Use of Commercially Available Optically Stimulated Luminescence Dosimeter As Extremity Dose Estimator.

In 2009, Idaho National Laboratory (INL) transitioned to an external dosimetry program using optically stimulated luminescent (OSL) technology. This process led to the introduction of the Landauer, Inc., nanoDot dosimeter and MicroStar reader to INL's radiological control program. At the time, a small, self-contained, single chip OSL dosimeter that could be easily read in the field was recognized as having many potential applications for a radiological control program. The ability to achieve a realistic extremity-dose estimate in the field shortly following work where significant exposure is expected is a much sought-after capability at INL. It was proposed to employ the Landauer nanoDot dosimeter as a supplemental extremity monitor as an alternative to time-motion dose analyses based on direct radiation measurements, which had proven to be inaccurate and operationally inefficient. Additionally, this process does not involve the nanoDot in the US Department of Energy Laboratory Accreditation Program (DOELAP) process, which significantly reduces operational complexity. A dose conversion value for the nanoDot dosimeter was derived from direct comparisons with a DOELAP-accredited extremity dosimeter. The geometry or placement of the nanoDot relative to the accredited extremity dosimeter was kept as proximate as possible to best replicate the expected results from the accredited extremity dosimeter. Upon implementation, the nanoDot has proven to be effective in providing reasonable and timely extremity-dose estimates for operational control.

Response to GH Treatment After Radiation Therapy Depends on Location of Irradiation.

OBJECTIVES: Cancer survivors with GH deficiency (GHD) receive GH therapy (GHT) after 1+ year observation to ensure stable tumor status/resolution. HYPOTHESIS: Radiation therapy (RT) to brain, spine, or extremities alters growth response to GHT. AIM: Identify differences in growth response to GHT according to type/location of RT. METHODS: The Pfizer International Growth Database was searched for cancer survivors on GHT for ≥5 years. Patient data, grouped by tumor type, were analyzed for therapy (surgery, chemotherapy, RT of the focal central nervous system, cranial, craniospinal, or total body irradiation [TBI] as part of bone marrow transplantation), sex, peak stimulated GH, age at GHT start, and duration from RT to GHT start. Kruskal-Wallis test and quantile regression modeling were performed. RESULTS: Of 1149 GHD survivors on GHT for ≥5 years (male 733; median age 8.4 years; GH peak 2.8 ng/mL), 431 had craniopharyngioma (251, cranial RT), 224 medulloblastoma (craniospinal RT), 134 leukemia (72 TBI), and 360 other tumors. Median age differed by tumor group (P < 0.001). Five-year delta height SD score (SDS) (5-year ∆HtSDS; median [10th-90th percentile]) was greatest for craniopharyngioma, 1.6 (0.3-3.0); for medulloblastoma, 5-year ∆HtSDS 0.9 (0.0-1.9); for leukemia 5-year ∆HtSDS, after TBI (0.3, 0-0.7) versus without RT (0.5, 0-0.9), direct comparison P < 0.001. Adverse events included 40 treatment-related, but none unexpected. CONCLUSIONS: TBI for leukemia had significant impact on growth response to GHT. Medulloblastoma survivors had intermediate GHT response, whereas craniopharyngioma cranial RT did not alter GHT response. Both craniospinal and epiphyseal irradiation negatively affect growth response to GH therapy compared with only cranial RT or no RT.

Neoadjuvant radiation improves margin-negative resection rates in extremity sarcoma but not survival.

BACKGROUND AND OBJECTIVES: Radiation improves limb salvage in extremity sarcomas. Timing of radiation therapy remains under investigation. We sought to evaluate the effects of neoadjuvant radiation (NAR) on surgery and survival of patients with extremity sarcomas. MATERIALS AND METHODS: A multi-institutional database was used to identify patients with extremity sarcomas undergoing surgical resection from 2000-2016. Patients were categorized by treatment strategy: surgery alone, adjuvant radiation (AR), or NAR. Survival, recurrence, limb salvage, and surgical margin status was analyzed. RESULTS: A total of 1483 patients were identified. Most patients receiving radiotherapy had high-grade tumors (82% NAR vs 81% AR vs 60% surgery; P < .001). The radiotherapy groups had more limb-sparing operations (98% AR vs 94% NAR vs 87% surgery; P < .001). NAR resulted in negative margin resections (90% NAR vs 79% surgery vs 75% AR; P < .0001). There were fewer local recurrences in the radiation groups (14% NAR vs 17% AR vs 27% surgery; P = .001). There was no difference in overall or recurrence-free survival between the three groups (OS, P = .132; RFS, P = .227). CONCLUSION: In this large study, radiotherapy improved limb salvage rates and decreased local recurrences. Receipt of NAR achieves more margin-negative resections however this did not improve local recurrence or survival rates over.

Neutron dose coefficients for local skin.

A draft report by the International Commission on Radiation Units and Measurements (ICRU) Report Committee 26 (RC26) will recommend alternative definitions of the operational quantities that are better estimators of radiation protection quantities. Dose coefficients for use with physical field quantities-fluence and, for photons, air kerma-are given for various particle types over a broad energy range. For the skin dosimetry, several changes are of particular interest. Specifically, the use of absorbed dose instead of dose equivalent has been selected as the operational quantity since deterministic effects are of primary interest in the skin. In addition, newly recommended phantoms are specified for computing the operational dose coefficients. The report also addresses computational approaches such as tally volumes, depths, source areas, and rotational angles. In this work, dose coefficients calculated for local skin in support of the ICRU report are presented. Energy-dependent dose coefficients were calculated in phantoms specified for the trunk (slab), the ankle or wrist (pillar), and the finger (rod). The phantom specifications in this work were taken directly from the draft report. Full transport of secondary charged particles from neutron interactions was performed and an analysis of the depth-dose profiles in the slab phantom is presented, The last complete set of neutron dose coefficients for the extremities was published more than 25 years ago. Given the limited data available, it is difficult for many facilities to obtain clear guidance on how monitoring should be performed and how dosimeters should be calibrated so spectra from commonly encountered neutron sources were used to generate source-specific dose coefficients in each of the phantoms. Both energy-dependent and source-specific dose coefficients are provided for rotational angles up to 180 degrees for the rod and pillar phantoms and up to 75 degrees for the slab phantom.

Does the addition of chemotherapy to neoadjuvant radiotherapy impact survival in high-risk extremity/trunk soft-tissue sarcoma?

BACKGROUND: The role of chemotherapy in extremity/trunk soft-tissue sarcoma (ET-STS) is controversial, even for patients at high risk for distant recurrence and death (those with high-grade tumors ≥5 cm in size). This study examines the impact of integrating chemotherapy with neoadjuvant radiotherapy (RT) on overall survival (OS) for patients with high-risk ET-STS. METHODS: The National Cancer Data Base was queried for adult patients with high-risk ET-STS who received neoadjuvant RT and limb salvage surgery between 2006 and 2014. Patients were stratified into RT and chemoradiotherapy (CRT) cohorts. OS for the RT and CRT cohorts was analyzed with the Kaplan-Meier method, log-rank tests, and Cox proportional hazards models. Propensity score matching (PSM) analysis was used to account for a potential treatment selection bias between the cohorts. RESULTS: A total of 884 patients were identified: 639 (72.3%) in the RT cohort and 245 (27.7%) in the CRT cohort. The unadjusted 5-year Kaplan-Meier OS rate was significantly higher in the CRT cohort: 72.0% versus 56.1% (P < .001). Neoadjuvant chemotherapy was associated with improved OS in univariate and multivariable analyses (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.41-0.78; P < .001). PSM identified 2 evenly matched cohorts of 212 patients each. The 5-year matched Kaplan-Meier OS rates were 69.8% and 55.4% for the CRT and RT cohorts, respectively (P = .002). The addition of neoadjuvant chemotherapy remained prognostic for OS on PSM (HR, 0.56; 95% CI, 0.39-0.83; P = .003). CONCLUSIONS: The addition of chemotherapy to neoadjuvant RT was associated with improved OS for patients with high-risk ET-STS. In the absence of randomized data evaluating CRT versus RT, these findings warrant further investigation.

The pretreatment erythrocyte sedimentation rate predicts survival outcomes after surgery and adjuvant radiotherapy for extremity soft tissue sarcoma.

BACKGROUND: Systemic inflammation plays a critical role in cancer progression and oncologic outcomes in cancer patients. We investigated whether preoperative inflammatory biomarkers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and neutrophil to lymphocyte ratio (NLR), could be surrogate biomarkers for predicting overall survival (OS) in soft tissue sarcoma (STS) patients treated with surgery and postoperative radiotherapy. METHODS: A series of 99 patients who presented with localized extremity STS were retrospectively reviewed. The preoperative CRP levels, ESR, and NLR were evaluated for associations with OS, disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS). Cutoff values for CRP, ESR, and NLR were derived from receiver-operating characteristic curve analysis. RESULTS: Elevated CRP (> 0.14 mg/dL), ESR (> 15 mm/h), and NLR (> 1.95) levels were seen in 33, 44, and 45 patients, respectively. Of these three inflammatory biomarkers, elevated CRP and ESR were associated with a poorer OS (CRP: P = 0.050; ESR: P = 0.001), DFS (CRP: P = 0.023; ESR: P = 0.003), and DMFS (CRP: P = 0.015; ESR: P = 0.001). By multivariate analysis, an elevated ESR was found to be an independent prognostic factor for OS (HR 3.580, P = 0.025) and DMFS (HR 3.850, P = 0.036) after adjustment for other established prognostic factors. CONCLUSIONS: The preoperative ESR level is a simple and useful surrogate biomarker for predicting survival outcomes in STS patients and might improve the identification of high-risk patients of tumor relapse in clinical practice.

Comparison of outcome and toxicity of postoperative intensity-modulated radiation therapy with two-dimensional radiotherapy in patients with soft tissue sarcoma of extremities and trunk.

BACKGROUND: To compare the survival outcomes and late toxicities of postoperative intensity-modulated radiation therapy (IMRT) with two-dimensional radiotherapy (2D-RT) for patients with soft tissue sarcoma (STS) of extremities and trunk. METHODS: 274 consecutive patients with nonmetastatic STS of extremities and trunk treated with postoperative IMRT (n = 187) and 2D-RT (n = 87) were analyzed. Survival was calculated by using Kaplan-Meier method. Independent prognostic factors were identified using Cox stepwise regression analysis for variables with a P-value <0.1 in univariate analysis. RESULTS: With a median follow-up time of 58.1 months, 30 local recurrences, 66 distant metastases, and 40 deaths occurred. Compared to 2D-RT group, the IMRT group had higher 5-year local recurrence-free survival (LRFS) (91.1% vs 80.8%; P = 0.029), distant metastasis-free survival (DMFS) (80.0% vs 69.7%; P = 0.048), disease-free survival (DFS) (75.2% vs 59.2%; P = 0.021), and overall survival (OS) (90.2% vs 81.0%; P = 0.029). Multivariate analysis showed IMRT was an independent favorable factor for LRFS, DMFS, DFS, and OS. For late toxicities, the patients in IMRT group enjoyed lower incidences of ≥Grade 2 joint stiffness (3.9% vs 12.3%; P = 0.041) and ≥Grade 3 fractures (0.0% vs 3.4%; P = 0.25) than those in 2D-RT group. ≥Grade 2 Edema was similar between these two groups (4.8% vs 9.2%; P = 0.183). CONCLUSIONS: When compared with conventional techniques, postoperative IMRT seems to provide better LRFS, DMFS, DFS, and OS and less late toxicities in patients with STS of extremities and trunk, which should be offered as a preferred treatment.

Neoadjuvant image-guided helical intensity modulated radiotherapy of extremity sarcomas - a single center experience.

BACKGROUND: Advanced radiotherapy (RT) techniques allow normal tissue to be spared in patients with extremity soft tissue sarcoma (STS). This work aims to evaluate toxicity and outcome after neoadjuvant image-guided radiotherapy (IGRT) as helical intensity modulated radiotherapy (IMRT) with reduced margins based on MRI-based target definition in patients with STS. METHODS: Between 2010 to 2014, 41 patients with extremity STS were treated with IGRT delivered as helical IMRT on a tomotherapy machine. The tumor site was in the upper extremity in 6 patients (15%) and lower extremity in 35 patients (85%). Reduced margins of 2.5 cm in longitudinal direction and 1.0 cm in axial direction were used to expand the MRI-defined gross tumor volume, including peritumoral edema, to the clinical target volume. An additional margin of 5 mm was added to receive the planning target volume. The full total dose of 50 Gy in 2 Gy fractions was sucessfully applied in 40 patients. Two patients received chemotherapy instead of surgery due to systemic progression. All patients were included into a strict follow-up program and were seen interdisciplinarily by the Departments of Orthopaedic Surgery and Radiation Oncology. RESULTS: Thirty eight patients that received total RT total dose and subsequent resection were analyzed for outcome. After a median follow-up of 38.5 months cumulative OS, local PFS and systemic PFS at 2 years were determined at 78.2, 85.2 and 54.5%, respectively. Two of 6 local recurrences were proximal marginal misses. Negative resection margins were achieved in 84% of patients. The rate of major wound complications was comparable to previous IMRT studies with 36.8%. RT was overall tolerable with low toxicity rates. CONCLUSIONS: IMRT-IGRT offers neoadjuvant treatment for extremity STS with reduced safety margins and thus low toxicity rates. Wound complication rates were comparable to previously reported frequencies. Two reported marginal misses suggest a word of caution for reduction of longitudinal safety margins.

RADIATION DOSES TO ANAESTHETISTS DURING PROSTATIC ARTERY EMBOLIZATION INTERVENTIONAL PROCEDURES.

The objective of this study was to assess the radiation doses received by anaesthetists from prostatic artery embolization (PAE) procedures. Ten PAE procedures conducted in a reference hospital in the city of Recife, Brazil were investigated. Occupational dosimetry was performed using thermoluminescent dosemeters which were located next to the eyes, close to the thyroid (over the shielding), on the thorax (under the apron), on the wrist and on the feet of the physician's body. The results showed that the anaesthetist's feet received the highest doses followed by the eyes and the hands. In some complex PAE procedures the doses received by anaesthetists on the lens of the eyes and the effective dose were higher than those received by the main operator due to the anaesthetist's close position to the patient's table and the use of oblique projections. The personal dose equivalent Hp(3) per procedure for the anaesthetist's right eyebrow ranged from 20.2 µSv to 568.3 µSv. This result shows that anaesthetists assisting PAE procedures can exceeds the annual eye lens dose limit of 20 mSv recommended by the ICRP with only one procedure per week if radiation protection measures are not implemented during procedures.

SIMULATION OF OSL AND TLD DOSEMETER RESPONSE FOR THE DEVELOPMENT OF NEW EXTREMITY DOSEMETERS.

The individual monitoring service at the Helmholtz Zentrum München is currently developing a new eye lens dosemeter to be integrated in radiation protection glasses and a new ring dosemeter using a new BeOSL detector element for extremity dosimetry developed by Dosimetrics. In the design process for the new eye lens dosemeter, MCNP6 Monte Carlo simulations were used to model the energy and angular response of new dosemeters before ordering the expensive tools for injection molding. This study describes the simulation of the dosemeter and detector, and the involved calculations do obtain the response in terms of the radiation protection quantity Hp(3). Simulations were carried out also for existing whole body dosemeters and TLD rings in order to verify the MC tools. With the final dosemeter prototypes becoming available earlier this year, all MC models could be verified and show very good agreement with experimental data.

QUANTITATIVE ESTIMATION OF EXPOSURE INHOMOGENEITY IN TERMS OF EYE LENS AND EXTREMITY MONITORING FOR RADIATION WORKERS IN THE NUCLEAR INDUSTRY.

To manage the equivalent doses for radiation workers, exposure inhomogeneity is an important factor in the decision-making process related to protection measures and additional monitoring. Our previous study proposed the methodology to evaluate the inhomogeneity of exposure quantitatively. In this study, we applied proposed method to five different types of actual exposure situations encountered in the nuclear industry. Two of them were conventionally characterized as homogeneous exposure, and the other three were conventionally characterized as inhomogeneous exposure. The evaluation of homogeneity exposure was conducted using Monte Carlo calculations with two simplified models, which were then verified with phantom experiments. Consequently, all of the evaluations reproduced the experimental results, implying that our proposed method would be applicable for actual work conditions in the nuclear industry. Furthermore, the two presumed homogeneous exposure situations were found to be rather inhomogeneous because of the contribution of positrons and the limited source region. The results also show that the worker's posture has an impact on the inhomogeneity rather than the energy of incident radiation in nuclear works. The investigation also implies that obtaining the information on the most probable posture of the exposed worker, as well as the existence of the weekly penetrating radiation such as ß± ray as a main source of exposure would be the key for more precise estimation.

Perioperative Management of Extremity Soft Tissue Sarcomas.

Surgery is potentially curative for primary nonmetastatic extremity soft tissue sarcomas. After surgery alone, patients may remain at risk for local recurrences and/or metastatic disease. To reduce the likelihood of a local relapse, the addition of radiotherapy (RT) to limb-sparing surgery may result in higher local control rates of at least 85%. Generally, it can be stated that local control after both preoperative and postoperative RT is comparable, but that preoperative RT comes with a more favorable toxicity profile after prolonged follow-up, albeit at the cost of a higher wound complication rate. Furthermore, recent data suggest that preoperative RT is more cost effective. To reduce the risk of subsequent metastatic disease, systemic chemotherapy can be introduced early during the primary management of these patients. These systemic chemotherapy regimens can also be applied both preoperatively and postoperatively. Finally, with the aim of increasing the antitumor response of perioperative RT, these agents may even be combined with RT, concurrently and sequentially. While designing new preoperative combination regimens, responses should be carefully monitored by both sophisticated radiologic and pathologic evaluations. This article reviews all these aspects, in addition to limb-sparing surgery.

Predicting Magnetostimulation Thresholds in the Peripheral Nervous System using Realistic Body Models.

Rapid switching of applied magnetic fields in the kilohertz frequency range in the human body induces electric fields powerful enough to cause Peripheral Nerve Stimulation (PNS). PNS has become one of the main constraints on the use of high gradient fields for fast imaging with the latest MRI gradient technology. In recent MRI gradients, the applied fields are powerful enough that PNS limits their application in fast imaging sequences like echo-planar imaging. Application of Magnetic Particle Imaging (MPI) to humans is similarly PNS constrained. Despite its role as a major constraint, PNS considerations are only indirectly incorporated in the coil design process, mainly through using the size of the linear region as a proxy for PNS thresholds or by conducting human experiments after constructing coil prototypes. We present for the first time, a framework to simulate PNS thresholds for realistic coil geometries to directly address PNS in the design process. Our PNS model consists of an accurate body model for electromagnetic field simulations, an atlas of peripheral nerves, and a neurodynamic model to predict the nerve responses to imposed electric fields. With this model, we were able to reproduce measured PNS thresholds of two leg/arm solenoid coils with good agreement.

Intraoperative radiotherapy for extremity soft-tissue sarcomas: can long-term local control be achieved?

BACKGROUND: Intraoperative electron-beam radiation therapy (IOERT) during limb-sparing surgery has the advantage of delivering a single high boost dose to sarcoma residues and surgical bed area near to radiosensitive structures with limited toxicity. Retrospective studies have suggested that IOERT may improve local control compared to standard radiotherapy and we aimed to demonstrate this theory. Therefore, we performed an observational prospective study to determine (1) if it is possible to achieve high local control by adding IOERT to external-beam radiation therapy (EBRT) in extremity soft-tissue sarcomas (STS), (2) if it is possible to improve long-term survival rates, and (3) if toxicity could be reduced with IOERT MATERIALS AND METHODS: From 1995-2003, 39 patients with extremity STS were treated with IOERT and postoperative radiotherapy. The median follow-up time was 13.2 years (0.7-19). Complications, locoregional control and survival rates were collected. RESULTS: Actuarial local control was attained in 32 of 39 patients (82%). Control was achieved in 88% of patients with primary disease and in 50% of those with recurrent tumors (p = 0.01). Local control was shown in 93% of patients with negative margins and in 50% of those with positive margins (p = 0.002). Limb-sparing was achieved in 32 patients (82%). The overall survival rate was 64%. 13% of patients had grade ≥3 acute toxicity, and 12% developed grade ≥3 chronic toxicity. CONCLUSION: IOERT used as a boost to EBRT provides high local control and limb-sparing rates in patients with STS of the extremities, with less toxicity than EBRT alone.

Primary tumor sites in relation to ultraviolet radiation exposure and skin visibility correlate with survival in cutaneous melanoma.

The prognostic value of detailed anatomic site and ultraviolet radiation (UVR) exposure patterns has not been fully determined in cutaneous melanoma. Thus, we reviewed medical records for detailed site in a population-based retrospective Swedish patient cohort diagnosed with primary invasive melanoma 1976-2003 (n = 5,973). We followed the patients from date of diagnosis until death, emigration or December 31st 2013, and evaluated melanoma-specific survival by subsite in a multivariable regression model adjusting for established prognostic factors. We found that melanoma on chronic UVR exposure sites (face, dorsum of hands; adjusted HR 0.6; CI 0.4-0.7) and moderately intermittent UVR sites (lateral arms, lower legs, dorsum of feet; HR 0.7; CI 0.6-0.8) were associated with a favorable prognosis compared with highly intermittent sites (chest, back, neck, shoulders and thighs). Further, melanoma on poorly visible skin sites upon self-examination (scalp, retroauricular area, back, posterior upper arms and thighs, buttocks, pubic area; HR 1.3; CI 1.1-1.5) had a worse prognosis than those on easily visible sites (face, chest, abdomen, anterior upper arms and thighs, lower arms and legs, dorsum of hands and feet, palms). In conclusion, highly intermittent UVR exposure sites and poor skin visibility presumably correlate with reduced melanoma survival, independent of established tumor characteristics. A limitation of the study was the lack of information on actual individual UVR exposure.

Bone marrow cell extract promotes the regeneration of irradiated bone.

Mandibular osteoradionecrosis is a severe side effect of radiotherapy after the treatment of squamous cell carcinomas of the upper aerodigestive tract. As an alternative to its treatment by micro-anastomosed free-flaps, preclinical tissular engineering studies have been developed. Total bone marrow (TBM) associated with biphasic calcium phosphate (BCP) significantly enhanced bone formation in irradiated bone. One mechanism, explaining how bone marrow cells can help regenerate tissues like this, is the paracrine effect. The bone marrow cell extract (BMCE) makes use of this paracrine mechanism by keeping only the soluble factors such as growth factors and cytokines. It has provided significant results in repairing various tissues, but has not yet been studied in irradiated bone reconstruction. The purpose of this study was to evaluate the effect of BMCE via an intraosseous or intravenous delivery, with a calcium phosphate scaffold, in irradiated bone reconstruction. Twenty rats were irradiated on their hind limbs with a single 80-Gy dose. Three weeks later, surgery was performed to create osseous defects. The intraosseous group (n = 12) studied the effect of BMCE in situ, with six combinations (empty defect, BCP, TBM, BCP-TBM, lysate only, BCP-lysate). After four different combinations of implantation (empty defect, BCP, TBM, BCP-TBM), the intravenous group (n = 8) received four intravenous injections of BMCE for 2 weeks. Five weeks after implantation, samples were explanted for histological and scanning electron microscopy analysis. Lysate immunogenicity was studied with various mixed lymphocyte reactions. Intravenous injections of BMCE led to a significant new bone formation compared to the intraosseous group. The BCP-TBM mixture remained the most effective in the intraosseous group. However, intravenous injections were more effective, with TBM placed in the defect, with or without biomaterials. Histologically, highly cellularized bone marrow was observed in the defects after intravenous injections, and not after an in situ use of the lysate. The mixed lymphocyte reactions did not show any proliferation after 3, 5, or 7 days of lysate incubation with lymphocytes from another species. This study evaluated the role of BMCE in irradiated bone reconstruction. There were significant results arguing in favor of BMCE intravenous injections. This could open new perspectives to irradiated bone reconstruction.

External-beam radiation therapy combined with limb-sparing surgery in elderly patients (>70 years) with primary soft tissue sarcomas of the extremities : A retrospective analysis.

PURPOSE: To report our experience with EBRT combined with limb-sparing surgery in elderly patients (>70 years) with primary extremity soft tissue sarcomas (STS). METHODS: Retrospectively analyzed were 35 patients (m:f 18:17, median 78 years) who all presented in primary situation without nodal/distant metastases (Charlson score 0/1 in 18 patients; ≥2 in 17 patients). Median tumor size was 10 cm, mainly located in lower limb (83%). Stage at presentation (UICC7th) was Ib:3%, 2a:20%, 2b:20%, and 3:57%. Most lesions were high grade (97%), predominantly leiomyosarcoma (26%) and undifferentiated pleomorphic/malignant fibrous histiocytoma (23%). Limb-sparing surgery was preceded (median 50 Gy) or followed (median 66 Gy) by EBRT. RESULTS: Median follow-up was 37 months (range 1-128 months). Margins were free in 26 patients (74%) and microscopically positive in 9 (26%). Actuarial 3­ and 5­year local control rates were 88 and 81% (4 local recurrences). Corresponding rates for distant control, disease-specific survival, and overall survival were 57/52%, 76/60%, and 72/41%. The 30-day mortality was 0%. Severe postoperative complications were scored in 8 patients (23%). Severe acute radiation-related toxicity was observed in 2 patients (6%). Patients with Charlson score ≥2 had a significantly increased risk for severe postoperative complications and acute radiation-related side effects. Severe late toxicities were found in 7 patients (20%), including fractures in 3 (8.6%). Final limb preservation rate was 97%. CONCLUSION: Combination of EBRT and limb-sparing surgery is feasible in elderly patients with acceptable toxicities and encouraging but slightly inferior outcome compared to younger patients. Comorbidity correlated with postoperative complications and acute toxicities. Late fracture risk seems slightly increased.

Improving the therapeutic efficacy of mesenchymal stromal cells to restore perfusion in critical limb ischemia through pulsed focused ultrasound.

Mesenchymal stem cells (MSC) are promising therapeutics for critical limb ischemia (CLI). Mechanotransduction from pulsed focused ultrasound (pFUS) upregulates local chemoattractants to enhance homing of intravenously (IV)-infused MSC and improve outcomes. This study investigated whether pFUS exposures to skeletal muscle would improve local homing of iv-infused MSCs and their therapeutic efficacy compared to iv-infused MSCs alone. CLI was induced by external iliac arterial cauterization in 10-12-month-old mice. pFUS/MSC treatments were delayed 14 days, when surgical inflammation subsided. Mice were treated with iv-saline, pFUS alone, IV-MSC, or pFUS and IV-MSC. Proteomic analyses revealed pFUS upregulated local chemoattractants and increased MSC tropism to CLI muscle. By 7 weeks post-treatment, pFUS + MSC significantly increased perfusion and CD31 expression, while reducing fibrosis compared to saline. pFUS or MSC alone reduced fibrosis, but did not increase perfusion or CD31. Furthermore, MSCs homing to pFUS-treated CLI muscle expressed more vascular endothelial growth factor (VEGF) and interleukin-10 (IL-10) than MSCs homing to non-pFUS-treated muscle. pFUS + MSC improved perfusion and vascular density in this clinically-relevant CLI model. The molecular effects of pFUS increased both MSC homing and MSC production of VEGF and IL-10, suggesting microenvironmental changes from pFUS also increased potency of MSCs in situ to further enhance their efficacy.

Unexpected UVR and non-UVR mutation burden in some acral and cutaneous melanomas.

Ultraviolet radiation (UVR) mutagenesis causes nearly all cutaneous melanomas, however, since UVR signatures are largely absent in acral melanoma, as well as melanoma in sun-protected sites, the cause of these melanomas is unknown. Whole-genome sequencing data generated as part of the Australian Melanoma Genome Project was supplemented with a detailed histopathological assessment with the melanomas then classified as UVR or non-UVR related, based on their mutation signatures. The clinicopathological characteristics of melanomas with mutation signatures for their subtype were compared. Three (of 35=8.6%) acral melanomas, all clinically and pathologically verified as arising from acral or subungual locations, had predominant UVR mutation burden, whereas four (of 140=2.9%) cutaneous melanomas showed predominant non-UVR mutations. Among the acral melanomas, the few that were UVR dominant occurred in younger patients, had a higher mutation load and a proportion of mutation burden due to UVR, which was similar to that in melanomas from intermittently UVR-exposed skin. Acral melanomas with a UVR signature occurred most frequently in subungual sites and included tumors harboring BRAF or NF1 mutations. Cutaneous melanomas dominated by non-UVR signatures had lower mutation burdens counts and their primary tumors were thicker and had more mitoses than in other cutaneous melanomas. No histopathological features predicted UVR dominance in acral melanomas or non-UVR dominance in cutaneous melanomas. Our finding of acral/subungual melanomas with predominant UVR mutagenesis suggests that the nail plate and acral skin do not provide complete protection from UVR. Our data also confirm that cutaneous melanomas not caused by UVR are infrequent. Identifying where mutation burden is discordant with primary tumor anatomical site is likely to be clinically significant when determining treatment options for metastatic acral and cutaneous melanoma patients.