-fraction equivalent dose ≥14 Gy corresponded to 12.1% risk for Grade 1–3 (P < 0.003) and 3.4% risk for Grade 3 necrosis (P < 0.001). Conclusions: These results compare favorably with the QUANTEC brain tolerance estimates for radiosurgery, providing optimism for lower toxicity in the modern era. Additional studies are needed to determine dose tolerance parameters across a broad spectrum of patients.

Die Herstellung von Werkzeugen ist eines der wichtigsten Merkmale der menschlichen Zivilisation. Dabei handelt es sich um einen Prozess, bei dem Werkstoffe durch physikalische Ver��nderungen ihrer Form und der Eigenschaften ihres Materials in neue Objekte umgewandelt werden. Mit der industriellen Revolution entwickelte sich eine gro��e Kunstfertigkeit und Erfahrung im Bereich der physikalischen Modifizierung von Werkstoffen in s��mtlichen Dimensionen. Der Mikrobereich (und noch schwieriger, der Nanobereich) bietet seit dem Beginn des 20. Jahrhunderts eine besondere Herausforderung. Die Nutzung von Mikro- und noch kleineren Ger��ten stellte eine der treibenden Kr��fte der Computerrevolution dar und erm��glichte das ��berschreiten v��llig neuer Grenzen menschlichen Strebens. Die meisten bekannten Methoden f��r physikalische Modifizierung im Mikrobereich, wie beispielsweise die Fotolithographie, sind in ihren Anwendungsm��glichkeiten relativ eingeschr��nkt; einige Methoden jedoch, wie die Oberfl��chenmodifizierung mit Hilfe von fokussierten Ionenstrahlen (Focused Ion Beams FIB), bieten ein Ma�� an Gestaltungsfreiheit wie bislang meist nur aus dem Makrobereich bekannt. Beim Sputtern mit fokussierten Ionenstrahlen handelt es sich um eine Technik, welche eine direkte topographische Modifizierung ann��hernd im Nanobereich erm��glicht, indem gezielt Material durch einen energetischen feinfokussierten Strahl ionisierter Atome abgetragen wird. Zum besseren Verst��ndnis sowie zur systematischeren Kontrolle dieses -��tzprozesses- durch FIB kommt die Simulation, bei der physikalische Theorien in ��berpr��fbare Resultate umgewandelt werden k��nnen, zum Einsatz. In der vorliegenden Dissertation wird eine rechnerisch effiziente Methode zur Simulation jener Ph��nomene pr��sentiert, welche mit dem Sputtern mit fokussierten Ionenstrahlen in Zusammenhang stehen - darunter Materialabtragung durch den Strahl, Redeposition von gesputterten Teilchen, Sputtern durch r��ckgestreute Ionen, sowie Redeposition von Atomen, welche von diesen r��ckgestreuten Ionen gesputtert werden. Hierf��r kommt ein Kontinuumsmodell zum Einsatz, das statistische Daten ��ber das Sputter-Verhalten nutzt, die durch Monte-Carlo-Simulation gesammelt wurden. Ebenso wird ein Algorithmus zur inversen Modellierung pr��sentiert, welcher eine speziell entwickelte K��figfunktion und ihre Beschr��nkung auf Dosisprofile zur Verbesserung der Effizienz nutzt; f��r eine inverse Modellierung kann das gezeigte Sputter-Modell angewendet werden, um ein Dosisprofil zu erzeugen, das zu einer durch den Benutzer kontrollierten, endg��ltigen Topographie f��hrt. Ein besonderer Fokus dieser Arbeit liegt au��erdem auf der Optimierung der statistischen Parameter, welche als Input f��r das Modell verwendet wurden. Diese Optimierung erfolgt durch den Vergleich der Resultate atomistischer Monte-Carlo-Simulationen des Ionenbeschusses mit experimentellen Daten (hierf��r kommt die Binary Collision Approximation BCA zur Anwendung). Durch diese Optimierung zeigte sich, dass Oberfl��chenrauigkeit f��r die pr��zise Reproduktion der experimentellen Daten unerl��sslich ist. Mit dem Hinzuziehen zahlreicher Modelle f��r die Simulation von Oberfl��chenrauigkeit konnte ein neues 1D-Modell mit einem Dichtegradienten vom Vakuum in Richtung Target entwickelt und angewendet werden. Es konnte gezeigt werden, dass eine Oberfl��chenschicht von 8,27 �� f��r die Replikation der experimentellen Daten erforderlich ist. Ein alternatives 2D-Modell f��r Oberfl��chenrauigkeit berechnet jedoch eine geringere Dicke, was darauf hinweist, dass mit Rauigkeitsmodellen, so n��tzlich sie im vorliegenden Modellierungskontext auch sein m��gen, keine tats��chlichen Rauigkeitswerte gewonnen werden k��nnen. Die Auswirkungen des Energiespektrums der gesputterten Teilchen wurde anschlie��end anhand eines zweiten Kontinuummodells untersucht. Dieses nach konkreten Energiewerten aufgeschl��sselte Modell zeigt, dass Sputtern bei h��heren Aspektverh��ltnissen (>3:1) aufgrund der energiereicheren gesputterten Atome, welche wieder auf das Target auftreffen (reflexives Sputtern), zu einer 28% h��heren simulierten Abtragungstiefe f��hren k��nnte ---was bei dem untersuchten System der Fall ist, bei welchem 30 keV Gallium auf Silizium auftreffen. Diese Untersuchungsergebnisse erweitern den Stand der Technik im Bereich der Simulation der Oberfl��chenmodifikation mit fokussierten Ionenstrahlen. Sie bieten die M��glichkeit, die menschlichen F��higkeiten bei der Strukturierung von Werkstoffen im Mikro- und Nanobereich weiter auszubauen., Tool-making is one of the defining traits of human civilization. This process involves transforming raw materials into new objects through the physical modification of the shape and properties of the underlying material. Human arts, through the industrial revolution, have been quite adept at physical modification of materials at all manner of dimensional scales. The micro-scale (further difficult the nanoscale) has been, and continues to be a challenging arena since the beginning of the 20th century. The computer revolution has been driven by the ability and the desire to make use of micro- and smaller devices to enable previously impossible frontiers of human endeavor. Of the known methods of physical modification at the micro-scale, most ---such a photolithography--- are quite restrictive in the manner in which they may be used; however, some methods such as milling by Focused Ion Beams (FIB) offer degrees of expressional freedom similar to those seen at the macro-scale. FIB milling by sputtering is a technique that allows for the direct modification of topography on a near nanoscale through the targeted removal of material via energy imparted by a finely focused beam of energetic ionized atoms. In order to better understand and exercise control over the FIB milling process, simulation is used to convert physical theories into testable outcomes. In this dissertation a computationally efficient method for the simulation of the phenomena involved in FIB milling by sputtering, including sputtering by the beam, redeposition of sputtered particles, sputtering by backscattered beam ions, and redeposition of atoms sputtered by backscattered beam ions is presented making use of a continuum model employing statistical sputtering properties gleaned from Monte-Carlo simulation. An inverse modeling algorithm utilizing a unique cage-function restriction on dose profiles to improve efficiency is also demonstrated; where the inverse modeler employs the demonstrated sputtering model in order to generate a dose profile that will result in a user-defined final topography. Special care is also taken to optimize the statistical parameters used as input for the model. This optimization occurs through the comparison of parameters obtained by Monte-Carlo atomistic simulation of ion impacts (making use of the binary collisions approximation) to experimental data. This optimization indicated that surface roughness is essential for the precise reproduction of the experimental data. Numerous models for simulating surface roughness were considered and a novel 1D model of surface roughness was implemented using a gradient in the density between the simulated target and the vacuum over the length of a small surface layer. It was determined that a surface layer 8.27 �� thick is needed to replicate the experimental data; however, an alternative 2D model of surface roughness predicts a smaller thickness indicating that these roughness models, while useful in the presented modeling context, may not serve to extract the true roughness values. The effects of the energy spectrum of sputtered particles were studied in a second continuum model. This energy-resolved model indicates that for higher aspect ratio features (>3:1) sputtering due to energetically sputtered atoms re-impinging the target (reflexive sputtering), may result in a 28% increase in the final simulated milling depth ---in the studied system of 30 keV gallium impinging on silicon. These results advance the state of the art with respect to simulation of FIB milling and offer the opportunity for further improvements in mankind's ability to control the shape of materials on the micro- and nanoscale.