ABSTRACT
Treatment with ionizing radiation (IR) can lead to the accumulation of tumor-infiltrating regulatory T cells (Treg cells) and subsequent resistance of tumors to radiotherapy. Here we focused on the contribution of the epidermal mononuclear phagocytes Langerhans cells (LCs) to this phenomenon because of their ability to resist depletion by high-dose IR. We found that LCs resisted apoptosis and rapidly repaired DNA damage after exposure to IR. In particular, we found that the cyclin-dependent kinase inhibitor CDKN1A (p21) was overexpressed in LCs and that Cdkn1a(-/-) LCs underwent apoptosis and accumulated DNA damage following IR treatment. Wild-type LCs upregulated major histocompatibility complex class II molecules, migrated to the draining lymph nodes and induced an increase in Treg cell numbers upon exposure to IR, but Cdkn1a(-/-) LCs did not. Our findings suggest a means for manipulating the resistance of LCs to IR to enhance the response of cutaneous tumors to radiotherapy.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p21/metabolism , Langerhans Cells/radiation effects , Radiation, Ionizing , T-Lymphocytes, Regulatory/radiation effects , Animals , Cell Survival/genetics , Cell Survival/radiation effects , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p21/genetics , Flow Cytometry , Mice , Microarray Analysis , Polymerase Chain Reaction , T-Lymphocytes, Regulatory/cytology , T-Lymphocytes, Regulatory/immunology , Up-RegulationABSTRACT
Although much progress has been made in the understanding of the ontogeny and function of dendritic cells (DCs), the transcriptional regulation of the lineage commitment and functional specialization of DCs in vivo remains poorly understood. We made a comprehensive comparative analysis of CD8(+), CD103(+), CD11b(+) and plasmacytoid DC subsets, as well as macrophage DC precursors and common DC precursors, across the entire immune system. Here we characterized candidate transcriptional activators involved in the commitment of myeloid progenitor cells to the DC lineage and predicted regulators of DC functional diversity in tissues. We identified a molecular signature that distinguished tissue DCs from macrophages. We also identified a transcriptional program expressed specifically during the steady-state migration of tissue DCs to the draining lymph nodes that may control tolerance to self tissue antigens.
Subject(s)
Cell Differentiation/immunology , Cell Lineage/immunology , Dendritic Cells/immunology , Transcription, Genetic , Cell Differentiation/genetics , Dendritic Cells/cytology , Gene Expression Profiling , HumansABSTRACT
PURPOSE: AAPM Task Group No. 263U1 (Update to Report No. 263 - Standardizing Nomenclatures in Radiation Oncology) disseminated a survey to receive feedback on utilization, gaps, and means to facilitate further adoption. METHODS: The survey was created by TG-263U1 members to solicit feedback from physicists, dosimetrists, and physicians working in radiation oncology. Questions on the adoption of the TG-263 standard were coupled with demographic information, such as clinical role, place of primary employment (e.g., private hospital, academic center), and size of institution. The survey was emailed to all AAPM, AAMD, and ASTRO members. RESULTS: The survey received 463 responses with 310 completed survey responses used for analysis, of whom most had the clinical role of medical physicist (73%) and the majority were from the United States (83%). There were 83% of respondents who indicated that they believe that having a nomenclature standard is important or very important and 61% had adopted all or portions of TG-263 in their clinics. For those yet to adopt TG-263, the staffing and implementation efforts were the main cause for delaying adoption. Fewer respondents had trouble adopting TG-263 for organs at risk (29%) versus target (44%) nomenclature. Common themes in written feedback were lack of physician support and available resources, especially in vendor systems, to facilitate adoption. CONCLUSIONS: While there is strong support and belief in the benefit of standardized nomenclature, the widespread adoption of TG-263 has been hindered by the effort needed by staff for implementation. Feedback from the survey is being utilized to drive the focus of the update efforts and create tools to facilitate easier adoption of TG-263.
Subject(s)
Radiation Oncology , Terminology as Topic , Humans , Radiation Oncology/standards , Surveys and Questionnaires , Radiotherapy Planning, Computer-Assisted/methods , Radiotherapy Planning, Computer-Assisted/standards , Neoplasms/radiotherapy , Organs at Risk/radiation effects , Practice Guidelines as Topic , PerceptionABSTRACT
BACKGROUND: Cervical foraminal stenosis on MRI may be assessed using the Kim, modified Kim or Siller methods. This study aimed to investigate which morphological features of cervical foraminal stenosis in patients with cervical radiculopathy correlated best with pre-operative and post-operative surgical outcome following Anterior Cervical Discectomy (ACD) or a Posterior Cervical Foraminotomy (PCF). METHODS: Pre-operative MRIs of adults with cervical radiculopathy were assessed by six raters. The following measurements were made; uncompressed nerve root diameter, maximal compressed nerve root diameter, anterior & posterior compression, length of the neuroforaminal canal where the diameter was less than the uncompressed nerve root diameter and the distance of maximum compression from the apex of the ligamentum flavum. The Kim, modified Kim and Siller grades were calculated. Neck Disability Index (NDI) was measured pre-operatively and six weeks post-operatively. The radiological measurements and grades were compared to the pre-operative and change in NDI. RESULTS: Mean NDI was higher in female (58.2) than male patients (45.6) p = 0.05. No other baseline, operative or radiological factors where significantly associated with the pre-operative NDI. The mean [±SD] post-operative NDI was 14.3 [±22.5]. This represents a change of 37.8 (p < 0.001). The pre-operative NDI correlated strongly with the post-operative NDI but no other patient, operation or radiological factors correlated significantly. Neither pre-operative NDI or change in NDI was statistically different in those treated with ACD and those treated with PCF. CONCLUSION: There was no association between pre-operative NDI and any of the radiological measurements or radiological grades. Furthermore, whilst surgery significantly improved NDI, for those patients with anterior compression, there was no difference in outcome between those treated with an ACD and those treated with a PCF. Current axial MRIs do not adequately assess the cervical nerve root foramina or predict surgical approach, 3D isotropic acquisition and DTI should be explored.
ABSTRACT
Despite accumulating evidence suggesting local self-maintenance of tissue macrophages in the steady state, the dogma remains that tissue macrophages derive from monocytes. Using parabiosis and fate-mapping approaches, we confirmed that monocytes do not show significant contribution to tissue macrophages in the steady state. Similarly, we found that after depletion of lung macrophages, the majority of repopulation occurred by stochastic cellular proliferation in situ in a macrophage colony-stimulating factor (M-Csf)- and granulocyte macrophage (GM)-CSF-dependent manner but independently of interleukin-4. We also found that after bone marrow transplantation, host macrophages retained the capacity to expand when the development of donor macrophages was compromised. Expansion of host macrophages was functional and prevented the development of alveolar proteinosis in mice transplanted with GM-Csf-receptor-deficient progenitors. Collectively, these results indicate that tissue-resident macrophages and circulating monocytes should be classified as mononuclear phagocyte lineages that are independently maintained in the steady state.
Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Lung/immunology , Macrophage Colony-Stimulating Factor/metabolism , Macrophages/immunology , Adult , Animals , Bone Marrow Transplantation , Cell Proliferation , Cell Survival , Cells, Cultured , Homeostasis , Humans , Interleukin-4/metabolism , Macrophages/transplantation , Mice , Mice, Knockout , Mice, Mutant Strains , Parabiosis , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/geneticsABSTRACT
Colony stimulating factor-1 (Csf-1) receptor and its ligand Csf-1 control macrophage development, maintenance, and function. The development of both Langerhans cells (LCs) and microglia is highly dependent on Csf-1 receptor signaling but independent of Csf-1. Here we show that in both mice and humans, interleukin-34 (IL-34), an alternative ligand for Csf-1 receptor, is produced by keratinocytes in the epidermis and by neurons in the brain. Mice lacking IL-34 displayed a marked reduction of LCs and a decrease of microglia, whereas monocytes, dermal, and lymphoid tissue macrophages and DCs were unaffected. We identified IL-34 as a nonredundant cytokine for the development of LCs during embryogenesis as well as for their homeostasis in the adult skin. Whereas inflammation-induced repopulation of LCs appears to be dependent on Csf-1, once inflammation is resolved, LC survival is again IL-34-dependent. In contrast, microglia and their yolk sac precursors develop independently of IL-34 but rely on it for their maintenance in the adult brain.
Subject(s)
Interleukins/physiology , Langerhans Cells/immunology , Microglia/immunology , Stromal Cells/metabolism , Animals , Brain/immunology , Brain/metabolism , Cell Differentiation/genetics , Epidermis/immunology , Epidermis/metabolism , Homeostasis , Humans , Inflammation/genetics , Inflammation/immunology , Inflammation/metabolism , Interleukins/genetics , Interleukins/immunology , Interleukins/metabolism , Keratinocytes/immunology , Keratinocytes/metabolism , Langerhans Cells/cytology , Langerhans Cells/metabolism , Mice , Microglia/cytology , Microglia/metabolism , Psoriasis/chemically induced , Psoriasis/immunology , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Signal Transduction , Skin/immunology , Skin/metabolismABSTRACT
Traumatic brain injury (TBI) constitutes injury that occurs to the brain as a result of trauma. It should be appreciated as a heterogeneous, dynamic pathophysiological process that starts from the moment of impact and continues over time with sequelae potentially seen many years after the initial event. Primary traumatic brain lesions that may occur at the moment of impact include contusions, haematomas, parenchymal fractures and diffuse axonal injury. The presence of extra-axial intracranial lesions such as epidural and subdural haematomas and subarachnoid haemorrhage must be anticipated as they may contribute greatly to secondary brain insult by provoking brain herniation syndromes, cranial nerve deficits, oedema and ischaemia and infarction. Imaging is fundamental to the management of patients with TBI. CT remains the imaging modality of choice for initial assessment due to its ease of access, rapid acquisition and for its sensitivity for detection of acute haemorrhagic lesions for surgical intervention. MRI is typically reserved for the detection of lesions that may explain clinical symptoms that remain unresolved despite initial CT. This is especially apparent in the setting of diffuse axonal injury, which is poorly discerned on CT. Use of particular MRI sequences may increase the sensitivity of detecting such lesions: diffusion-weighted imaging defining acute infarction, susceptibility-weighted imaging affording exquisite data on microhaemorrhage. Additional advanced MRI techniques such as diffusion tensor imaging and functional MRI may provide important information regarding coexistent structural and functional brain damage. Gaining robust prognostic information for patients following TBI remains a challenge. Advanced MRI sequences are showing potential for biomarkers of disease, but this largely remains at the research level. Various global collaborative research groups have been established in an effort to combine imaging data with clinical and epidemiological information to provide much needed evidence for improvement in the characterisation and classification of TBI and in the identity of the most effective clinical care for this patient cohort. However, analysis of collaborative imaging data is challenging: the diverse spectrum of image acquisition and postprocessing limits reproducibility, and there is a requirement for a robust quality assurance initiative. Future clinical use of advanced neuroimaging should ensure standardised approaches to image acquisition and analysis, which can be used at the individual level, with the expectation that future neuroimaging advances, personalised to the patient, may improve prognostic accuracy and facilitate the development of new therapies.
Subject(s)
Brain Injuries/pathology , Brain Stem/pathology , Corpus Callosum/pathology , Diffuse Axonal Injury/diagnosis , Multimodal Imaging , Neuroimaging/methods , Subarachnoid Hemorrhage/diagnosis , Brain Injuries/complications , Diffuse Axonal Injury/etiology , Diffusion Magnetic Resonance Imaging , Diffusion Tensor Imaging , Glasgow Coma Scale , Humans , Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Multimodal Imaging/methods , Prognosis , Subarachnoid Hemorrhage/etiology , Tomography, X-Ray ComputedABSTRACT
PURPOSE: The demand for paediatric epilepsy surgery in the UK greatly exceeds the number of operations performed. Hence, Children's Epilepsy Surgery Service (CESS) was commenced in 2012. This study is aimed to characterise the changes in service delivery in the North East of England Paediatric Neuroscience Network and nationally. METHODS: A retrospective cohort study of paediatric epilepsy surgery in Leeds between 2005 and 2012 is presented followed by analysis of British Paediatric Neurosurgical Group (BPNG) data before and after CESS commissioning. RESULTS: During the study period, 42 children underwent epilepsy surgery in Leeds. The commonest aetiologies were neoplasm (33%), focal cortical dysplasia (19%) and mesial temporal sclerosis (19%). Seizure outcome was 71 % EngelI and 83% EngelI+II. Complications included one infection (2%), two temporary (5%) and one permanent (2%) motor deficits, three new/worsened visual field deficits (7%). There were six re-craniotomies (14%). The BPNG data show a 48% increase in paediatric epilepsy surgery in England between 2009 (90 cases) and 2012 (133 cases), and a 20% fall in 2013 (106 cases)--the first calendar year for CESS. On average, 64% of all operations were performed in London. CONCLUSIONS: The number of children receiving surgery for epilepsy in England had increased annually up to, and declined after, the establishment of CESS centres. The yearly caseload in neurosurgical units outside of London is small. The outcomes from Leeds are comparable to those published elsewhere. Other UK units are encouraged to publish outcomes to facilitate patient, commissioner and provider decision making.
Subject(s)
Epilepsy/surgery , Management Audit/methods , Management Audit/trends , Neurophysiological Monitoring/methods , Neurosurgical Procedures/methods , Child , Child, Preschool , Cohort Studies , Electroencephalography , England/epidemiology , Female , Humans , Male , Reference Values , Treatment OutcomeABSTRACT
OBJECTIVE: We utilized the National Cancer Database (NCDB) to evaluate trends and assess outcomes in radiation therapy (RT) boost modality and total dose among medically inoperable endometrial cancer (EC) patients with locoregional disease. METHODS: Patients with International Federation of Gynecology and Obstetrics (FIGO) stage I - IIIC2 inoperable EC treated with RT ± chemotherapy were analyzed. Practice patterns compared external beam RT (EBRT) versus high-dose-rate brachytherapy (BT) boost and total RT dose (palliative: ≤3000 cGy, definitive low dose [DLD]: 4500 - 6249 cGy, definitive high dose [DHD]: ≥6250 cGy) over time. Kaplan-Meier method evaluated overall survival (OS) and Cox proportional hazard modeling assessed variables associated with OS. RESULTS: NCDB included 1755 total cases, of which 1209 received a radiotherapy boost. From 2004 to 2019, boost modality rates differed with increasing utilization of BT consolidation and a decreasing rate of palliation. Predictors of a palliative dose were stage III disease, Black race, N2 disease, and poorly or undifferentiated grade. Multivariable analysis found BT boost was associated with lower mortality compared to EBRT (HR: 0.81, CI: 0.68-0.97; pâ¯=â¯0.019). Mortality rates were higher for palliation versus DHD. Additional factors associated with inferior survival were increasing age, worse Charlson-Deyo score, higher T stage, higher N stage, and moderately, poorly, or undifferentiated grade. CONCLUSIONS: Utilization of BT boost for locoregionally confined, medically inoperable EC has increased since 2004. Brachytherapy consolidation remains an effective RT modality for medically inoperable EC, associated with lower mortality compared to EBRT consolidation.
ABSTRACT
BACKGROUND: The degree of cervical foraminal stenosis on MRI scans may be measured and categorised using the Kim or modified Kim methods. These grading scales have not previously been validated in a cohort of patients awaiting surgery. OBJECTIVES: To establish the normal foraminal and root diameters as well as the consistency of inter and intra-rater grading using the Kim and modified Kim grading systems in pre-operative surgical patients. METHODS: Asymptomatic cervical nerve roots and foramina demonstrated on the pre-operative MRI scans of adult surgical patients with cervical radiculopathy were measured and categorised by six raters using the Kim and modified Kim grading methods. Repeat "second pass" measurements were made by the same assessors on the same images a minimum of one month later. RESULTS: Foraminal diameters (mm) in asymptomatic foramina were C2/C3 (mean±SD): 4.18±1.44, C3/C4 2.96±1.23, C4/C5 3.02±1.19, C5/C6 3.15±1.33, C6/C7 3.53±1.36, C7/T1 3.93±1.34. Nerve root diameters were C3 3.11±0.87, C4 2.95±0.77, C5 2.56±0.73, C6 2.26±0.76, C7 2.56±0.82, C8 3.83±0.86. Inter-rater consistency was kappa [95% CI]: Kim 0.01 [0.00, 0.03], modified Kim 0.08 [0.05, 0.10]. Intra-rater consistency was kappa [95% CI]: Kim 0.81 [0.77, 0.86], modified Kim 0.69 [0.62, 0.76]. CONCLUSION: There was poor inter-rater consistency but good intra-rater consistency when assessing the severity of foraminal stenosis on axial T2 MRI scans. Foraminal diameter was narrowest at C3/C4 and C4/C5, whereas the smallest root diameter was C5/C6. Volumetric or oblique MR may improve consistency.
ABSTRACT
INTRODUCTION: This retrospective study aimed to determine the percentage of MRI-detected breast cancers diagnosed using targeted ultrasound and standard 14-gauge (14g) biopsy in the setting of an Australian breast MRI service. This is of clinical relevance because malignancies not identifiable on mammography or by ultrasound may then require more invasive, technically demanding and costly MRI-guided interventional procedures, usually by large-core vacuum-assisted biopsy (VAB) or hook-wire localisation with open surgical biopsy. METHODS: On review of the 12-year period 2006-2018, we identified 67 new breast cancer events in 64 women where the diagnosis was made on the basis of the MRI scan findings either alone (n = 60) or in combination with a concurrent mammogram (n = 7), with no recorded clinical abnormality. The percentage in which malignancy was confirmed on histopathology using targeted ultrasound in combination with 14g biopsy was determined versus other biopsy methods, for both invasive cancer and in situ disease. RESULTS: Ultrasound-guided 14g biopsy was successful in establishing the presence of malignancy in 42/46 (91%) of events with a final diagnosis of invasive cancer, with 2 more proven by MRI-guided interventional procedures (1 VAB and 1 hook-wire) and 1 by open surgical biopsy. In the final case, a 5 mm focus on MRI with no sonographic correlate at the initial presentation was only identified and biopsied by ultrasound at 12-month follow-up. For events with a final diagnosis of DCIS/pLCIS (pleomorphic LCIS, n = 2), US-guided 14g biopsy was successful in 10/21 (48%), while 4/7 events with corresponding mammographic microcalcifications were proven by x-ray stereotactic interventions. A further 5 events had MRI-guided interventions (3 VAB and 2 hook-wires) and 1 an open surgical biopsy to confirm malignancy. In the final case (a woman with a 30 × 20 mm focal area of non-mass enhancement with corresponding microcalcifications consistent with DCIS), a pathologic diagnosis was not made until the patient presented 5 years later with invasive disease. There were also 3 instances of upgrades to invasion on final surgical pathology, one from pLCIS to microinvasion and 2 others from DCIS to IDC. Among the DCIS/pLCIS events, semi-random 14g core biopsy (sampling at the expected location of the MRI abnormality without a specific sonographic correlate) proved to be successful in 3 women. CONCLUSION: Ultrasound-guided 14g core biopsy established a malignant diagnosis in 91% of invasive cancers and in 48% of DCIS/pLCIS cases. This relatively non-invasive, technically easy to perform and low-cost biopsy procedure can be used immediately when targeted ultrasound shows a correlate for a suspicious MRI scan finding. Careful imaging-pathologic correlation is required after 14g biopsy, and a discordant result will usually prompt recourse to an MRI-guided VAB or hook-wire localisation.
Subject(s)
Breast Neoplasms , Calcinosis , Carcinoma, Intraductal, Noninfiltrating , Australia , Biopsy, Large-Core Needle , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/diagnostic imaging , Carcinoma, Intraductal, Noninfiltrating/pathology , Female , Humans , Image-Guided Biopsy , Magnetic Resonance Imaging , Mammography , Retrospective StudiesABSTRACT
Identification and assessment of extramammary findings on contrast-enhanced breast MRI scans is particularly important in the setting of newly diagnosed invasive cancer as metastatic lesions may be encountered in the liver, lungs, pleural cavity or bones. Establishing that stage IV disease is present has a profound effect on patient management. The sternum is routinely included on breast MRI studies and can be an early site for breast cancer metastases. These appear as enhancing lesions with high signal on fat-suppressed T2-weighted images. However, incidental benign lesions, notably haemangiomas, may also be encountered, and careful analysis is required to avoid false-positive results. Clinical context is important with a much lower likelihood of malignancy in the setting of routine screening of young women with no personal history of breast cancer. This pictorial essay illustrates findings encountered with lesions in the sternum and offers insights into how to interpret and manage them.
Subject(s)
Breast Neoplasms , Breast , Breast/pathology , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Female , Humans , Magnetic Resonance Imaging/methods , Radiography , Sternum/diagnostic imaging , Sternum/pathologyABSTRACT
PURPOSE: We previously reported on the clinical outcomes of treating oligometastases with radiation using an elective simultaneous integrated boost technique (SIB), delivering higher doses to known metastases and reduced doses to adjacent bone or nodal basins. Here we compare outcomes of oligometastases receiving radiation targeting metastases alone (MA) versus those treated via an SIB. METHODS: Oligometastatic patients with ≤5 active metastases treated with either SIB or MA radiation at two institutions from 2013 to 2019 were analyzed retrospectively for treatment-related toxicity, pain control, and recurrence patterns. Tumor metastasis control (TMC) was defined as an absence of progression in the high dose planning target volume (PTV). Marginal recurrence (MR) was defined as recurrence outside the elective PTV but within the adjacent bone or nodal basin. Distant recurrence (DR) was defined as any recurrence that is not within the PTV or surrounding bone or nodal basin. The outcome rates were estimated using the Kaplan-Meier method and compared between the two techniques using the log-rank test. RESULTS: 101 patients were treated via an SIB to 90 sites (58% nodal and 42% osseous) and via MA radiation to 46 sites (22% nodal and 78% osseous). The median follow-up among surviving patients was 24.6 months (range 1.4-71.0). Of the patients treated to MA, the doses ranged from 18 Gy in one fraction (22%) to 50 Gy in 10 fractions (50%). Most patients treated with an SIB received 50 Gy to the treated metastases and 30 Gy to the elective PTV in 10 fractions (88%). No acute grade ≥3 toxicities occurred in either cohort. Late grade ≥3 toxicity occurred in 3 SIB patients (vocal cord paralysis and two vertebral body compression), all related to the high dose PTV and not the elective volume. There was similar crude pain relief between cohorts. The MR-free survival rate at 2 years was 87% (95% CI: 70%, 95%) in the MA group and 98% (95% CI: 87%, 99%) in the SIB group (p = 0.07). The crude TMC was 89% (41/46) in the MA group and 94% (85/90) in the SIB group. There were no significant differences in DR-free survival (65% (95% CI: 55-74%; p = 0.24)), disease-free survival (60% (95% CI: 40-75%; p = 0.40)), or overall survival (88% (95% CI: 73-95%; p = 0.26)), between the MA and SIB cohorts. CONCLUSION: Both SIB and MA irradiation of oligometastases achieved high rates of TMC and similar pain control, with a trend towards improved MR-free survival for oligometastases treated with an SIB. Further investigation of this technique with prospective trials is warranted.
ABSTRACT
BACKGROUND: Osteolytic lesions are present in 75% of patients with multiple myeloma (MM) and frequently require palliation with radiation therapy (RT). Prior case series of patients with MM with bone pain undergoing palliative RT suggests doses ≥12 Gy (equivalent dose in 2Gy fractions, EQD2) provide excellent bone pain relief. However, recent advances in care and novel biologic agents have significantly improved overall survival and quality of life for patients with MM. We hypothesized that lower-dose RT (LDRT, EQD2 <12 Gy) offers an effective alternative to higher-dose RT (HDRT, EQD2 ≥12 Gy) for palliation of painful, uncomplicated MM bone lesions. METHODS: We retrospectively identified patients with MM treated with RT for uncomplicated, painful bone lesions and stratified by EQD2 ≥/< 12 Gy. Clinical pain response (CPR) rates, acute and late toxicity, pain response duration, and retreatment rates between LDRT and HDRT groups were analyzed. RESULTS: Thirty-five patients with 70 treated lesions were included: 24 patients (48 lesions) treated with HDRT and 11 patients (22 lesions) with LDRT. Median follow-up was 14 and 16.89 months for HDRT and LDRT, respectively. The median dose of HDRT treatment was 20 Gy versus 4 Gy in the LDRT group. The CPR rate was 98% for HDRT and 95% for LDRT. There was no significant difference in any-grade acute toxicity between the HDRT and LDRT cohorts (24.5% vs 9.1%, Χ2 Pâ¯=â¯.20). Pain recurred in 10% of lesions (12% HDRT vs 9.5% LDRT). Median duration of pain response did not significantly differ between cohorts (Pâ¯=â¯.91). Five lesions were retreated, 2 (9.5%) in the LDRT cohort, and 3 (6.3%) in the HDRT cohort. CONCLUSION: In this study, LDRT effectively palliated painful, uncomplicated MM bony lesions with acceptable CPR and duration of palliation. These data support prospective comparisons of LDRT versus HDRT for palliation of painful, uncomplicated MM bony lesions.
ABSTRACT
The unfolded protein response (UPR) is an evolutionary conserved adaptive mechanism that permits cells to react and adjust to conditions of endoplasmic reticulum (ER) stress. In addition to UPR, phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal regulated kinase (ERK) signaling pathways protect a variety of cells from ER stress. The goal of the present study was to assess the susceptibility of chondrocytes to ER stress and to determine the signaling pathways involved in their survival. We found that low concentration of thapsigargin (10 nM) reduced the viability of a chondrocyte cell line (N1511 cells) and that these cells were approximately 100 fold more susceptible to thapsigargin-induced stress than fibroblasts. Interestingly, in thapsigargin and tunicamycin-stressed chondrocytes induction of the proapoptotic transcription factor CHOP preceded that of the anti-apoptotic BiP by 12 h. Although both of these agents caused sustained Akt and ERK phosphorylation; inhibition of Akt phosphorylation sensitized chondrocytes to ER stress, while blocking ERK signaling by U0126 had no effect. We found that Akt-1, but not Akt-2 or Akt-3, is predominantly expressed in N1511 chondrocytes. Furthermore, siRNA-mediated knockdown of Akt-1 sensitized chondrocytes to ER stress, which was associated with increased capsase-3 activity and decreased Bcl(XL) expression. These data suggest that under condition of ER stress, multiple signaling processes regulate chondrocyte's survival-death decisions. Thus, rapid upregulation of CHOP likely contributes to chondrocyte death, while Akt-1-mediated inactivation of caspase 3 and induction of BclXL promotes survival.
Subject(s)
Chondrocytes/enzymology , Endoplasmic Reticulum/enzymology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Stress, Physiological , Animals , Bone Morphogenetic Protein 2/metabolism , Butadienes/pharmacology , Caspase 3/metabolism , Cell Line , Cell Survival , Chondrocytes/drug effects , Chondrocytes/pathology , Chromones/pharmacology , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum Chaperone BiP , Enzyme Inhibitors/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , Heat-Shock Proteins/metabolism , Mice , Morpholines/pharmacology , Nitriles/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors , Phosphorylation , Proto-Oncogene Proteins c-akt/genetics , RNA Interference , Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & inhibitors , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism , Signal Transduction/drug effects , Thapsigargin/pharmacology , Time Factors , Transcription Factor CHOP/metabolism , Tunicamycin/pharmacology , Unfolded Protein Response , bcl-X Protein/metabolismABSTRACT
PURPOSE: Fiberoptic laryngoscopy (FOL) is a critical tool for the diagnosis, staging, assessment of treatment response, and detection of recurrence for head and neck (H&N) malignancies. No standardized recommendations exist for procedural FOL education in radiation oncology. We therefore implemented a pilot simulation workshop to train radiation oncology residents in pertinent H&N anatomy and FOL technique. METHODS AND MATERIALS: A 2-phase workshop and simulation session was designed. Residents initially received a lecture on H&N anatomy and the logistics of the FOL examination. Subsequently, residents had a practical session in which they performed FOL in 2 simulated environments: a computerized FOL program and mannequin-based practice. Site-specific attending physicians were present to provide real-time guidance and education. Pre- and postworkshop surveys were administered to the participants to determine the impact of the workshop. Subsequently, postgraduate year (PGY)-2 residents were required to complete 6 supervised FOL examinations in clinic and were provided immediate feedback. RESULTS: Annual workshops were performed in 2017 to 2019. The survey completion rate was 14 of 18 (78%). Participants ranged from fourth-year medical students to PGY-2 to PGY-5 residents. All PGY-2 residents completed their 6 supervised FOL examinations. On a 5-point Likert scale, mean H&N anatomy knowledge increased from 2.4 to 3.7 (standard deviation = 0.6, P < .0001). Similarly, mean FOL procedural skill confidence increased from 2.2 to 3.3 (standard deviation = 0.7, P < .0001). These effects were limited to novice (fourth-year medical students to PGY-2) participants. All participants found the exercise clinically informative. CONCLUSIONS: A simulation-based workshop for teaching FOL procedural skills increased confidence and procedural expertise of new radiation oncology residents and translated directly to supervised clinical encounters. Adoption of this type of program may help to improve resident training in H&N cancer.
Subject(s)
Fiber Optic Technology/education , Head and Neck Neoplasms/diagnosis , Internship and Residency , Laryngoscopy/education , Radiation Oncology/education , Simulation Training/organization & administration , Feasibility Studies , Humans , Students, MedicalABSTRACT
Purpose: To perform a multi-institutional analysis following treatment of limited osseous and/or nodal metastases in patients using a novel hypofractionated image-guided radiotherapy with simultaneous-integrated boost (HIGRT-SIB) technique. Methods: Consecutive patients treated with HIGRT-SIB for ≤5 active metastases at Duke University Medical Center or Durham Veterans' Affairs Medical Center between 2013 and 2018 were analyzed to determine toxicities and recurrence patterns following treatment. Most patients received 50 Gy to the PTVboost and 30 Gy to the PTVelect simultaneously in 10 fractions. High-dose treatment volume recurrence (HDTVR) and low-dose treatment volume recurrence (LDTVR) were defined as recurrences within PTVboost and PTVelect, respectively. Marginal recurrence (MR) was defined as recurrence outside PTVelect, but within the adjacent bone or nodal chain. Distant recurrence (DR) was defined as recurrences not meeting HDTVR, LDTVR, or MR criteria. Freedom from pain recurrence (FFPR) was calculated in patients with painful osseous metastases prior to HIGRT-SIB. Outcome rates were estimated at 12 months using the Kaplan-Meier method. Results: Forty-two patients met inclusion criteria with 59 sites treated with HIGRT-SIB (53% nodal and 47% osseous). Median time from diagnosis to first metastasis was 31 months and the median age at HIGRT-SIB was 69 years. The most common primary tumors were prostate (36%), gastrointestinal (24%), and lung (24%). Median follow-up was 11 months. One acute grade ≥3 toxicity (febrile neutropenia) occurred after docetaxel administration immediately following HIGRT-SIB. Four patients developed late grade ≥3 toxicities: two ipsilateral vocal cord paralyzes and two vertebral compression fractures. The overall pain response rate was 94% and the estimated FFPR at 12 months was 72%. The estimated 12 month rate of HDTVR, LDTVR, MR, and DR was 3.6, 6.2, 7.6, and 55.8%, respectively. DR preceded MR, HDTVR, or LDTVR in each instance. The estimated 12 month probability of in-field and marginal control was 90.0%. Conclusion: Targeting areas at high-risk for occult disease with a lower radiation dose, while simultaneously boosting gross disease with HIGRT in patients with limited osseous and/or nodal metastases, has a high rate of treated metastasis control, a low rate of MR, acceptable toxicity, and high rate of pain palliation. Further investigation with prospective trials is warranted.
ABSTRACT
OBJECTIVES:: To examine whether the model of Getting It Right First Time (GIRFT) could be relevant to the surveillance of non-operated vestibular schwannomas (vs) by testing the following hypotheses: (1) in the UK there is a great variation in the imaging protocol for the follow-up of vs; (2) high-resolution, T 2 weighted MRI (HRT 2W-MRI) has an equivalent accuracy to gadolinium-enhanced T 1 weighted MRI (Gd-MRI) in the assessment of vs size and; (3) imaging with HRT 2W-MRI rather than Gd-MRI could offer financial savings. METHODS:: Two neuroradiologists independently performed measurements of 50 vs imaged with HRT 2W-MRI and Gd-MRI. Differences in mean tumour measurements between HRT 2W-MRI and Gd-MRI were determined, as were intra- and interobserver concordance. Level of agreement was measured using Bland-Altman plots. Consultant neuroradiologists within 30 adult neurosurgical units in the UK were contacted via email and asked to provide the MRI protocol used for the surveillance of non-operated vs in their institution. The financial difference between scanning with HRT 2W-MRI and Gd-MRI was determined within Leeds Teaching Hospitals NHS Trust. RESULTS:: There was no statistically significant difference in the mean diameter of vs size, measured on HRT 2W-MRI and Gd-MRI (p = 0.28 & p = 0.74 for observers 1 and 2 respectively). Inter- and intraobserver concordance were excellent (Interclass correlation coefficient = 0.99, Interclass correlation coefficient ≥ 0.98 respectively). Differences between the two sequences were within limits of agreement. 26 of 30 UK neuroscience centres (87 % response rate) provided imaging protocols. 16 of the 26 (62%) centres use Gd-MRI for the surveillance of vs. HRT 2-MRI is £36.91 cheaper per patient than Gd-MRI. CONCLUSION:: Variation exits across UK centres in the imaging surveillance of non-operated vs. HRT 2W-MRI and Gd-MRI have equivalent accuracy when measuring vs. Imaging with HRT 2W-MRI rather than Gd-MRI offers potential financial savings. ADVANCES IN KNOWLEDGE:: This study highlights the potential health and economic benefits of a national standardized imaging protocol for the surveillance of non-operated vs.