Lipopolysaccharide-Preconditioned Periodontal Ligament Stem Cells Induce M1 Polarization of Macrophages through Extracellular Vesicles.

Periodontitis is a common disease characterized by chronic inflammation and tissue destruction of gums. Human periodontal ligament stem cells (PDLSCs), derived from the periodontium, have stem cell properties similar to those of mesenchymal stem cells. PDLSCs possess not only the potential to differentiate into other tissues, but also immunomodulatory abilities. Macrophages play a critical role in periodontal disease, but little is known regarding the role of PDLSCs in macrophage modulation during inflammation. In this study, we investigated the effect of PDLSCs on the macrophage cell line. While the conditioned media from PDLSCs under normal culture conditions did not affect macrophage polarization, the lipopolysaccharide (LPS)-preconditioned PDLSCs induced significant changes in M1 polarization. Extracellular vesicles (EVs) isolated from the conditioned media of LPS-preconditioned PDLSCs induced strong M1 polarization of macrophages. Additionally, the M1 polarization was abolished by DNase I treatment of EVs. Therefore, the LPS-stimulated PDLSCs induce M1 polarization of macrophages through EVs, suggesting that the EVs from PDLSCs might be a potential therapeutic target for inflammation in the periodontium.

Salvage percutaneous high-dose-rate brachyablation after stereotactic body radiation therapy for early-stage non-small cell lung cancer.

Patients with primary tumor progression after stereotactic body radiation therapy (SBRT) for stage I non-small cell lung cancer (NSCLC) have a second chance at complete tumor eradication with salvage local therapies, including lung resection, repeat course of SBRT, and percutaneous ablative therapies. In this paper, we presented our institution's initial experience with percutaneous high-dose-rate (HDR) brachyablation for a relapsed stage I NSCLC that had been treated with SBRT 4.3 years earlier. Lung tumor measuring approximately 5 cm in maximum tumor dimension at the time of relapse was histopathologically confirmed to be persistent squamous cell carcinoma, and successfully treated with a single fraction of 24 Gy with HDR brachyablation. Treatment was delivered via two percutaneous catheters inserted under CT-guidance, and treated in less than 20 minutes. The patient was discharged home later the same day without the need for a chest tube, and has been monitored with serial surveillance scans every 3 to 6 months without evidence of further lung cancer progression or complications at 2.8 years post-HDR brachyablation procedure and 7.8 years after initial SBRT.

Analytical HDR prostate brachytherapy planning with automatic catheter and isotope selection.

BACKGROUND: High dose rate (HDR) brachytherapy is commonly used to treat prostate cancer. Existing HDR planning systems solve the dwell time problem for predetermined catheters and a single energy source. PURPOSE: Additional degrees of freedom can be obtained by relaxing the catheters' pre-designation and introducing more source types, and may have a dosimetric benefit, particularly in improving conformality to spare the urethra. This study presents a novel analytical approach to solving the corresponding HDR planning problem. METHODS: The catheter and dual-energy source selection problem was formulated as a constrained optimization problem with a non-convex group sparsity regularization. The optimization problem was solved using the fast-iterative shrinkage-thresholding algorithm (FISTA). Two isotopes were considered. The dose rates for the HDR 4140 Ytterbium (Yb-169) source and the Elekta Iridium (Ir-192) HDR Flexisource were modeled according to the TG-43U1 formalism and benchmarked accordingly. Twenty-two retrospective HDR prostate brachytherapy patients treated with Ir-192 were considered. An Ir-192 only (IRO), Yb-169 only (YBO), and dual-source (DS) plan with optimized catheter location was created for each patient with N catheters, where N is the number of catheters used in the clinically delivered plans. The DS plans jointly optimized Yb-169 and Ir-192 dwell times. All plans and the clinical plans were normalized to deliver a 15 Gy prescription (Rx) dose to 95% of the clinical treatment volume (CTV) and evaluated for the CTV D90%, V150%, and V200%, urethra D0.1cc and D1cc, bladder V75%, and rectum V75%. Dose-volume histograms (DVHs) were generated for each structure. RESULTS: The DS plans ubiquitously selected Ir-192 as the only treatment source. IRO outperformed YBO in organ at risk (OARs) OAR sparing, reducing the urethra D0.1cc and D1cc by 0.98% ( p = 2.22 ∗ 10 - 9 $p\ = \ 2.22*{10^{ - 9}}$ ) and 1.09% ( p = 1.22 ∗ 10 - 10 $p\ = \ 1.22*{10^{ - 10}}$ ) of the Rx dose, respectively, and reducing the bladder and rectum V75% by 0.09 ( p = 0.0023 $p\ = \ 0.0023$ ) and 0.13 cubic centimeters (cc) ( p = 0.033 $p\ = \ 0.033$ ), respectively. The YBO plans delivered a more homogenous dose to the CTV, with a smaller V150% and V200% by 3.20 ( p = 4.67 ∗ 10 - 10 $p\ = \ 4.67*{10^{ - 10}}$ ) and 1.91 cc ( p = 5.79 ∗ 10 - 10 $p\ = \ 5.79*{10^{ - 10}}$ ), respectively, and a lower CTV D90% by 0.49% ( p = 0.0056 $p\ = \ 0.0056$ ) of the prescription dose. The IRO plans reduce the urethral D1cc by 2.82% ( p = 1.38 ∗ 10 - 4 $p\ = \ 1.38*{10^{ - 4}}$ ) of the Rx dose compared to the clinical plans, at the cost of increased bladder and rectal V75% by 0.57 ( p = 0.0022 $p\ = \ 0.0022$ ) and 0.21 cc ( p = 0.019 $p\ = \ 0.019$ ), respectively, and increased CTV V150% by a mean of 1.46 cc ( p = 0.010 $p\ = \ 0.010$ ) and CTV D90% by an average of 1.40% of the Rx dose ( p = 8.80 ∗ 10 - 8 $p\ = \ 8.80*{10^{ - 8}}$ ). While these differences are statistically significant, the clinical differences between the plans are minimal. CONCLUSIONS: The proposed analytical HDR planning algorithm integrates catheter and isotope selection with dwell time optimization for varying clinical goals, including urethra sparing. The planning method can guide HDR implants and identify promising isotopes for specific HDR clinical goals, such as target conformality or OAR sparing.

High-dose-rate skin brachytherapy with interstitial, surface, or a combination of interstitial and surface mold technique.

Purpose: In order to demonstrate capabilities of brachytherapy in skin cancer treatment, we reviewed clinical outcomes of patients with non-melanoma skin cancer (NMSC) treated with high-dose-rate brachytherapy (HDR-BT) at a single-institution. Material and methods: A surface custom mold (SC), interstitial (IS), or a combination of IS and SC applicator (IS + SC) was used for treatment based on depth of tumor invasion. Contoured growth tumor volume plus a 0.5 cm margin for basal cell carcinomas (BCC) and a 1-1.5 cm margin for squamous cell carcinomas (SCC) was considered a target. A prescription dose of 41.6 Gy in 8 fractions was delivered to BCC, and 46.8 Gy in 9 fractions to SCC. Results: From 2013 to 2018, a total of 751 NMSC patients (534 BCCs and 217 SCCs) were treated with HDR-BT (518 with IS, 225 with SC, and 8 with IS + SC technique). Thirty patients (4%) partially responded to treatment, and 721 patients (96%) had complete responses. Only 3 patients (0.4%) displayed local recurrences. Grade 1, 2, and 3 acute toxicities were observed in 28.0%, 46.7%, and 1.2% of patients, respectively. Grade 1, 2, and 3 late toxicities were observed in 3.3%, 1.3%, and 0.1% of cases. Cosmetic results were excellent in 79.9%, good in 17.8%, fair in 1.7%, and poor in 0.5% of patients. Conclusions: HDR-BT using SC, IS, or IS + SC is an effective treatment for NMSC with good outcomes and cosmetic results in both BCC and SCC.

Motion artifacts occurring at the lung/diaphragm interface using 4D CT attenuation correction of 4D PET scans.

For PET/CT, fast CT acquisition time can lead to errors in attenuation correction, particularly at the lung/diaphragm interface. Gated 4D PET can reduce motion artifacts, though residual artifacts may persist depending on the CT dataset used for attenuation correction. We performed phantom studies to evaluate 4D PET images of targets near a density interface using three different methods for attenuation correction: a single 3D CT (3D CTAC), an averaged 4D CT (CINE CTAC), and a fully phase matched 4D CT (4D CTAC). A phantom was designed with two density regions corresponding to diaphragm and lung. An 8 mL sphere phantom loaded with 18F-FDG was used to represent a lung tumor and background FDG included at an 8:1 ratio. Motion patterns of sin(x) and sin4(x) were used for dynamic studies. Image data was acquired using a GE Discovery DVCT-PET/CT scanner. Attenuation correction methods were compared based on normalized recovery coefficient (NRC), as well as a novel quantity "fixed activity volume" (FAV) introduced in our report. Image metrics were compared to those determined from a 3D PET scan with no motion present (3D STATIC). Values of FAV and NRC showed significant variation over the motion cycle when corrected by 3D CTAC images. 4D CTAC- and CINE CTAC-corrected PET images reduced these motion artifacts. The amount of artifact reduction is greater when the target is surrounded by lower density material and when motion was based on sin4(x). 4D CTAC reduced artifacts more than CINE CTAC for most scenarios. For a target surrounded by water equivalent material, there was no advantage to 4D CTAC over CINE CTAC when using the sin(x) motion pattern. Attenuation correction using both 4D CTAC or CINE CTAC can reduce motion artifacts in regions that include a tissue interface such as the lung/diaphragm border. 4D CTAC is more effective than CINE CTAC at reducing artifacts in some, but not all, scenarios.

High-Dose Rate Interstitial Spine Brachytherapy Using an Intraoperative Mobile Computed Tomography-Guided Surgical Navigation System.

BACKGROUND: Up to 15% of previously irradiated metastatic spine tumors will progress. Re-irradiation of these tumors poses a significant risk of exceeding the radiation tolerance to the spinal cord. High-dose rate (HDR) brachytherapy is a treatment alternative. OBJECTIVE: To develop a novel HDR spine brachytherapy technique using an intraoperative computed tomography-guided navigation (iCT navigation). METHODS: Patients with progressive metastatic spine tumors were included in the study. HDR brachytherapy catheters were placed under iCT navigation. CT-based planning with magnetic resonance imaging fusion was performed to ensure conformal dose delivery to the target while sparing normal tissue, including the spinal cord. Patients received single fraction radiation treatment. RESULTS: Five patients with thoracolumbar tumors were treated with HDR brachytherapy. Four patients previously received radiotherapy to the same spinal level. Preimplant plans demonstrated median clinical target volume (CTV) D90 of 116.5% (110.8%-147.7%), V100 of 95.7% (95.5%-99.6%), and Dmax of 8.08 Gy (7.65-9.8 Gy) to the spinal cord/cauda equina. Postimplant plans provided median CTV D90 of 113.8% (93.6%-120.1%), V100 of 95.9% (87%-99%), and Dmax of 9.48 Gy (6.5-10.3 Gy) to cord/cauda equina. Patients who presented with back pain (n = 3) noted symptomatic improvement at a median follow-up of 22 d after treatment. Four patients demonstrated local tumor control of spinal metastatic tumor at a median follow-up of 92 d after treatment. One patient demonstrated radiographic evidence of local tumor progression 2.7 mo after treatment. CONCLUSION: HDR spine brachytherapy with iCT navigation is a promising treatment alternative to induce local tumor control and reduce pain symptoms associated with metastatic spine disease.

Automatic marker detection and 3D position reconstruction using cine EPID images for SBRT verification.

In previous studies, an electronic portal imaging device (EPID) in cine mode was used for validating respiratory gating and stereotactic body radiation therapy (SBRT) by tracking implanted fiducials. The manual marker tracking methods that were used were time and labor intensive, limiting the utility of the validation. The authors have developed an automatic algorithm to quickly and accurately extract the markers in EPID images and reconstruct their 3D positions. Studies have been performed with gold fiducials placed in solid water and dynamic thorax phantoms. In addition, the authors have examined the cases of five patients being treated under an SBRT protocol for hepatic metastases. For each case, a sequence of images was created by collecting the exit radiation using the EPID. The markers were detected and recognized using an image processing algorithm based on the Laplacian of Gaussian function. To reduce false marker detection, a marker registration technique was applied using image intensity as well as the geometric spatial transformations between the reference marker positions produced from the projection of 3D CT images and the estimated marker positions. An average marker position in 3D was reconstructed by backprojecting, towards the source, the position of each marker on the 2D image plane. From the static phantom study, spatial accuracies of <1 mm were achieved in both 2D and 3D marker locations. From the dynamic phantom study, using only the Laplacian of the Gaussian algorithm, the marker detection success rate was 88.8%. However, adding a marker registration technique which utilizes prior CT information, the detection success rate was increased to 100%. From the SBRT patient study, intrafractional tumor motion (3.1-11.3 mm) in the SI direction was measured using the 2D images. The interfractional patient setup errors (0.1-12.7 mm) in the SI, AP, and LR directions were obtained from the average marker locations reconstructed in 3D and compared to the reference planning CT image. The authors have developed an automatic algorithm to extract marker locations from MV images and have evaluated its performance. The measured intrafractional tumor motion and the interfractional daily patient setup error can be used for off-line retrospective verification of SBRT.

Extracellular Vesicles From KSHV-Infected Cells Stimulate Antiviral Immune Response Through Mitochondrial DNA.

Kaposi's Sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma, which is the most common cancer in acquired immune deficiency syndrome patients. KSHV contains a variety of immunoregulatory proteins. There have been many studies on the modulation of antiviral response by these immunoregulatory proteins of KSHV. However, the antiviral effects of extracellular vesicles (EVs) during de novo KSHV infection have not been investigated to our best knowledge. In this study, we showed that KSHV-infected cells induce interferon-stimulated genes (ISGs) response but not type I interferon in uninfected bystander cells using EVs. mRNA microarray analysis showed that ISGs and IRF-activating genes were prominently activated in EVs from KSHV-infected cells (KSHV EVs)-treated human endothelial cells, which were validated by RT-qPCR and western blot analysis. We also found that this response was not associated with cell death or apoptosis by virus infection. Mechanistically, the cGAS-STING pathway was linked with these KSHV EVs-mediated ISGs expressions, and mitochondrial DNA on the surface of KSHV EVs was one of the causative factors. Besides, KSHV EVs-treated cells showed lower infectivity for KSHV and viral replication activity than mock EVs-treated cells. Our results indicate that EVs from KSHV-infected cells could be an initiating factor for the innate immune response against viral infection, which may be critical to understanding the microenvironment of virus-infected cells.

A novel method for estimating SBRT delivered dose with beam's-eye-view images.

Stereotactic body radiation therapy is predicated on a high degree of targeting accuracy. However, inaccurate patient setup as well as intra-fractional motion can hinder the delivery of high doses preferentially to the target. To ensure that the coverage delivered to the patient is as planned, an image-guided verification system has been created to estimate the delivered dose retrospectively. This will not only aid the assessment of treatment techniques, but will also allow for more accurate dose response analysis. Patients with limited hepatic metastases from solid tumors were treated with SBRT. Implanted gold markers were used as target surrogates and a body frame and compression plate provided stereotactic localization and target immobilization, respectively. During treatment, an electronic portal imaging device (EPID), operating in cine mode, collected the exit dose. The sequences of images for each field were processed off-line using in-house software for registration and seed localization. The beam's-eye-view seed positions in the treatment images were compared to those in the DRR's to determine the target shifts in the imaging plane. These target shifts were then imported into the treatment planning software. Each original field was multiplied by the number of images taken during treatment. The calculated shift from each image was then applied to each of the new subfields. Summing all of these subfields together gives the dose distribution that was actually delivered to the patient. The dose-volume histograms for the planned and delivered distributions for four patients' complete treatments are shown. For two of the patients, underdosing due to a setup error or intra-fractional drift was not wholly resolved by subsequent fractions. For one of these patients two alternative corrective strategies have been applied, retrospectively, and the prescribed target coverage recovered for both. The delivered dose can be estimated using the information contained in cine EPID images acquired during irradiation. Calculating the dose actually delivered to the target will allow us to assess treatment procedures as well as more accurately report clinical results.

Evaluation of the combined effects of target size, respiratory motion and background activity on 3D and 4D PET/CT images.

Gated (4D) PET/CT has the potential to greatly improve the accuracy of radiotherapy at treatment sites where internal organ motion is significant. However, the best methodology for applying 4D-PET/CT to target definition is not currently well established. With the goal of better understanding how to best apply 4D information to radiotherapy, initial studies were performed to investigate the effect of target size, respiratory motion and target-to-background activity concentration ratio (TBR) on 3D (ungated) and 4D PET images. Using a PET/CT scanner with 4D or gating capability, a full 3D-PET scan corrected with a 3D attenuation map from 3D-CT scan and a respiratory gated (4D) PET scan corrected with corresponding attenuation maps from 4D-CT were performed by imaging spherical targets (0.5-26.5 mL) filled with (18)F-FDG in a dynamic thorax phantom and NEMA IEC body phantom at different TBRs (infinite, 8 and 4). To simulate respiratory motion, the phantoms were driven sinusoidally in the superior-inferior direction with amplitudes of 0, 1 and 2 cm and a period of 4.5 s. Recovery coefficients were determined on PET images. In addition, gating methods using different numbers of gating bins (1-20 bins) were evaluated with image noise and temporal resolution. For evaluation, volume recovery coefficient, signal-to-noise ratio and contrast-to-noise ratio were calculated as a function of the number of gating bins. Moreover, the optimum thresholds which give accurate moving target volumes were obtained for 3D and 4D images. The partial volume effect and signal loss in the 3D-PET images due to the limited PET resolution and the respiratory motion, respectively were measured. The results show that signal loss depends on both the amplitude and pattern of respiratory motion. However, the 4D-PET successfully recovers most of the loss induced by the respiratory motion. The 5-bin gating method gives the best temporal resolution with acceptable image noise. The results based on the 4D scan protocols can be used to improve the accuracy of determining the gross tumor volume for tumors in the lung and abdomen.

The effect of storage temperature on the biological activity of extracellular vesicles for the complement system.

Extracellular vesicles (EVs) are mediators of intercellular communication by transporting cargo containing proteins, lipids, mRNA, and miRNA. There is increasing evidence that EVs have various roles in regulating migration, invasion, stemness, survival, and immune functions. Previously, we have found that EVs from Kaposi's sarcoma-associated herpesvirus (KSHV)-infected human endothelial cells have the potential to activate the complement system. Although many studies have shown that the physical properties of EVs can be changed by their storage condition, there have been few studies for the stability of biological activity of EVs in various storage conditions. In this study, we investigated various conditions to identify the best conditions to store EVs with functional stability for 25 d. Furthermore, the correlation between the function and other characteristics of EVs, including the expression of EV markers, size distribution, and particle number, were also analyzed. Our results demonstrated that storage temperature is an important factor to maintain the activity of EVs and would be useful information for basic research and clinical application using EVs.

Head and neck cancer reirradiation with interstitial high-dose-rate brachytherapy.

BACKGROUND: As high-dose-rate (HDR) brachytherapy can preferentially spare normal anatomic structures surrounding the radiation target, we report on our experience using this technique in head and neck cancer reirradiation. METHODS: Twenty patients received HDR brachytherapy reirradiation with curative or palliative intent from 2010-2015. Clinical and toxicity outcomes were recorded. Actuarial outcomes were calculated using Kaplan-Meier analysis. RESULTS: For curative treatment, actuarial 2-year rates of local control and overall survival (OS) were 73% and 56%, respectively. Palliatively, a 6-month local control rate of 65% was seen. Age >70 years was associated with poorer OS (P = .042). Prior salvage resection showed a trend toward improved local control and OS (P = .069 and P = .063, respectively). Thirty-three percent had grade 3 to 4 late toxicities. CONCLUSION: Curative-intent HDR brachytherapy reirradiation can provide excellent local control and encouraging OS. Given the late toxicity rates, patient selection is essential, with particular utility for younger patients or those treated with salvage resection.

Clinical outcomes using image-guided interstitial brachytherapy for definitive cervical cancer patients with high-risk clinical target volumes greater than 30 cc.

PURPOSE: Given the limited data using an interstitial approach with 3D-based planning for definitive cervical cancer utilizing the GEC-ESTRO defined high-risk clinical target volume (HR-CTV), we reviewed our institutional experience of cervical cancer patients with HR-CTVs ≥ 30 cc to determine whether our clinical and toxicity outcomes are acceptable. METHODS: A retrospective review of 37 cervical cancer patients with high-risk clinical target volumes (HR-CTVs) ≥30 cc treated with interstitial image-guided brachytherapy (IS IGBT) was performed. All patients received external beam radiotherapy to a median dose of 45 Gy, followed by IS IGBT delivered in a single implant to a median dose of 6 Gy × 5 fractions. Median HR-CTV was 59 cc. A median HR-CTV D90 of 87.44 Gy was achieved. Kaplan-Meier method was used to evaluate local control (LC), distant control, and overall survival (OS), with stratification by overall treatment time (OTT) ≤ 7 or >7 weeks. RESULTS: Median followup was 17 months. The estimated 2-year LC, distant control, and OS were 77.6% (confidence interval [CI]: 63.8-94.5%), 56.8% (CI: 41.3-78.1%), and 54.4% (CI: 39.4-75%), respectively. The 2-year LC for OTT ≤7 weeks and >7 weeks were 100% and 58.3%, respectively (p = 0.026). The 2-year OS for OTT ≤7 weeks and >7 weeks were 77.8% and 38%, respectively (p = 0.021). DISCUSSIONS: IS IGBT can achieve a high D90 to the HR-CTV even in the setting of large-volume disease and results in a favorable LC and toxicity profile. OTT > 7 weeks is associated with significant decrease in LC and OS. CONCLUSIONS: Efforts should be made to complete whole treatment within 7 weeks as this is associated with improved clinical outcomes.

Activation of the complement system in an osteosarcoma cell line promotes angiogenesis through enhanced production of growth factors.

There is increasing evidence that the complement system is activated in various cancer tissues. Besides being involved in innate immunity against pathogens, the complement system also participates in inflammation and the modulation of tumor microenvironment. Recent studies suggest that complement activation promotes tumor progression in various ways. Among some cancer cell lines, we found that human bone osteosarcoma epithelial cells (U2-OS) can activate the alternative pathway of the complement system by pooled normal human serum. Interestingly, U2-OS cells showed less expression of complement regulatory proteins, compared to other cancer cell lines. Furthermore, the activated complement system enhanced the production of growth factors, which promoted angiogenesis of human endothelial cells. Our results demonstrated a direct linkage between the complement system and angiogenesis using the in vitro model, which suggest the complement system and related mechanisms might be potential targets for cancer treatment.

Comparison of patient-reported acute urinary and sexual toxicity scores in a 6- versus 2-fraction course of high-dose-rate prostate brachytherapy monotherapy.

INTRODUCTION: To identify differences in acute urinary and sexual toxicity between a 6-fraction and 2-fraction high-dose-rate brachytherapy monotherapy regimen and correlate dosimetric constraints to short-term toxicity. METHODS: A single institution retrospective study of 116 men with prostate cancer treated with HDR monotherapy from 2010 to 2015 was conducted. Eighty-one men had 7.25 Gy × 6-fractions and 35 men had 13.5 Gy × 2-fractions. Patients had two CT-planned implants spaced 1-2 weeks apart. Patient baseline characteristics, International Prostate Symptom Scores (IPSS) and Sexual Health Inventory for Men (SHIM) scores were collected pre-treatment and 3, 6 and 12 months post-implantation. Mixed effect modelling was undertaken to compare baseline, 1-6 month and 7-12 month scores between groups. Poisson regression analysis was performed to correlate dosimetric constraints with acute toxicity. RESULTS: There was no difference between baseline and post-implantation IPSS scores between 6-fraction and 2-fraction groups. SHIM scores for men treated with 6-fractions had a steeper decline at 1-6 months, but resolved at 7-12 months. Pre-treatment alpha-blocker use correlated with worse short-term acute urinary toxicity. Worsened SHIM score correlated with increasing age, diabetes mellitus and androgen-deprivation therapy. In a dosimetric analysis of outcomes, prostate V150 dose and bladder wall (D01.cc, D1cc, D2cc) dose correlated with increased IPSS score. CONCLUSION: No increased acute genitourinary or sexual dysfunction has been observed in men when transitioning from 6-fraction to 2-fraction HDR monotherapy. A dosimetric correlation was found between the V150 and bladder wall doses for acute urinary toxicity. Future research should continue to standardize and validate dose constraints for prostate HDR monotherapy patients.

Design of a very high-resolution small animal PET scanner using a silicon scatter detector insert.

A small animal positron emission tomography (PET) instrument using a high-resolution solid-state detector insert in a conventional PET system was investigated for its potential to achieve sub-millimeter spatial resolution for mouse imaging. Monte Carlo simulations were used to estimate the effect of detector configurations (thickness, length and radius) on sensitivity. From this initial study, a PET system having an inner cylindrical silicon detector (4 cm ID, 4 cm length and 1.6 cm thickness composed of 16 layers of 300 microm x 300 microm x 1 mm pads), for scattering, surrounded by an outer cylindrical BGO scintillation detector (17.6 cm ID, 16 cm length and 2 cm thickness segmented into 3 mm x 3 mm x 20 mm crystals), for capture was evaluated in detail. In order to evaluate spatial resolution, sensitivity and image quality of the PET system, 2D images of multiple point and cylinder sources were reconstructed with the simulation data including blurring from positron range and annihilation photon acollinearity using filtered backprojection (FBP). Simulation results for (18)F demonstrate 340 microm FWHM at the center of the field of view with 1.0% sensitivity from the coincidence of single scattering events in both silicon detectors and 1.0 mm FWHM with 9.0% sensitivity from the coincidence of single scattering in the silicon and full energy absorption of the second photon in the BGO detector.

Performance evaluation of a very high resolution small animal PET imager using silicon scatter detectors.

A very high resolution positron emission tomography (PET) scanner for small animal imaging based on the idea of inserting a ring of high-granularity solid-state detectors into a conventional PET scanner is under investigation. A particularly interesting configuration of this concept, which takes the form of a degenerate Compton camera, is shown capable of providing sub-millimeter resolution with good sensitivity. We present a Compton PET system and estimate its performance using a proof-of-concept prototype. A prototype single-slice imaging instrument was constructed with two silicon detectors 1 mm thick, each having 512 1.4 mm x 1.4 mm pads arranged in a 32 x 16 array. The silicon detectors were located edgewise on opposite sides and flanked by two non-position sensitive BGO detectors. The scanner performance was measured for its sensitivity, energy, timing, spatial resolution and resolution uniformity. Using the experimental scanner, energy resolution for the silicon detectors is 1%. However, system energy resolution is dominated by the 23% FWHM BGO resolution. Timing resolution for silicon is 82.1 ns FWHM due to time-walk in trigger devices. Using the scattered photons, time resolution between the BGO detectors is 19.4 ns FWHM. Image resolution of 980 microm FWHM at the center of the field-of-view (FOV) is obtained from a 1D profile of a 0.254 mm diameter (18)F line source image reconstructed using the conventional 2D filtered back-projection (FBP). The 0.4 mm gap between two line sources is resolved in the image reconstructed with both FBP and the maximum likelihood expectation maximization (ML-EM) algorithm. The experimental instrument demonstrates sub-millimeter resolution. A prototype having sensitivity high enough for initial small animal images can be used for in vivo studies of small animal models of metabolism, molecular mechanism and the development of new radiotracers.

American Brachytherapy Society recurrent carcinoma of the endometrium task force patterns of care and review of the literature.

PURPOSE: The purpose of this American Brachytherapy Society task force is to present a literature review and patterns of care by a panel of experts for the management of vaginal recurrence of endometrial cancer. METHODS AND MATERIALS: In 2016, the American Brachytherapy Society Board selected a panel of experts in gynecologic brachytherapy to update our current state of knowledge for managing vaginal recurrence of endometrial cancer. Practice patterns were evaluated via an online survey and clinical updates occurred through a combination of literature review and clinical experience and/or expertise. RESULTS: There are various retrospective series of patients treated with radiation for vaginal recurrence of endometrial cancer, which include a varied group of patients, multiple treatment techniques, and a range of total doses and demonstrate a wide scope of local control and overall survival outcomes. In the era of image-guided brachytherapy, high local control rates with low significant late-term morbidities can be achieved. Lower rates of local control and higher late-term toxicity are reported in the retreatment setting. In patients with no previous history of radiation treatment, external beam radiation therapy followed by brachytherapy boost should be used. There are varying practices with regard to the definition and appropriate doses of both the high-risk clinical target volume and the intermediate-risk clinical target volume in the setting of vaginal recurrence of endometrial cancer. There are limited data to provide appropriate dose constraints for some organs at risk with the majority of guidance taken from the definitive cervical cancer literature. CONCLUSIONS: A summary of literature and expert practice patterns for patient selection, dose recommendations, and constraints are provided as guidance for practitioners.

High-dose-rate brachytherapy monotherapy without androgen deprivation therapy for intermediate-risk prostate cancer.

PURPOSE: Outcomes using high-dose-rate (HDR) brachytherapy monotherapy (without androgen deprivation therapy or external beam radiation therapy) for National Comprehensive Cancer Network-defined intermediate-risk (IR) patients are limited. We report our long-term data using HDR monotherapy for this patient population. METHODS AND MATERIALS: One-hundred ninety IR prostate cancer patients were treated 1996-2013 with HDR monotherapy. Biochemical prostate-specific antigen (PSA) failure was per the Phoenix definition. Acute and late genitourinary and gastrointestinal toxicities were graded according to Common Toxicity Criteria of Adverse Events, version 4. Kaplan-Meier (KM) biochemical progression-free survival (BPFS), cause-specific survival, and overall survival rates were calculated. Univariate analyses were performed to determine relationships with BPFS. The median patient age was 66 years (43-90), and the median initial PSA was 7.4 ng/mL. The Gleason score was ≤6 in 26%, 3 + 4 in 62%, and 4 + 3 in 12%. The median treatment BED1.5 was 254 Gy; 83% of patients were treated with a dose of 7.25 Gy × six fractions delivered in two separate implants. RESULTS: With a median follow-up of 6.2 years, KM BPFS at 5/8 years was 97%/90%, cause-specific survival at 8 years was 100%, and overall survival at 5/8 years was 93%/88%. Late genitourinary toxicities were 36.3% Grade 1, 18.9% Grade 2, and 3.7% Grade 3. Late gastrointestinal toxicities were 6.3% Grade 1, 1.1% Grade 2, and no Grade ≥3. Of the patients with no sexual dysfunction before treatment, 68% maintained potency. Age, initial PSA, T stage, Gleason score, prostate volume, and percent positive cores did not correlate with BPFS. Stratifying by favorable vs. unfavorable IR groups did not affect BPFS. CONCLUSIONS: HDR brachytherapy monotherapy represents a safe and highly effective treatment for IR prostate cancer patients with long-term follow-up.

Pretreatment 3T multiparametric MRI staging predicts for biochemical failure in high-risk prostate cancer treated with combination high-dose-rate brachytherapy and external beam radiotherapy.

PURPOSE: To determine whether pretreatment 3T multiparametric MRI (mpMRI) staging impacts biochemical recurrence-free survival (BRFS) or distant metastasis-free survival (DMFS) for men with high-risk prostate cancer treated with combination high-dose-rate (HDR) brachytherapy and external beam radiation therapy (EBRT). MATERIALS AND METHODS: This institutional review board-approved retrospective study included a cohort of 37 men with high-risk prostate cancer treated with HDR brachytherapy and EBRT after 3T mpMRI. Kaplan-Meier analysis was used to evaluate whether mpMRI evidence of extracapsular extension or seminal vesicle invasion (SVI) resulted in differences in BRFS or DMFS. Pretreatment and treatment-related variables were evaluated for association with biochemical failure (Phoenix definition) and distant metastatic failure using univariate Cox regression analysis. RESULTS: The median prostate-specific antigen at diagnosis was 9 ng/mL (range 2-100). Biopsy Gleason score (bGS) was ≤8 in 38% and nine in 62%. Clinical T-category was T1-T2 in 89%, T3a in 8%, and T3b in 3%. With a median followup of 30.6 months, actuarial 3-year BRFS and DMFS were 76% and 86%, respectively. Kaplan-Meier analysis revealed that mpMRI evidence of extracapsular extension or SVI resulted in significantly higher rates of both biochemical recurrence and distant failure. Using Cox regression analysis, only mpMRI evidence of SVI vs. no SVI predicted for biochemical failure (hazard ratio 13.98, p = 0.0055). CONCLUSIONS: For high-risk prostate cancer treated with combination HDR brachytherapy and EBRT, mpMRI evidence of SVI predicted for biochemical failure, whereas traditional pretreatment variables did not. Therefore, pretreatment 3T mpMRI appears useful for identifying men who may benefit from treatment intensification.