Focal therapy for oligometastatic and oligoprogressive renal cell carcinoma: a narrative review.

Metastatic renal cell carcinoma (RCC) can present with oligometastatic disease and/or develop oligoprogression following systemic therapy. Cytoreductive and focal metastasis-directed therapy options include resection, stereotactic ablative radiation and thermal ablation. Aggressive focal therapy may allow delay in initiation of or modification to systemic therapy and improve clinical outcomes. In this narrative review we synthesize current practice guidelines and prospective data on focal therapy management options and highlight future research. Patient selection and the choice of focal treatment techniques are controversial due to limited and heterogeneous data and patients may benefit from multidisciplinary evaluation. Prospective comparative trials with clearly defined inclusion criteria and relevant end points are needed to clarify the risks and benefits of different approaches.

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Colony size buffers interactions between neonicotinoid exposure and cold stress in bumblebees.

Social bees are critical for supporting biodiversity, ecosystem function and crop yields globally. Colony size is a key ecological trait predicted to drive sensitivity to environmental stressors and may be especially important for species with annual cycles of sociality, such as bumblebees. However, there is limited empirical evidence assessing the effect of colony size on sensitivity to environmental stressors or the mechanisms underlying these effects. Here, we examine the relationship between colony size and sensitivity to environmental stressors in bumblebees. We exposed colonies at different developmental stages briefly (2 days) to a common neonicotinoid (imidacloprid) and cold stress, while quantifying behaviour of individuals. Combined imidacloprid and cold exposure had stronger effects on both thermoregulatory behaviour and long-term colony growth in small colonies. We find that imidacloprid's effects on behaviour are mediated by body temperature and spatial location within the nest, suggesting that social thermoregulation provides a buffering effect in large colonies. Finally, we demonstrate qualitatively similar effects in size-manipulated microcolonies, suggesting that group size per se, rather than colony age, drives these patterns. Our results provide evidence that colony size is critical in driving sensitivity to stressors and may help elucidate mechanisms underlying the complex and context-specific impacts of pesticide exposure.

X-ray microscopy enables multiscale high-resolution 3D imaging of plant cells, tissues, and organs.

Capturing complete internal anatomies of plant organs and tissues within their relevant morphological context remains a key challenge in plant science. While plant growth and development are inherently multiscale, conventional light, fluorescence, and electron microscopy platforms are typically limited to imaging of plant microstructure from small flat samples that lack a direct spatial context to, and represent only a small portion of, the relevant plant macrostructures. We demonstrate technical advances with a lab-based X-ray microscope (XRM) that bridge the imaging gap by providing multiscale high-resolution three-dimensional (3D) volumes of intact plant samples from the cell to the whole plant level. Serial imaging of a single sample is shown to provide sub-micron 3D volumes co-registered with lower magnification scans for explicit contextual reference. High-quality 3D volume data from our enhanced methods facilitate sophisticated and effective computational segmentation. Advances in sample preparation make multimodal correlative imaging workflows possible, where a single resin-embedded plant sample is scanned via XRM to generate a 3D cell-level map, and then used to identify and zoom in on sub-cellular regions of interest for high-resolution scanning electron microscopy. In total, we present the methodologies for use of XRM in the multiscale and multimodal analysis of 3D plant features using numerous economically and scientifically important plant systems.

Coverage, inequity and predictors of hepatitis B birth vaccination in Myanmar from 2011-2016: results from a national survey.

BACKGROUND: Hepatitis B virus birth dose (HepB-BD) vaccination is recommended to reduce mother to infant transmission. We evaluated the HepB-BD status of women who gave birth between 2011 and 2016 (N = 3,583) using the 2015-2016 Myanmar Demographic and Health Survey. METHODS: Frequency distributions of HepB-BD vaccination across maternal and health system factors, concentration indices, and logistic regression models were used to estimate coverage, inequity, and factors associated with vaccination. RESULTS: The majority of participants were younger than 30 years of age, lived in rural areas, and were multiparous. Almost all received antenatal care (ANC), but only 43% received recommended ANC services, and 60% gave birth at home. The overall HepB-BD coverage rate was 26%. Vaccination coverage was higher in urban areas and was inequitably concentrated among children of more educated and wealthier women. HepB-BD coverage was also positively associated with receipt of ANC at non-governmental facilities, and delivery at a facility, skilled provider at birth and Cesarean delivery. After adjusting for sociodemographic and health system factors, receipt of the HepB-BD was positively associated with weekly media exposure, receipt of recommended ANC, and Cesarean delivery, and inversely associated with home delivery. CONCLUSIONS: Both socioeconomic and health systems factors influenced suboptimal and inequitable vaccination coverage. Improved access to quality ANC and delivery services may increase HepB-BD coverage although targeted approaches to reach home births are likely required to achieve national goals.

Learning Neuroscience with Technology: A Scaffolded, Active Learning Approach.

Mobile applications (apps) for learning technical scientific content are becoming increasingly popular in educational settings. Neuroscience is often considered complex and challenging for most students to understand conceptually. iNeuron is a recently developed iOS app that teaches basic neuroscience in the context of a series of scaffolded challenges to create neural circuits and increase understanding of nervous system structure and function. In this study, four different ways to implement the app within a classroom setting were explored. The goal of the study was to determine the app's effectiveness under conditions closely approximating real-world use, and to evaluate whether collaborative play and student-driven navigational features contributed to its effectiveness. Students used the app either individually or in small groups, and used a version with either a fixed or variable learning sequence. Student performance on a pre- and post- neuroscience content assessment was analyzed and compared between students who used the app and a control group receiving standard instruction, and logged app data were analyzed. Significantly greater learning gains were found for all students who used the app compared to control. All four implementation modes were effective in producing student learning gains relative to controls, but did not differ in their effectiveness to one another. In addition, students demonstrated transfer of information learned in one context to another within the app. These results suggest that teacher-led neuroscience instruction can be effectively supported by a scaffolded, technology-based curriculum which can be implemented in multiple ways to enhance student learning.

Stereotactic Body Radiation Therapy for Primary Renal Cell Carcinoma: A Case-Based Radiosurgery Society Practice Guide.

Traditionally, renal cell carcinoma (RCC) was considered a radioresistant tumor, thereby limiting definitive radiation therapy management options. However, several recent studies have demonstrated that stereotactic body radiation therapy (SBRT) can achieve high rates of local control for the treatment of primary RCC. In the setting of expanding use of SBRT for primary RCC, it is crucial to provide guidance on practical considerations such as patient selection, fractionation, target delineation, and response assessment. This is particularly important in challenging scenarios where a paucity of evidence exists, such as in patients with a solitary kidney, bulky tumors, or tumor thrombus. The Radiosurgery Society endorses this case-based guide to provide a practical framework for delivering SBRT to primary RCC, exemplified by 3 cases. This article explores topics of tumor size and dose fractionation, impact on renal function and treatment in the setting of a solitary kidney, and radiation's role in the management of inferior vena cava tumor thrombus. Additionally, we review existing evidence and expert opinion on target delineation, advanced techniques such as magnetic resonance imaging guided SBRT, and SBRT response assessment.

Identifying and preventing fraudulent responses in online public health surveys: Lessons learned during the COVID-19 pandemic.

Web-based survey data collection has become increasingly popular, and limitations on in-person data collection during the COVID-19 pandemic have fueled this growth. However, the anonymity of the online environment increases the risk of fraudulent responses provided by bots or those who complete surveys to receive incentives, a major risk to data integrity. As part of a study of COVID-19 and the return to in-person school, we implemented a web-based survey of parents in Maryland between December 2021 and July 2022. Recruitment relied, in part, on social media advertisements. Despite implementing many existing best practices, we found the survey challenged by sophisticated fraudsters. In response, we iteratively improved survey security. In this paper, we describe efforts to identify and prevent fraudulent online survey responses. Informed by this experience, we provide specific, actionable recommendations for identifying and preventing online survey fraud in future research. Some strategies can be deployed within the data collection platform such as careful crafting of survey links, Internet Protocol address logging to identify duplicate responses, and comparison of client-side and server-side time stamps to identify responses that may have been completed by respondents outside of the survey's target geography. Other strategies can be implemented during the survey design phase. These approaches include the use of a 2-stage design in which respondents must be eligible on a preliminary screener before receiving a personalized link. Other design-based strategies include within-survey and cross-survey validation questions, the addition of "speed bump" questions to thwart careless or computerized responders, and the use of optional open-ended survey questions to identify fraudsters. We describe best practices for ongoing monitoring and post-completion survey data review and verification, including algorithms to expedite some aspects of data review and quality assurance. Such strategies are increasingly critical to safeguarding survey-based public health research.

Benign mucinous metaplasia of the genital mucosa: histomorphological and immunohistochemical features and criteria for differentiation from extramammary Paget disease.

BACKGROUND: Benign mucinous metaplasia of the genitalia (BMM) is a rare condition typified by cells with foamy mucinous cytoplasm. Differential diagnoses include extramammary Paget disease (PD) and human papillomavirus (HPV)-induced vulval intraepithelial neoplasia (VIN) with mucinous differentiation. OBJECTIVES: To characterize histopathological and immunohistochemical features of BMM and to forge criteria for differentiation from PD and VIN with mucinous differentiation. METHODS: Eight biopsy specimens of BMM were stained with haematoxylin and eosin, periodic acid-Schiff and alcian blue, and for cytokeratin (CK) 7, CK10, CK14, CK20, carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), S100, gross cystic disease fluid protein-15 (GCDFP-15), lysozyme and Ki67 and compared with PD. Polymerase chain reaction was performed in order to identify HPV-specific DNA. RESULTS: BMM showed mucin deposition in superficial epithelial layers ranging from numerous large goblet cells to subtle deposits. The epithelium often showed polygonal (squamoid) or cuboidal differentiation while columnar differentiation was an inconsistent feature. A band-like inflammatory infiltrate was consistently present. Metaplastic epithelium consistently expressed CK7, CEA and EMA either in the entire epithelium or in a superficial band, while CK14, CK10, GCDFP-15 and lysozyme were largely not expressed, and staining for CK20 and S100 was negative. Comparison with PD demonstrated similar staining characteristics, but in a scattered pattern of mucinous cells within preserved squamous epithelium and not in a band-like pattern as in BMM. Nuclear pleomorphism and Ki67-positive mucinous cells in superficial epithelial layers were seen only in PD; GCDFP-15 and/or lysozyme were expressed in the majority of cases of PD. No evidence of HPV-specific DNA was found in BMM. CONCLUSIONS: The spectrum of changes in BMM is distinctive, and BMM can be differentiated with surety from both PD and VIN with mucinous differentiation.

[The long journey from palpation to biopsy : The history of diagnosing prostate cancer]. / Der lange Weg von der Palpation zur Biopsie : Zur Geschichte der Prostatakarzinomdiagnostik.

Though it is thousands of years old, prostate cancer (PCa) has only been known for 200 years. Until about 50 years ago, the diagnosis could only be made by digital rectal examination. Although the first prostate biopsies were already implemented in the beginning of the last century, it only obtained importance with the introduction of prostate-specific antigen (PSA) testing in the early screening for PCa and the pathologist, thus, became an essential partner for the urologist. In more recent years, specific MRI has significantly increased the accuracy of prostate biopsies. Thus, the question arises whether this technique is going to be so meaningful one day that prostate biopsy and the associated pretherapeutic histology are going to be redundant.

Zero Preventable Deaths by 2020: Analysis of Prehospital and Emergency Department Deaths Following Penetrating Trauma Stratified by Anatomic Location.

INTRODUCTION: Preventable deaths following trauma are high and unchanged over the last two decades. The objective of this study was to describe the location of death in patients with penetrating trauma, stratified by anatomic location of injury, in order to better tailor our approach to reducing preventable deaths from trauma. METHODS: This retrospective analysis of a prospectively maintained trauma registry included consecutive adult trauma activations with penetrating trauma at a level 1 trauma center between 07/2012 and 03/2018. Injuries were categorized as extremity, junctional, and torso. Head and neck injuries were excluded. Patients injured in >1 defined location were categorized as "multiple." Location of death was defined as on-scene, emergency department (ED), or hospital. Two-sided χ2 tests were used to compare groups. Multivariate analysis was performed using logistic regression. RESULTS: A total of 1024 patients were included with an overall case fatality rate (CFR) of 7.8%. The CFR following extremity injury (3.0%) was significantly lower than all other injury sites (P = .02).There were no significant differences in CFR for junctional (10.4%), torso (8.3%), or multiple injuries (9.6%). Forty percent of fatalities following junctional injury occurred on-scene and an additional 20% occurred in the ED. DISCUSSION: To our knowledge, this is the first study to describe location of death stratified by anatomic location of injury. There was no difference in the CFRs of junctional and torso injuries, and a large proportion of deaths occurred prior to reaching the hospital or in the trauma bay. These findings support reevaluating the classical algorithms and care pathways for patients with proximal penetrating trauma.

Oculocardiac Reflex During ROP Exams.

PURPOSE: Reducing physiologic stress including bradycardia during staging eye exams for retinopathy of prematurity (ROP) is desirable. We observed heart rate change during routine retinopathy of prematurity eye examinations and compared the response with our ongoing study of oculocardiac reflex (OCR) elicited by uniform EOM tension during strabismus surgery. PATIENTS AND METHODS: Electrocardiograph was prospectively monitored during ROP exams featuring indirect ophthalmoscopy with Alfonso lid speculum and see-through scleral depressor without topical anesthesia. Clinical data were retrieved from ROP-Check software. OCR was defined as maximally changed heart rate (HR) as a percent of baseline. Strabismus surgery patients under general anesthesia served as controls. RESULTS: From 10/2017 to 9/2020, 281 infants had ROP exams, and the median OCR was 55.9% of baseline HR (IQR 41.4% to 72.6%), the kurtosis 0.93 and skewness 1.01 representing a drop from HR 169 ± 16 bpm to 102 ± 39 bpm. In comparison, 1493 adult and pediatric strabismus surgery patients had less OCR median bradycardia 87.8% (IQR 72-98%), kurtosis 1.60 and skewness -1.18. ROP %OCR correlated with birth gestational age (%OCR = 2.5 (GA) - 11, r(279)=0.33, p<0.01) and with birthweight (%OCR = 0.02 (BW) + 38, r(279) =0.35, p<0.01). The duration of bradycardia induced by ROP exam averaged 92 ± 34 seconds (range 34-240 seconds). CONCLUSION: Bradycardia is common during eye exams in the smallest premature infants with greater degree, more rapid onset and longer duration than OCR during strabismus surgery.

Human chorionic gonadotropin: its possible role in maternal lymphocyte suppression.

Human chorionic gonadotropin completely inhibits the response of lymphocytes to phytohemagglutinin. The effect is both reversible and noncytotoxic. These observations support the theory that the fetus is accepted because human chorionic gonadotropin represents trophoblastic surface antigen and blocks the action of maternal lymphocytes.

Interaction of choriocarcinoma cells and human peripheral blood lymphocytes. Resistance of cultured choriocarcinoma cells to cell-mediated cytotoxicity by mitogen-activated lymphocytes.

Cultured choriocarcinoma (Be Wo) cells exist that share many of the morphologic and bio-synthetic properties of normal human trophoblasts. In an attempt to develop a model for the immunologic relationship between a sensitized mother and fetus, we mixed Be Wo cells with mitogen-activated cytotoxic lymphocytes in vitro. Be Wo cells were resistant to the cytolytic effects of the activated lymphocytes despite 24-h exposure and intimate cell-to-cell contact as determined by microscopy. Control target cells, a line of human hepatoma cells, were readily destroyed. Cytotoxicity was measured by determining residual radioactivity of [(3)H]thymidine-labeled target cells after exposure to activated lymphocytes. Employing the quantitative assay, we confirmed the morphologic results and showed that Be Wo and a number of other choriocarcinoma cell lines were resistant to the cytotoxic effects of lymphocytes activated by phytohemagglutinin, pokeweed mitogen, and allogeneic cells in mixed lymphocyte cultures. Moreover, Be Wo cells were resistant to injury over a wide range of killer to target cell ratios. Significant killing of the Be Wo cells occurred only after prolonged exposure (48 and 72 h) to the activated lymphocytes. We suggest that one mechanism that may assist the fetus (or a choriocarcinoma) in its immunologic survival is the intrinsic resistance of trophoblast cells to lymphocyte-mediated cytotoxicity.

The Wiskott-Aldrich syndrome. Results of transfer factor therapy.

12 patients with Wiskott-Aldrich syndrome were treated with therapeutic doses of transfer factor in an attempt to induce cellular immunity. Clinical improvement was noted after transfer factor therapy in 7 of the 12 patients treated. Because this disease has a variable course and temporary spontaneous improvement can occur, the observed improvement cannot necessarily be attributed to the transfer factor. However, in two patients repeated remissions consistently followed transfer factor administration on repeated occasions. This included freedom from infections, regression of splenomegaly, and clearing of eczema. An unexpected finding was a decrease in bleeding in 3 of the 10 patients who had bleeding. Conversion of skin reactivity was obtained in all seven patients who clinically seemed to respond to transfer factor. In vitro studies performed after the administration of transfer factor demonstrated that the lymphocytes of the patients now produced migration inhibitory factor in response to appropriate test antigens, but did not undergo increased radioactive thymidine incorporation in response to the same antigens. A defect in the monocyte IgG receptors has been found in certain patients with the disease, and the current study shows that all patients with defective monocyte IgG receptors responded to transfer factor, whereas only one patient with normal receptors showed any response. This test may thus prove to be useful in predicting the results of transfer factor therapy in patients with Wiskott-Aldrich syndrome, although evaluation of a larger series of patients will be necessary to confirm this point. We conclude that cellular immunity can be induced, that there appears to be clinical benefit in certain patients with Wiskott-Aldrich syndrome by the use of transfer factor, and that this mode of therapy warrents trial in these patients and others with defects of cellular immunity.

Changes in clonal expression during the course of acute leukemia: possible subsets in childhood leukemia.

We studied cell surface markers and chromosomes in the leukemia cells of a boy with the initial diagnosis of acute lymphocytic leukemia during 18 months from diagnosis to demise. During this time he received induction therapy, underwent bone marrow transplantation, and relapsed. The leukemia cells expressed three membrane phenotypes during different stages of disease: T-cell at diagnosis; T-cell, B-cell, and monocyte during the induction period; T-cell in the first relapse after bone marrow transplantation; and T-cell and B-cell during the terminal stage. Some cells expressed markers of two cell types, indicating a common origin of these cells. Cytogenetic studies during post-transplantation relapse showed abnormal marker chromosomes that indicated two major sublines. However, there was enough sharing of other aberrant chromosomes to suggest that these two populations presented sublines within the same neoplastic clone. We suggest that these leukemia cells were derived from a pluripotential cell prior to differentiation into cells of the lymphoid and monocytic series. This particular case may represent a subset of acute leukemia and may account for the resistance to conventional therapy.

Bone marrow transplantation for childhood Ki-1 lymphoma.

Two children with Ki-1 antigen-positive, non-Hodgkin's lymphoma received high-dose chemotherapy, fractionated total body irradiation (TBI), and allogeneic bone marrow transplantation. Both patients had relapsed multiple times on conventional chemotherapy and radiation therapy. Following transplantation, there was successful engraftment with disappearance of clinical signs and symptoms of their disease. As of June 1, 1989 they are in continuous unmaintained complete remission, 56 and 40 months, respectively, after bone marrow transplantation.

Treatment of advanced neuroblastoma with supralethal chemotherapy, radiation, and allogeneic or autologous marrow reconstitution.

Ten children with recurrent metastatic (stage IV) neuroblastoma received local radiation therapy, supralethal chemotherapy, and total-body irradiation. Rescue with infusions of either allogeneic (four patients) or autologous (six patients) bone marrow followed. The drugs given to the first two patients were individualized combinations based on previous tumor responses. Both patients died with recurrent tumor three and nine months posttransplant. The eight remaining patients were treated more uniformly with local irradiation, VM-26, doxorubicin, melphalan (L-phenylalanine mustard), and 1,000-rad total-body irradiation in three fractions. Two of these patients had cardiac dysfunction and received no doxorubicin. Three children died in the immediate posttransplant period with disseminated fungal infections. A fourth relapsed and died nine months posttransplant. As of December 1, 1983, two children who received allogeneic marrow grafts have survived in complete remission for 54 and 36 months, and two children who received autologous marrow grafts have survived in complete remission for 35 and 22 months. These results suggest that relapsed metastatic neuroblastoma can be controlled by supralethal combinations of chemotherapy and irradiation coupled with bone-marrow rescue.

Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors. The Children's Cancer Group.

PURPOSE: This study was designed to determine the toxicity, radiographic response rate, and outcome following high-dose thiotepa, etoposide, and autologous bone marrow rescue (ABMR) for young patients with recurrent malignant brain tumors. METHODS: Eligibility criteria required adequate renal, hepatic, and pulmonary function, and no bone marrow infiltration. Thiotepa 300 mg/m2 and etoposide 500 mg/ m2 were infused on 3 consecutive days, and autologous bone marrow was infused 72 hours following chemotherapy. RESULTS: Forty-five patients with recurrent high-grade brain tumors, aged 8 months to 36 years (median, 8 years), were treated. Seven patients (16%) died of treatment-related toxicities within 56 days of marrow reinfusion. Delayed platelet engraftment occurred in 44% of patients who survived beyond day 56. Of 35 patients with radiographically measurable disease who survived at least 28 days following ABMR, there were two complete responses (CRs) and six partial responses (PRs), for an overall response (CRs plus PRs) rate of 23% (SE = 7%). Objective responses were observed in four of 14 assessable patients with high-grade glioma and in two of six with primitive neuroectodermal tumors (PNETs)/ medulloblastoma. Survival was significantly improved in patients treated with minimal residual disease (P < .0005). Five of 18 patients (28%) with high-grade gliomas remain free of disease at 39+, 44+, 49+, 52+, and 59+ months post-ABMR. CONCLUSION: The combination of high-dose thiotepa and etoposide has activity against a variety of recurrent childhood brain tumors. These results merit further evaluation in children and young adults with both recurrent and newly diagnosed high-grade brain tumors.

Histological and ultrastructural findings in chloroquine-induced cardiomyopathy.

Light microscopic and ultrastructural findings in patients suffering from chloroquine-induced cardiomyopathy are reviewed. Based on our own observations in an autopsy case, functional and morphological similarities between chloroquine effects and hereditary lysosomal storage diseases are discussed.

Clinical and physiologic studies of two siblings with prekallikrein (Fletcher factor) deficiency.

Two siblings with hereditary Fletcher factor (prekallikrein) deficiency were studied for alterations of fibrinolysis, platelet function, skin inflammatory responses, permeability factor (PF/dil) formation and leukocyte chemotaxis. In vivo stimulation of fibrinolytic activity was normal; the bleeding time and platelet functions (adhesivity, aggregation, release reaction) were also normal. Both immediate (wheal-flare reaction to histamine, bradykinin, prostaglandin E1, physical agents) and delayed sensitivity skin test reactions were within normal limits. Migration of subjects' leukocytes to attractants in skin windows and in Boyden-type chambers was the same as that of control leukocytes. Serum complement components were essentially normal. One subject's leukocytes showed normal tissue factor production on stimulation by endotoxin, although prekallikrein deficiency did impair the endotoxin-stimulated generation of serum procoagulant activity. PF/dil caused increased vessel permeability in human skin; in vitro generation of PF/dil required both the Hageman factor and prekallikrein. The Fletcher factor-deficient subjects responded in a normal manner to PF/dil. Based on the Fletcher factor-coagulation assay, the biologic half-disappearance time of prekallikrein (after the transfusion of normal plasma in one of the subjects) was estimated at 35 hours. Therefore, these studies suggest that severe prekallikrein (Fletcher factor) deficiency in man is not associated with any clinically significant impairment in hemostasis, fibrinolysis, inflammatory responses or leukocyte function.