CT and cone-beam CT of ablative radiation therapy for pancreatic cancer with expert organ-at-risk contours.

We describe a dataset from patients who received ablative radiation therapy for locally advanced pancreatic cancer (LAPC), consisting of computed tomography (CT) and cone-beam CT (CBCT) images with physician-drawn organ-at-risk (OAR) contours. The image datasets (one CT for treatment planning and two CBCT scans at the time of treatment per patient) were collected from 40 patients. All scans were acquired with the patient in the treatment position and in a deep inspiration breath-hold state. Six radiation oncologists delineated the gastrointestinal OARs consisting of small bowel, stomach and duodenum, such that the same physician delineated all image sets belonging to the same patient. Two trained medical physicists further edited the contours to ensure adherence to delineation guidelines. The image and contour files are available in DICOM format and are publicly available from The Cancer Imaging Archive ( https://doi.org/10.7937/TCIA.ESHQ-4D90 , Version 2). The dataset can serve as a criterion standard for evaluating the accuracy and reliability of deformable image registration and auto-segmentation algorithms, as well as a training set for deep-learning-based methods.

Deep-learning-based image registration and automatic segmentation of organs-at-risk in cone-beam CT scans from high-dose radiation treatment of pancreatic cancer.

PURPOSE: Accurate deformable registration between computed tomography (CT) and cone-beam CT (CBCT) images of pancreatic cancer patients treated with high biologically effective radiation doses is essential to assess changes in organ-at-risk (OAR) locations and shapes and to compute delivered dose. This study describes the development and evaluation of a deep-learning (DL) registration model to predict OAR segmentations on the CBCT derived from segmentations on the planning CT. METHODS: The DL model is trained with CT-CBCT image pairs of the same patient, on which OAR segmentations of the small bowel, stomach, and duodenum have been manually drawn. A transformation map is obtained, which serves to warp the CT image and segmentations. In addition to a regularity loss and an image similarity loss, an OAR segmentation similarity loss is also used during training, which penalizes the mismatch between warped CT segmentations and manually drawn CBCT segmentations. At test time, CBCT segmentations are not required as they are instead obtained from the warped CT segmentations. In an IRB-approved retrospective study, a dataset consisting of 40 patients, each with one planning CT and two CBCT scans, was used in a fivefold cross-validation to train and evaluate the model, using physician-drawn segmentations as reference. Images were preprocessed to remove gas pockets. Network performance was compared to two intensity-based deformable registration algorithms (large deformation diffeomorphic metric mapping [LDDMM] and multimodality free-form [MMFF]) as baseline. Evaluated metrics were Dice similarity coefficient (DSC), change in OAR volume within a volume of interest (enclosing the low-dose PTV plus 1 cm margin) from planning CT to CBCT, and maximum dose to 5 cm3 of the OAR [D(5cc)]. RESULTS: Processing time for one CT-CBCT registration with the DL model at test time was less than 5 seconds on a GPU-based system, compared to an average of 30 minutes for LDDMM optimization. For both small bowel and stomach/duodenum, the DL model yielded larger median DSC and smaller interquartile variation than either MMFF (paired t-test P < 10-4 for both type of OARs) or LDDMM (P < 10-3 and P = 0.03 respectively). Root-mean-square deviation (RMSD) of DL-predicted change in small bowel volume relative to reference was 22% less than for MMFF (P = 0.007). RMSD of DL-predicted stomach/duodenum volume change was 28% less than for LDDMM (P = 0.0001). RMSD of DL-predicted D(5cc) in small bowel was 39% less than for MMFF (P = 0.001); in stomach/duodenum, RMSD of DL-predicted D(5cc) was 18% less than for LDDMM (P < 10-3 ). CONCLUSIONS: The proposed deep network CT-to-CBCT deformable registration model shows improved segmentation accuracy compared to intensity-based algorithms and achieves an order-of-magnitude reduction in processing time.

Inhibition of HECT E3 ligases as potential therapy for COVID-19.

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.

Histologic and Immunohistochemical Evaluation of 65 Placentas From Women With Polymerase Chain Reaction-Proven Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

CONTEXT.­: Coronavirus disease 2019 (COVID-19) has been shown to have effects outside of the respiratory system. Placental pathology in the setting of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains a topic of great interest because earlier studies have shown mixed results. OBJECTIVE.­: To ascertain whether maternal SARS-CoV-2 infection is associated with any specific placental histopathology, and to evaluate the virus's propensity for direct placental involvement. DESIGN.­: Placentas from 65 women with polymerase chain reaction-proven SARS-CoV-2 infection underwent histologic evaluation using Amsterdam consensus group criteria and terminology. Another 85 placentas from women without SARS-CoV-2 constituted the negative control group. A total of 64 of the placentas from the SARS-CoV-2-positive group underwent immunohistochemical staining for SARS-CoV-2 nucleocapsid protein. RESULTS.­: Pathologic findings were divided into maternal vascular malperfusion, fetal vascular malperfusion, chronic inflammatory lesions, amniotic fluid infection sequence, increased perivillous fibrin, intervillous thrombi, increased subchorionic fibrin, meconium-laden macrophages (M-LMs) within fetal membranes, and chorangiosis. There was no statistically significant difference in prevalence of any specific placental histopathology between the SARS-CoV-2-positive and SARS-CoV-2-negative groups. There was no immunohistochemical evidence of SARS-CoV-2 virus in any of the 64 placentas that underwent staining for viral nucleocapsid protein. CONCLUSIONS.­: Our study results and a literature review suggest that there is no characteristic histopathology in most placentas from women with SARS-CoV-2 infection. Likewise, direct placental involvement by SARS-CoV-2 is a rare event.

Elective Neck Dissection, but Not Adjuvant Radiation Therapy, Improves Survival in Stage I and II Oral Tongue Cancer with Depth of Invasion >4 mm.

Purpose/objective(s) In early-stage, node negative oral tongue cancer, there is limited data supporting tumor depth of invasion (DOI) as an indication for post-operative radiotherapy (PORT) to the primary site. The primary aim of this study is to examine the effect of tumor DOI and PORT on overall survival (OS). Materials and methods The National Cancer Database (NCDB) was used to query patients with AJCC stage I and II oral tongue cancer (2006-2013). Patients were stratified by receipt of PORT, elective neck dissection (ND), and DOI (≤4 mm or >4 mm). Kaplan-Meier analysis was performed to compare OS (using the log-rank test) between PORT versus no-PORT. Multivariable Cox proportional hazards regression model performed to evaluate the independent effect of PORT and neck dissection on OS. Results Among 939 patients, 69.3% were clinical stage I, 67.4% received ND, 23.4% had DOI >4 mm, and 10.4% received PORT. The addition of PORT did not improve OS with tumor DOI ≤4 mm (p = 0.634) or >4 mm (p = 0.816). The addition of elective neck dissection improved OS for DOI >4 mm (p = 0.010), but not for ≤4 mm (p = 0.128). On multivariable analysis, ND improved OS if DOI >4 mm (HR, 0.37; 95% CI, 0.17-0.81 [p = .012]), when also controlling for age, sex, PORT status, clinical stage, and pathological stage. Conclusion Tumor DOI should not be used as a sole indication for PORT in early stage oral tongue cancers. Elective neck dissection at the time of excision of the primary tumor results in higher OS for tumors with DOI >4 mm.

Radiation and Immunotherapy in High-grade Gliomas: Where Do We Stand?

High-grade glioma is the most common primary brain tumor, with glioblastoma multiforme (GBM) accounting for 52% of all brain tumors. The current standard of care (SOC) of GBM involves surgery followed by adjuvant fractionated radiotherapy and chemotherapy. However, little progress has been made in extending overall survival, progression-free survival, and quality of life. Attempts to characterize and customize treatment of GBM have led to mitigating the deleterious effects of radiotherapy using hypofractionated radiotherapy, as well as various immunotherapies as a promising strategy for the incurable disease. A combination of radiotherapy and immunotherapy may prove to be even more effective than either alone, and preclinical evidence suggests that hypofractionated radiotherapy can actually prime the immune system to make immunotherapy more effective. This review addresses the complications of the current radiotherapy regimen, various methods of immunotherapy, and preclinical and clinical data from combined radioimmunotherapy trials.

The State of Surgical Axillary Management and Adjuvant Radiotherapy for Early-stage Invasive Breast Cancer in the Modern Era.

BACKGROUND: For clinical T1-2N0 breast cancer, sentinel lymph node biopsy (SLNB) has been shown in American College of Surgeons Oncology Group (ACOSOG) Z0011 to be sufficient for women with 1 to 2 positive sentinel lymph nodes with no added benefit for completion axillary lymph node dissection (ALND). Z0011 specified whole breast radiotherapy (RT) using standard tangential fields; however, later analysis showed variation in field design. We assessed nationwide practice patterns and examined factors associated with patients undergoing completion ALND and subsequent radiation field design. PATIENTS AND METHODS: Women with clinical T1-2N0 breast cancer who underwent breast-conserving surgery, axillary staging, and whole breast RT in 2012 to 2013 were identified in the National Cancer Database. Multivariable logistic regression modeling was used to examine axillary management and RT, adjusting for demographic and clinicopathologic factors. RESULTS: Among 83,555 patients meeting criteria, 9.3% underwent upfront ALND, 75.8% underwent SLNB only, and 14.9% underwent SLNB with completion ALND. From 2012 to 2013, upfront SLNB increased from 90.1% to 91.4% (odds ratio, 1.14; P < .001). Among 9474 patients that underwent SLNB with 1 to 2 positive sentinel nodes, 31.2% received completion ALND. Among patients with 1 to 2 positive sentinel nodes, SLNB increased from 65.8% to 72.1% from 2012 to 2013 (P < .001). For patients with 1 to 2 positive lymph nodes that underwent SLNB only, 63.4% underwent breast RT, whereas 36.6% received breast and nodal RT. CONCLUSIONS: Nationwide practice patterns of axillary management vary. Despite an increasing rate of SLNB, many patients still receive upfront and completion ALND. Furthermore, there is significant variation in RT field design, and modern treatment guidelines are warranted for this patient population.

Advances in Radiotherapy for Glioblastoma.

External beam radiotherapy (RT) has long played a crucial role in the treatment of glioblastoma. Over the past several decades, significant advances in RT treatment and image-guidance technology have led to enormous improvements in the ability to optimize definitive and salvage treatments. This review highlights several of the latest developments and controversies related to RT, including the treatment of elderly patients, who continue to be a fragile and vulnerable population; potential salvage options for recurrent disease including reirradiation with chemotherapy; the latest imaging techniques allowing for more accurate and precise delineation of treatment volumes to maximize the therapeutic ratio of conformal RT; the ongoing preclinical and clinical data regarding the combination of immunotherapy with RT; and the increasing evidence of cancer stem-cell niches in the subventricular zone which may provide a potential target for local therapies. Finally, continued development on many fronts have allowed for modestly improved outcomes while at the same time limiting toxicity.

Excellent Long-term Breast Preservation Rate After Accelerated Partial Breast Irradiation Using a Balloon Device.

BACKGROUND: Accelerated partial breast irradiation (APBI) using a balloon device has been well tolerated. A recent retrospective population-based study showed an increase in the rate of subsequent mastectomy for patients who undergo APBI compared with whole breast radiation therapy. Our aim was to analyze the long-term results of patients treated with APBI at our institution to determine the salvage mastectomy and locoregional recurrence rates and cosmesis outcomes. MATERIALS AND METHODS: After institutional review board approval, we conducted a retrospective review of 111 patients treated from June 2003 to October 2014 at our institution for early-stage breast cancer using a balloon device. After lumpectomy and nodal staging, the patients underwent APBI with high-dose rate iridium-192 brachytherapy. A computed tomography-based 3-dimensional plan was created, and a dose of 34 Gy in 10 fractions was given twice daily, 6 hours apart, over 5 days. Follow-up examinations were performed 2 to 3 times annually by either a surgeon and/or a radiation oncologist. Annual mammograms were obtained. The patients included postmenopausal women with node-negative early-stage invasive ductal carcinoma with a tumor size < 3 cm (n = 93) or ductal carcinoma in situ (n = 18). Cosmesis was evaluated using the Harvard criteria, as excellent, good, fair, or poor. RESULTS: At a median follow-up period of 66 months (range, 1-139 months) after completing treatment, with a minimum of 5 years of follow-up data for 62 patients (55.9%), the incidence of ipsilateral breast tumor recurrence (IBTR) was 2.7% (n = 3) and the incidence of ipsilateral axilla nodal recurrence was 1.8% (n = 2). The ipsilateral breast preservation rate was 97.3%. The salvage mastectomy rate was 2.7% (n = 3), and the 5-year salvage mastectomy-free rate was 98.7% (95% confidence interval, 91.0%-99.8%). No distant failure developed, and no breast cancer-related deaths occurred. The 5-year overall survival rate was 91.7% (95% confidence interval, 83.2%-96.0%), and the 10-year breast cancer-specific survival rate was 100%. Of the 3 cases of IBTR, 2 were estrogen receptor negative (P = .076). The mean interval to IBTR was 78.7 ± 27.5 months from treatment completion. A significant association was noted between African-American ethnicity and IBTR (P = .0398). Excellent to good cosmesis was observed in 98.1% of the patients. The maximum skin dose (mean value) for patients with excellent, good, and fair cosmesis was 302.2 Gy, 315.4 Gy, and 372.5 Gy (88.9%, 92.7%, and 109.5% of the prescription dose), respectively. The maximum skin dose was < 340 Gy (100% of the prescribed dose) in 69.9% of patients with excellent to good cosmesis. CONCLUSION: The long-term follow-up data of patients receiving APBI with a balloon device showed a low salvage mastectomy rate with durable long-term breast preservation. Excellent local control with good cosmesis was noted in these postmenopausal patients treated with APBI.

FDA Adverse Event Reporting System: Recruiting Doctors to Make Surveillance a Little Less Passive.

Within the last few decades, a shift has taken place in FDA's approach to drug development, with greater emphasis put on postmarketing data collection and less on the traditional premarketing scheme. The FDA Adverse Event Reporting System (FAERS) is the primary system for collecting Adverse Events, but has been criticized for years for the low reporting rate into the system and the poor quality of the information submitted. This paper argues that physicians need to be required to submit adverse event reports to FAERS, because such a requirement (1) would produce a greater number of the high quality reports necessary to better determine causality; (2) is merely an extension of physicians' ethical obligations; and (3) aligns with the approach in the Vaccine Adverse Event Reporting System (VAERS). Furthermore, advances in electronic health records can aid in reporting efficiency.

Radiation-induced epithelial-myoepithelial carcinoma in a patient previously treated with mantle-field radiation therapy for Hodgkin lymphoma.

BACKGROUND: Radiation-induced salivary gland tumors are well described in the literature, with mucoepidermoid cancer being the most common histologic entity. Epithelial-myoepithelial carcinoma is a rare tumor accounting for <1% of all tumors in the salivary glands. METHODS AND RESULTS: We describe the first case of radiation-induced epithelial-myoepithelial carcinoma in the English-language medical literature. A 48-year-old man presented with right-sided mandibular pain and trismus, 25 years after mantle-field radiation therapy (RT) for Hodgkin lymphoma. He underwent excision of a right submandibular mass, which revealed a diagnosis of epithelial-myoepithelial carcinoma. Although typically a low-grade tumor, the histology revealed extensive necrosis and high mitotic activity. The patient required multiple resections and adjuvant therapy after multiple recurrences over a 4-year period. CONCLUSION: Reports of epithelial-myoepithelial carcinoma are relatively rare and this case highlights the importance of long-term follow-up and increased awareness of the risks of salivary gland tumors in this population.

Routine histopathologic characteristics can predict oncotype DX(TM) recurrence score in subsets of breast cancer patients.

This study assessed whether routine pathologic parameters could predict Oncotype DX(TM) recurrence score (RS) in 72 breast cancers diagnosed from 2008-2012. Comparing patients with low RS (0-17) vs. intermediate RS (18-30) vs. high RS (>30), the mean Nottingham score increased (5.5 vs. 6.3 vs. 7.2, respectively, p = .001) and the mean PR Allred score decreased (6.7 vs. 4.9 vs. 3.3, respectively, p = .001). A high RS was least likely for low-grade tumors (0% had high RS, p = .005), and strong PR positivity (9% had high RS, p = .017). A low RS was least likely for cancers that were both high grade and PR weak/negative.

Arsenic removal from water using lignocellulose adsorption medium (LAM).

Arsenate in water is readily adsorbed on lignocellulose adsorption medium (LAM) which is cotton-based and has been coated with iron(III) by soaking cotton pellets in ferric chloride solution. Capacities achieved with LAM average 32.8 mg As/g of medium at influent arsenic concentrations ranging from 20-30 mg As/L. Adsorption follows (R2 = 0.993) a Freundlich isotherm, (x/M) = 22.845 Ce0.25, where (x/M) is the ratio of milligrams of contaminant adsorbed per gram of adsorbent and Ce is the equilibrium concentration. As is often the case with adsorption from solution, the fit using a Langmuir isotherm was not as good (R2 = 0.8786). The adsorbent when saturated can be regenerated by treatment with dilute sodium hydroxide. After five regenerations, the capacity dropped by 11.5%. Arsenate washed off the adsorbent after regeneration, as well as that left on the medium, may be concentrated and disposed of properly or perhaps recycled. Consideration of costs shows that one ton of iron(III)-treated adsorbent can be used to remove arsenate at toxic levels from drinking water at a cost of about 3.20/ton US dollars plus the cost of media without regeneration.

Enhanced adsorption and regeneration with lignocellulose-based phosphorus removal media using molecular coating nanotechnology.

The removal of phosphorus in point and non-point-source pollution has become one of the leading problems in water quality since the beginning of the 21st century. Several natural, domestic, and industrial treatment systems already exist, but with very limited efficiencies and serious procedural defects. Lignocellulose-based Anion Removal Media (LAM) was developed in association with iron nanocoating technology as means of phosphorus adsorption from various concentrations of contaminated water. Results revealed that trivalent iron coated lignocellulose pellets can be used to effectively remove phosphorus contaminants from point and non-point-source polluted water. Removal capacities of pelletized cotton media surpass existing materials for phosphorus removal by at least 22 times, while remaining both efficient and cost effective. The materials were also investigated for regeneration, yielding high removal capacities even after the fifth regeneration. Treatment methodology and outlines are proposed, and procedural mechanisms are explored in this study. An economic evaluation of this technology is also assessed for a practical application of LAM to point/non-point-source polluted water.