Intravesical oncolytic virotherapy and immunotherapy for non-muscle-invasive bladder cancer mouse model.

OBJECTIVES: To test if intravesical instillation of both an anti-programmed cell death protein 1 (PD-1) inhibitor and an oncolytic reovirus would demonstrate a greater effect than either treatment alone, as non-muscle-invasive bladder cancer that is refractory to intravesical bacillus Calmette-Guérin can be treated by systemic anti-PD-1 immunotherapy and we previously demonstrated improved overall survival (OS) with six once-weekly instillations of intravesical anti-PD-1 in a murine model. MATERIALS AND METHODS: Using an orthotopic syngeneic C3H murine model of MBT2 urothelial bladder cancer, groups of 10 mice were compared between no treatment, intravesical anti-PD-1, intravesical oncolytic reovirus, or intravesical reovirus + anti-PD-1. A single intravesical treatment session was given. The primary outcome was OS, and the secondary outcomes included long-term immunity and tumour-immune profile. RESULTS: With a median follow-up of 9 months, all mice that received no treatment died with a median survival of 41 days, while the comparison median OS was not reached for reovirus (hazard ratio [HR] 14.4, 95% confidence interval [CI] 3.9-32.6; P < 0.001), anti-PD-1 (HR 28.4, 95% CI 7.0-115.9; P < 0.001), and reovirus + anti-PD-1 (HR 28.4, 95% CI 7.0-115.9; P < 0.001). Monotherapy with anti-PD-1 or reovirus demonstrated no significant differences in survival (P = 0.067). Mass cytometry showed that reovirus + anti-PD-1 treatment enriched monocytes and decreased myeloid-derived suppressor cells, generating an immuno-responsive tumour microenvironment. Depletion of CD8+ T cells eliminated the survival advantage provided by the intravesical treatment. CONCLUSIONS: Treatment of murine orthotopic bladder tumours with a single instillation of intravesical reovirus, anti-PD-1 antibody, or the combination confers superior survival compared to controls. Tumour-immune microenvironment differences indicated myeloid-derived suppressor cells and CD8+ T cells mediate the treatment response.

Intravesical Anti-PD-1 Immune Checkpoint Inhibition Treats Urothelial Bladder Cancer in a Mouse Model.

PURPOSE: Nonmuscle-invasive bladder cancer is treated by resection within the bladder and bladder instillment with bacillus Calmette-Guérin or chemotherapy. For bacillus Calmette-Guérin-refractory disease, systemic anti-PD-1 (programmed cell death protein 1) immune checkpoint inhibition is a treatment. Our aim is to test whether intravesical instillment with anti-PD-1 inhibitor treats localized bladder cancer as effectively as systemic administration. MATERIALS AND METHODS: We investigated an orthotopic mouse model of urothelial bladder cancer using MBT2 cells instilled into the bladders of syngeneic, wild-type C3H mice. Groups of 10 mice received each treatment for comparison of intravesical anti-PD-1, intraperitoneal anti-PD1, and intravesical chemotherapy. The primary outcome was overall survival and secondary outcomes included long-term immunity and toxicity. RESULTS: Anti-PD-1 administered by bladder instillment (intravesical route) successfully treats localized bladder cancer and has similar overall survival to anti-PD-1 by systemic route. Anti-PD-1 by either route provides a significant survival advantage over control antibody. Anti-PD-1 increases CD8+ cell infiltration in tumors, particularly when administered intravesically. Antibody treatment avoids toxicity observed for intravesical chemotherapy. Mice who cleared their tumors after initial treatment were rechallenged with tumor engraftment 3-9 months later without any additional treatment. Initial anti-PD-1-treated mice did not grow tumors when rechallenged, which suggests long-term immunity exists, but initial mitomycin-treated mice readily grew tumors indicating no immunity occurred by chemotherapy treatment. CONCLUSIONS: Intravesical administration of anti-PD-1 is a promising treatment route for localized bladder cancer, with comparable overall survival to systemic anti-PD-1 in this mouse model. Intravesical anti-PD-1 increases CD8+ T cells in treated tumors and long-term immunity was seen to tumor rechallenge.

Prospective observational trial of low-dose skin electron beam therapy in mycosis fungoides using a rotational technique.

INTRODUCTION: Low-dose total skin electron beam therapy provides a durable treatment response for skin lesions caused by cutaneous T-cell lymphoma. We prospectively assessed the durability of response and quality of life for patients receiving low-dose total skin electron beam therapy using a novel rotational technique and dosing regimen. METHODS: Patients completed baseline Skindex-29 quality-of-life surveys and had baseline Modified Severity-Weighted Assessment Tool score recorded. Patients received 12 Gy in 12 fractions with a dual-field rotational technique. The primary outcome was overall response rate, with the secondary outcomes being time to treatment response, duration of clinical benefit, and quality-of-life change. RESULTS: We enrolled 20 patients and recorded an overall response rate of 90%. The median time to treatment response was 6.5 weeks. The baseline Modified Severity-Weighted Assessment Tool score was 55.6 and it declined to a median of 2.2 at last follow-up (P < .001). The median duration of clinical benefit was 21 months. There was a decline in the Skindex-29 total score and every subdomain when each follow-up visit was compared (P = .004). CONCLUSIONS: This prospective study demonstrated a very high overall response rate and improvement in skin-related quality of life. Low-dose rotational total skin electron beam therapy can be implemented routinely in clinical practice.

An autoimmune-based, paraneoplastic neurologic syndrome following checkpoint inhibition and concurrent radiotherapy for merkel cell carcinoma: case report.

PURPOSE: Merkel cell carcinoma is highly sensitive to both radiation and immunotherapy. Moreover, concurrent radioimmunotherapy may capitalize on anti-tumor immune activity and improve Merkel cell treatment response, although an enhanced immune system may cross-react with native tissues and lead to significant sequelae. METHODS: Here we present a case study of a patient with metastatic Merkel cell carcinoma treated with radiotherapy concurrent with pembrolizumab. RESULTS: After radioimmunotherapy, the patient developed sensory neuropathy, visual hallucinations, and mixed motor neuron findings. Neurologic dysfunction progressed to profound gastrointestinal dysmotility necessitating parenteral nutrition and intubation with eventual expiration. CONCLUSION: This case represents a unique autoimmune paraneoplastic neurologic syndrome, likely specific to neuroendocrine tumors and motivated by concurrent radioimmunotherapy. Recognition of the potential role of radioimmunotherapy may provide an advantage in anticipating these severe sequelae.

Treatment approach and outcomes of vaginal melanoma.

OBJECTIVE: To describe the characteristics of primary vaginal melanoma patients in the Surveillance, Epidemiology, and End Result database and to determine the outcome from the treatment approaches. MATERIALS/METHODS: From the Surveillance, Epidemiology, and End Result registry, 201 patients with vaginal melanoma were identified. Patients' characteristics and prognostic factors including age, race, extent of surgery, and use of radiation therapy were obtained. RESULTS: The median age was 68 years (range, 28-100 years). The population was 73% white, 11% black, and 16% Asian/American Indian. International Federation of Gynecology and Obstetrics staging results were stage I (46%), stage II (18%), stage III (3%), stage IVA (3%), stage IVB (12%), and unknown (18%). Treatment approach included surgical resection of the primary site in 70%, whereas 35% of the patients underwent lymph node resection. Approximately 40% of the patients received radiotherapy, which was primarily used in the adjuvant setting. Overall survival at 2 and 5 years was 24% and 15%, respectively. Presence of lymph nodes at diagnosis was associated with worse overall survival (hazard ratio, 1.98; P = 0.02). Adjuvant radiation did not offer a statistically significant overall survival advantage compared to surgery alone. CONCLUSIONS: Vaginal melanoma is a rare diagnosis primarily affecting the elderly. Overall survival is low even for patients presenting with disease limited to the vagina. Lymph node involvement at diagnosis is strongly predictive of worse overall survival. Most patients are treated with surgical resection with varying use of adjuvant radiotherapy. Further research is needed to identify the etiology and improve the outcome of this aggressive disease.

Crystal structure of the Epstein-Barr virus (EBV) glycoprotein H/glycoprotein L (gH/gL) complex.

The Epstein-Barr virus (EBV) is a γ-herpesvirus that infects B cells and epithelial cells and that has been linked to malignancies in both cell types in vivo. EBV, like other herpesviruses, has three glycoproteins, glycoprotein B (gB), gH, and gL, that form the core membrane fusion machinery mediating viral penetration into the cell. The gH and gL proteins associate to form a heterodimeric complex, which is necessary for efficient membrane fusion and also implicated in direct binding to epithelial cell receptors required for viral entry. To gain insight into the mechanistic role of gH/gL, we determined the crystal structure of the EBV gH/gL complex. The structure is comprised of four domains organized along the longest axis of the molecule. Comparisons with homologous HSV-2 gH/gL and partial pseudorabies virus gH structures support the domain boundaries determined for the EBV gH/gL structure and illustrate significant differences in interdomain packing angles. The gL subunit and N-terminal residues of gH form a globular domain at one end of the structure, implicated in interactions with gB and activation of membrane fusion. The C-terminal domain of gH, proximal to the viral membrane, is also implicated in membrane fusion. The gH/gL structure locates an integrin binding motif, implicated in epithelial cell entry, on a prominent loop in the central region of the structure. Multiple regions of gH/gL, including its two extreme ends, are functionally important, consistent with the multiple roles of gH/gL in EBV entry.

Radiation Fibrosis After Stereotactic Body Radiation Therapy for Osseous Metastases: A Case Report.

Radiation-induced fibrosis is a potentially severe late complication after high-dose radiotherapy. Over the last decade, there has been increasing use of stereotactic body radiation therapy (SBRT) to treat both primary and metastatic malignancies. While there has been evolving evidence of appropriate dose constraints for certain organs receiving hypofractionated radiotherapy, the risk, and appropriate dose constraints to limit the risk of radiation-induced muscle fibrosis are poorly defined. In this report, two patients are presented who underwent SBRT for osseous oligometastatic renal cell carcinoma. While the treatment was well-tolerated with no acute toxicities and complete local control of the metastasis, both patients experienced late toxicity of radiation-induced fibrosis in the adjacent musculature. In both cases, toxicity was nonresponsive to medical interventions and was severe enough to require surgical resection of the affected tissue. Following surgery, both patients reported improved pain relief and mobility. Further studies are needed to explore the dose constraints that may reduce the risk of radiation-induced muscle fibrosis in five-fraction treatment.

Academic patterns of practice regarding CT simulation scans and radiology review.

OBJECTIVE: Currently, there are no consensus guidelines about handling incidental radiological findings on radiotherapy planning CT simulation scans. Retrospective studies analyzing incidental findings on CT simulations show a small, but not insignificant, rate of both oncologic and non-oncologic findings. These findings may have medico-legal, financial, and clinical implications. Given a lack of guidelines, we obtained a formal survey of multiple academic institutions to evaluate how CT simulations are handled in regard to incidental findings. METHODS: A formal survey was developed consisting of 12 questions related to institutional practices regarding CT simulation scans. From 7/18/21 to 8/27/21 and 5/6/22 to 5/24/22, the survey was administered electronically by REDCap to key personnel at Academic Radiation Oncology Programs identified through the American Society for Radiation Oncology (ASTRO) with inclusion criteria including an active ACGME approved Radiation Oncology residency program. RESULTS: In total, 88 academic radiation oncology programs were surveyed with total of 45 responses (51%). 1 out of 45 departments who responded has formal guidelines regarding workup of incidental findings. There is variability about sending CT simulation scans for official radiology review if an incidental finding is identified. CONCLUSIONS: Based on a measurable rate of incidental findings on radiotherapy planning CT simulations and their possible implications, our survey illustrates a likely need for consensus recommendations for handling such findings to improve patient care and safety.

Evaluation of 5 Fraction Stereotactic Body Radiation Therapy (SBRT) for Osseous Renal Cell Carcinoma Metastases.

OBJECTIVES: The best fractionation for stereotactic body radiotherapy (SBRT) in renal cell carcinoma (RCC) metastases has not been well defined. In addition, the literature on outcomes using 5-fraction SBRT in the setting of osseous metastases has not been well reported. MATERIALS AND METHODS: Thirty-nine patients with 69 RCC osseous metastases were treated using 5-fraction SBRT at a single institution using 2 dose-fractionation schemes. Overall survival and local-control (LC) outcomes of the 2 fractionation schemes were studied using Kaplan-Meier curves. RESULTS: Of the 69 lesions included in the study, 20 were treated with 30 grays (Gy) in 5 fractions and 49 were treated with 40 Gy in 5 fractions. The median age of patients at diagnosis was 58.4 years. The 1-year LC rate for all treated lesions was 85.5% (59/69) with an LC of 90% (18/20) for lesions receiving 30 Gy and 83.7% (41/49) in lesions receiving 40 Gy. There was no statistically significant difference in 1-year LC rate between the 2 fractionation schemes (P-value, 0.553). CONCLUSIONS: Patients with osseous RCC metastases undergoing 5 fractions of SBRT had favorable LC outcomes. There was no difference in survival or LC between the 40 Gy and 30 Gy treatment arms.

Radiopharmaceuticals as Novel Immune System Tracers.

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigms for multiple cancers. However, ICI therapy often fails to generate measurable and sustained antitumor responses, and clinically meaningful benefits remain limited to a small proportion of overall patients. A major obstacle to development and effective application of novel therapeutic regimens is optimized patient selection and response assessment. Noninvasive imaging using novel immunoconjugate radiopharmaceuticals (immuno-positron emission tomography and immuno-single-photon emission computed tomography) can assess for expression of cell surface immune markers, such as programmed cell death protein ligand-1 (PD-L1), akin to a virtual biopsy. This emerging technology has the potential to provide clinicians with a quantitative, specific, real-time evaluation of immunologic responses relative to cancer burden in the body. We discuss the rationale for using noninvasive molecular imaging of the programmed cell death protein-1 and PD-L1 axis as a biomarker for immunotherapy and summarize the current status of preclinical and clinical studies examining PD-L1 immuno-positron emission tomography. The strategies described in this review provide insight for future clinical trials exploring the use of immune checkpoint imaging as a biomarker for both ICI and radiation therapy, and for the rational design of combinatorial therapeutic regimens.

The Use of Low-Dose Radiation Therapy in Osteoarthritis: A Review.

Despite its clinical use and investigation in other countries, low dose radiation therapy (LDRT) in the treatment of osteoarthritis (OA) is minimally used in the United States (US). Numerous recent studies published outside the US have shown moderate to long-term pain relief and improvement of mobility after treatment with LDRT for joints affected by OA. Here, we review the most recent literature published on the use of LDRT in OA. We provide a brief outline on the epidemiology, pathophysiology, current treatments, and health care burden of OA within the US. We provide a brief history of the historic use of LDRT in the US as well as a history of LDRT within the modern era of radiation oncology, discuss criticisms of LDRT including recently published randomized trials questioning its benefit as well as the risk of secondary malignancy from LDRT, and provide an outline of treatment planning considerations and recommendations regarding dose and fractionation, energy, beam arrangements, and immobilization techniques. LDRT has been shown to be a cost-effective, noninvasive treatment with minimal side effects. Further investigation into the potential role in the treatment of OA with modern LDRT is recommended.

Towards differentiation of brain tumor from radiation necrosis using multi-parametric MRI: Preliminary results at 4.7 T using rodent models.

BACKGROUND: It remains a clinical challenge to differentiate brain tumors from radiation-induced necrosis in the brain. Despite significant improvements, no single MRI method has been validated adequately in the clinical setting. METHODS: Multi-parametric MRI (mpMRI) was performed to differentiate 9L gliosarcoma from radiation necrosis in animal models. Five types of MRI methods probed complementary information on different scales i.e., T2 (relaxation), CEST based APT (probing mobile proteins/peptides) and rNOE (mobile macromolecules), qMT (macromolecules), diffusion based ADC (cell density) and SSIFT iAUC (cell size), and perfusion based DSC (blood volume and flow). RESULTS: For single MRI parameters, iAUC and ADC provide the best discrimination of radiation necrosis and brain tumor. For mpMRI, a combination of iAUC, ADC, and APT shows the best classification performance based on a two-step analysis with the Lasso and Ridge regressions. CONCLUSION: A general mpMRI approach is introduced to choosing candidate multiple MRI methods, identifying the most effective parameters from all the mpMRI parameters, and finding the appropriate combination of chosen parameters to maximize the classification performance to differentiate tumors from radiation necrosis.

Targeting for stereotactic radiosurgical thalamotomy based on tremor treatment response.

OBJECTIVE: Stereotactic radiosurgery (SRS) treats severe, medically refractory essential tremor and tremor-dominant Parkinson disease. However, the optimal target for SRS treatment within the thalamic ventral intermediate nucleus (VIM) is not clearly defined. This work evaluates the precision of the physician-selected VIM target, and determines the optimal SRS target within the VIM by correlation between early responders and nonresponders. METHODS: Early responders and nonresponders were assessed retrospectively by Elements Basal Ganglia Atlas autocontouring of the VIM on the pre-SRS-treatment 1-mm slice thickness T1-weighted MRI and correlating the center of the post-SRS-treatment lesion. Using pre- and posttreatment diffusion tensor imaging, the fiber tracking package in the Elements software generated tremor-related tracts from autosegmented motor cortex, thalamus, red nucleus, and dentate nucleus. Autocontouring of the VIM was successful for all patients. RESULTS: Among 23 patients, physician-directed SRS targets had a medial-lateral target range from +2.5 mm to -2.0 mm from the VIM center. Relative to the VIM center, the SRS isocenter target was 0.7-0.9 mm lateral for 6 early responders and 0.9-1.1 mm medial for 4 nonresponders (p = 0.019), and without differences in the other dimensions: 0.2 mm posterior and 0.6 mm superior. Dose-volume histogram analyses for the VIM had no significant differences between responders and nonresponders between 20 Gy and 140 Gy, mean or maximum dose, and dose to small volumes. Tractography data was obtained for 4 patients. CONCLUSIONS: For tremor control in early responders, the Elements Basal Ganglia Atlas autocontour for the VIM provides the optimal SRS target location that is 0.7-0.9 mm lateral to the VIM center.

Noninvasive Thalamotomy for Refractory Tremor by Frameless Radiosurgery.

PURPOSE: We sought to determine whether a more widely accessible, noninvasive, frameless approach to radiosurgical thalamotomy would improve objective measures of refractory essential or parkinsonian tremor without added toxicity compared with reports of frame-based radiosurgery. METHODS AND MATERIALS: We conducted a single-arm pilot observational prospective trial of adult patients with essential or parkinsonian tremor from 2013 to 2019 and report results at 1-year follow-up. Patients were treated with frameless unilateral radiosurgical ablation of the thalamic ventral intermediate nucleus to a maximum dose of 160 Gy. Treatment response was measured by the Fahn-Tolosa-Marin (FTM) tremor rating scale and the Quality of Life in Essential Tremor or Parkinson's Disease Questionnaire obtained before treatment and at 3, 6, 9, and 12 months. RESULTS: Thirty-three patients, including 23 with essential tremor and 10 with Parkinson's disease, were enrolled. Overall treatment response rate per FTM was 83% (15 of 18) at 6 months. There was a marked improvement in tremor, with an average total FTM reduction of 21% at 3 months (from 46 to 30 points; P = .003) and 41% at 6 months (from 46 to 24 points; P = .001). At 6 months, functional decline had regressed by 54% (from 15 to 7 points; P = .001). Quality of life improved by 57% (P = .001) at 6 months in patients with essential tremor, and patients with Parkinson's disease had unchanged quality of life. At 1-year follow-up, grade 2 neurologic adverse events were observed in 6% (2 of 33) of patients without any grade ≥ 3 events. CONCLUSION: Noninvasive, frameless radiosurgical thalamotomy may be a feasible treatment for patients with refractory tremor and demonstrates short-term safety at 1-year follow-up. This pilot study provides promising preliminary descriptions of efficacy, and definitive estimates of long-term safety and benefit require further study with longer follow-up.

Rodent Model of Brain Radionecrosis Using Clinical LINAC-Based Stereotactic Radiosurgery.

Purpose: Our purpose was to develop a rodent model of brain radionecrosis using clinical linear accelerator based stereotactic radiosurgery. Methods and Materials: Single fraction maximum prescription points in the mouse's left hemisphere were irradiated using linear accelerator-based stereotactic radiosurgery with multiple arcs at 60 (n = 5), 100 (n = 5), and 140 (n = 5) Gy. Rats (n = 6) were similarly treated with 140 Gy. Gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) was used to track radiation injury in mice over weeks (100 and 140 Gy) or months (60 Gy). Target accuracy was measured by the distance from the prescription point to the center of the earliest Gd-MRI enhancement. Confirmation of necrosis via histology was performed at the subject endpoints. Results: Radiation injury as indicated by Gd-MRI was first identified at 2 weeks (140 Gy), 4 to 6 weeks (100 Gy), and 8 months (60 Gy). A volumetric time course showed rapid growth in the volume of Gd-MRI signal enhancement after the appearance of apparent necrosis. Histopathologic features were consistent with radionecrosis. Conclusions: The presented method uses a commonly available clinical linear accelerator to induce radiation necrosis in both mice and rats. The treatment is modeled after patient therapy for a more direct model of human tissue under a range of doses used in clinical neuro-ablation techniques. The short time to onset of apparent necrosis, accurate targeting of the prescription point, high incidence of necrosis, and similar pathologic features make this a suitable animal model for further research in radionecrosis.

Selective Cell Size MRI Differentiates Brain Tumors from Radiation Necrosis.

Brain metastasis is a common characteristic of late-stage lung cancers. High doses of targeted radiotherapy can control tumor growth in the brain but can also result in radiotherapy-induced necrosis. Current methods are limited for distinguishing whether new parenchymal lesions following radiotherapy are recurrent tumors or radiotherapy-induced necrosis, but the clinical management of these two classes of lesions differs significantly. Here, we developed, validated, and evaluated a new MRI technique termed selective size imaging using filters via diffusion times (SSIFT) to differentiate brain tumors from radiotherapy necrosis in the brain. This approach generates a signal filter that leverages diffusion time dependence to establish a cell size-weighted map. Computer simulations in silico, cultured cancer cells in vitro, and animals with brain tumors in vivo were used to comprehensively validate the specificity of SSIFT for detecting typical large cancer cells and the ability to differentiate brain tumors from radiotherapy necrosis. SSIFT was also implemented in patients with metastatic brain cancer and radiotherapy necrosis. SSIFT showed high correlation with mean cell sizes in the relevant range of less than 20 µm. The specificity of SSIFT for brain tumors and reduced contrast in other brain etiologies allowed SSIFT to differentiate brain tumors from peritumoral edema and radiotherapy necrosis. In conclusion, this new, cell size-based MRI method provides a unique contrast to differentiate brain tumors from other pathologies in the brain. SIGNIFICANCE: This work introduces and provides preclinical validation of a new diffusion MRI method that exploits intrinsic differences in cell sizes to distinguish brain tumors and radiotherapy necrosis.

Mapping the N-terminal residues of Epstein-Barr virus gp42 that bind gH/gL by using fluorescence polarization and cell-based fusion assays.

Epstein-Barr virus (EBV) requires at a minimum membrane-associated glycoproteins gB, gH, and gL for entry into host cells. B-cell entry additionally requires gp42, which binds to gH/gL and triggers viral entry into B cells. The presence of soluble gp42 inhibits membrane fusion with epithelial cells by forming a stable heterotrimer of gH/gL/gp42. The interaction of gp42 with gH/gL has been previously mapped to residues 36 to 81 at the N-terminal region of gp42. In this study, we further mapped this region to identify essential features for binding to gH/gL by use of synthetic peptides. Data from fluorescence polarization, cell-cell fusion, and viral infection assays demonstrated that 33 residues corresponding to 44 to 61 and 67 to 81 of gp42 were indispensable for maintaining low-nanomolar-concentration gH/gL binding affinity and inhibiting B-cell fusion and epithelial cell fusion as well as viral infection. Overall, specific, large hydrophobic side chain residues of gp42 appeared to provide critical interactions, determining the binding strength. Mutations of these residues also diminished the inhibition of B-cell and epithelial cell fusions as well as EBV infection. A linker region (residues 62 to 66) between two gH/gL binding regions served as an important spacer, but individual amino acids were not critical for gH/gL binding. Probing the binding site of gH/gL and gp42 with gp42 peptides is critical for a better understanding of the interaction of gH/gL with gp42 as well as for the design of novel entry inhibitors of EBV and related human herpesviruses.

Eosinophilic pleural effusion complicating allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is primarily a disease of patients with cystic fibrosis or asthma, who typically present with bronchial obstruction, fever, malaise, and expectoration of mucus plugs. We report a case of a young man with a history of asthma who presented with cough, left-sided pleuritic chest pain and was found to have lobar atelectasis and an eosinophilic, empyematous pleural effusion. Bronchoscopy and sputum cultures grew Aspergillus fumigatus, and testing confirmed strong allergic response to this mold, all consistent with a diagnosis of ABPA. This novel and unique presentation of ABPA expands on the differential diagnosis of eosinophilic pleural effusions.

Structure of Epstein-Barr virus glycoprotein 42 suggests a mechanism for triggering receptor-activated virus entry.

Epstein-Barr virus requires glycoproteins gH/gL, gB, and gp42 to fuse its lipid envelope with B cells. Gp42 is a type II membrane protein consisting of a flexible N-terminal region, which binds gH/gL, and a C-terminal lectin-like domain that binds to the B-cell entry receptor human leukocyte antigen (HLA) class II. Gp42 triggers membrane fusion after HLA binding, a process that requires simultaneous binding to gH/gL and a functional hydrophobic pocket in the lectin domain adjacent to the HLA binding site. Here we present the structure of gp42 in its unbound form. Comparisons to the previously determined structure of a gp42:HLA complex reveals additional N-terminal residues forming part of the gH/gL binding site and structural changes in the receptor binding domain. Although the core of the lectin domain remains similar, significant shifts in two loops and an alpha helix bordering the essential hydrophobic pocket suggest a structural mechanism for triggering fusion.

Patient Reported Quality of Life Outcomes After Definitive Radiation Therapy With Absorbable Spacer Hydrogel for Prostate Cancer.

PURPOSE: SpaceOAR is a device approved for conventional radiation in prostate cancer. We sought to observe prospectively how SpaceOAR Hydrogel effected quality of life and dosimetry to organs at risk at our institution. METHODS AND MATERIALS: We prospectively enrolled patients with low risk or favorable-intermediate risk localized prostate cancer. Baseline Expanded Prostate Cancer Index Composite (EPIC-26) scores along with baseline American Urology Association Symptom Index (AUA-SI) scores were collected. SpaceOAR was placed for all patients who then received stereotactic body radiation therapy, low dose rate brachytherapy, conventionally fractionated radiation therapy, or moderately hypofractionated radiation therapy. We evaluated postimplant dosimetry to critical structures, and prospectively collected follow-up EPIC-26 and AUA-SI scores. We performed a repeated measures analysis of variance to compare patient-specific responses and correlated survey data with dosimetric metrics by generating linear regression models. RESULTS: We enrolled 59 patients in this study with a median follow-up of 366 days (interquartile range, 507). At final follow-up, the "?>prostate-specific antigen had a significant decline compared with baseline (P < .0001). There were no grade 3 toxicities on treatment. There were no significant changes in the AUA-SI score (P = .69) at final follow-up compared with baseline, nor was there any change in EPIC-26 domain scores (P = .19) during the course of the study period. There were no significant associations between AUA scores and EPIC-26 scores and the dose to the rectum, bladder, or urethra with the exception being dose to the 2 mL rectum correlated with decline in EPIC-26 rectal score (ß, -0.002; P = .006). Patient-reported declines in bowel domains were less than previously reported data. CONCLUSIONS: Use of SpaceOAR results in favorable dosimetry to the organs at risk and portends excellent short-term quality of life as measured by the association with the patient reported outcome measures. Longer-term follow-up is ongoing and necessary to assess the long-term effect and association of the hydrogel.