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According to the study’s results, various preparation designs exhibited distinct. frequencies of modes of failure. Nevertheless, these differences were not significant. More than half of the restoration fractures noted in this study involved damage to both the die and the restorative material. This observation is consistent with the results documented in previous studies by Johnson et al., And Alberto et al., .
|
PMC11699763_p44
|
PMC11699763
|
Discussion
| 3.270719 |
biomedical
|
Study
|
[
0.9947659969329834,
0.0006376056117005646,
0.004596333019435406
] |
[
0.9986826777458191,
0.0007340278825722635,
0.0005128327757120132,
0.00007034884038148448
] |
en
| 0.999997 |
This study had several limitations. These limitations include that it was conducted in vitro, differing from a clinical setting where factors such as saliva and restricted access for the scanner inside the oral cavity would affect the precision of scanning prepared teeth. The internal adaptability was not evaluated in the study and faced challenges in accurately simulating a clinical setting.
|
PMC11699763_p45
|
PMC11699763
|
Discussion
| 2.650472 |
biomedical
|
Study
|
[
0.9981544613838196,
0.0007190207834355533,
0.0011264246422797441
] |
[
0.9969664216041565,
0.002499002730473876,
0.00032925832783803344,
0.00020538599346764386
] |
en
| 0.999999 |
According to the results of this research:
|
PMC11699763_p46
|
PMC11699763
|
Conclusions
| 1.454425 |
biomedical
|
Other
|
[
0.6318063735961914,
0.002230460988357663,
0.3659631907939911
] |
[
0.2275983840227127,
0.7651280760765076,
0.0058509353548288345,
0.0014225952327251434
] |
en
| 0.999997 |
All tested groups showed marginal fit results within clinically acceptable parameters. All preparation designs utilized in this study for creating overlay restorations from ALD ceramics demonstrated acceptable fracture resistance. Higher fracture resistance was shown with intact marginal ridges and less extensive preparations. Modification of tooth preparation significantly impacted the magnitude of the fracture resistance and the marginal gap observed around ALD overlays. Thermal aging affected the marginal gaps of the three groups following the same pattern as before thermal aging.
|
PMC11699763_p47
|
PMC11699763
|
Conclusions
| 4.086622 |
biomedical
|
Study
|
[
0.9983079433441162,
0.0007945504039525986,
0.0008975821547210217
] |
[
0.9994377493858337,
0.00023208430502563715,
0.0002751197898760438,
0.00005507835157914087
] |
en
| 0.999995 |
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an acquired multi-system disease characterized by persistent fatigue and exertional intolerance with a disproportionate worsening after physical or cognitive exertion referred to as post-exertional malaise (PEM). Furthermore, it is accompanied by a variety of other symptoms that are related to immunological, cognitive, and autonomic dysfunction.
|
PMC11699797_p0
|
PMC11699797
|
Introduction
| 3.926058 |
biomedical
|
Other
|
[
0.9984034895896912,
0.0012358070816844702,
0.0003606955287978053
] |
[
0.08394426852464676,
0.535676121711731,
0.3750360608100891,
0.005343515891581774
] |
en
| 0.999995 |
The worldwide prevalence was estimated at 0.89% in a pre-pandemic meta-analysis, though estimates vary according to the case definitions used. 1 While there is evidence for a genetic predisposition to ME/CFS, 2 it is most often triggered by viral infections. 3 Since the COVID-19 pandemic, SARS-CoV-2 has become the leading viral trigger for ME/CFS. 4 Given the high incidence of COVID-19, the prevalence of ME/CFS is expected to strongly increase.
|
PMC11699797_p1
|
PMC11699797
|
Introduction
| 3.628614 |
biomedical
|
Study
|
[
0.9993913173675537,
0.00025582389207556844,
0.0003528306551743299
] |
[
0.4838787317276001,
0.06432997435331345,
0.45062634348869324,
0.0011649916414171457
] |
en
| 0.999996 |
The diagnosis of ME/CFS is based on established diagnostic criteria, with the most frequently used being the Canadian Consensus Criteria (CCC) and the Institute of Medicine (IOM) criteria. These require the presence of key symptoms including lingering fatigue, PEM, unrefreshing sleep, cognitive impairment, and/or orthostatic intolerance. 5 ME/CFS diagnosis relies so far on these clinical criteria, although most patients present with objective clinical findings including diminished handgrip strength or autonomic dysfunction. 4
|
PMC11699797_p2
|
PMC11699797
|
Introduction
| 3.831017 |
biomedical
|
Review
|
[
0.9951393604278564,
0.003989851102232933,
0.0008707562228664756
] |
[
0.027677778154611588,
0.1294601410627365,
0.8403354287147522,
0.002526695840060711
] |
en
| 0.999997 |
The pathophysiological mechanism of ME/CFS is not yet known, but numerous studies suggest dysregulation of the immune system. Elevated antibodies were found in ME/CFS patients in several studies, most frequently against adrenergic and muscarinic receptors. 6 , 7 Elevated β1 and β2 adrenergic receptor autoantibodies (β1/β2 AR-AB) and M3/M4 acetylcholine receptor autoantibodies (M3/M4 AChR-AB) are likely to modulate the autonomic nervous system function and vasoregulation. 7 , 8
|
PMC11699797_p3
|
PMC11699797
|
Introduction
| 4.111707 |
biomedical
|
Study
|
[
0.9997549653053284,
0.00011816468759207055,
0.00012697062629740685
] |
[
0.9911310076713562,
0.0009441022993996739,
0.007799188606441021,
0.0001256699179066345
] |
en
| 0.999995 |
Levels of these autoantibodies were found to be associated with symptom severity and structural alterations in the central nervous system in both post-COVID syndrome (PCS) and ME/CFS. 9 , 10 , 11 , 12 , 13 The β2 AR-AB was the best marker for distinguishing PCS from recovered patients, and levels of β2 AR-AB were associated with both fatigue and vasomotor symptoms in PCS-ME/CFS patients. 10 , 14 Apart from elevated autoantibodies a chronic activation of inflammatory pathways and an alteration in memory B-cells were shown. 15 , 16
|
PMC11699797_p4
|
PMC11699797
|
Introduction
| 4.114207 |
biomedical
|
Study
|
[
0.999665379524231,
0.0001850252301665023,
0.0001495035830885172
] |
[
0.9940798282623291,
0.00032314914278686047,
0.0054859016090631485,
0.00011117015674244612
] |
en
| 0.999998 |
The goal of immunoadsorption (IA) is to improve the clinical condition of patients with autoantibody-mediated diseases by selectively removing immunoglobulins from circulation via extracorporeal adsorption from their plasma. 17 , 18 Unlike plasmapheresis, IA employs a high-affinity column that specifically binds and eliminates immunoglobulins including autoantibodies and immune complexes, leaving other plasma components behind. 18
|
PMC11699797_p5
|
PMC11699797
|
Introduction
| 3.959991 |
biomedical
|
Other
|
[
0.9984331727027893,
0.0011869905283674598,
0.00037981904461048543
] |
[
0.252191960811615,
0.6587595343589783,
0.08669722080230713,
0.002351326635107398
] |
en
| 0.999996 |
Given the previous evidence for a potential role of autoantibodies in PCS and ME/CFS and the effectiveness of IA in postinfectious ME/CFS, we here aimed to evaluate the effectiveness of IA treatment specifically in post-COVID ME/CFS patients. 19 , 20 Effectiveness was measured by assessing patient-reported outcomes and hand grip strength. We hypothesized that IA would lead to clinical improvement in ME/CFS patients four weeks after treatment, with an additional beneficial effect from repeat IA in responders with relapse.
|
PMC11699797_p6
|
PMC11699797
|
Introduction
| 4.11081 |
biomedical
|
Study
|
[
0.9955490827560425,
0.0041641914285719395,
0.00028670154279097915
] |
[
0.996938943862915,
0.0021278630010783672,
0.0006154718575999141,
0.0003176805912517011
] |
en
| 0.999996 |
This prospective cohort study, conducted at the outpatient department for immunodeficiencies at the Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, recruited patients between October 2022 and October 2023. Patients received IA treatment and follow-up visits for 12 months. Responders to the first cycle of IA were offered a second cycle. An interim report of the first 10 patients was published in October 2023. 21 This study was being conducted within the National Clinical Studies Group (NKSG), a clinical trial and translational research platform focused on developing therapies for PCS and ME/CFS, funded by the German Ministry of Education and Research (BMBF). 22
|
PMC11699797_p7
|
PMC11699797
|
Study design
| 3.730855 |
biomedical
|
Study
|
[
0.9715566039085388,
0.02754555456340313,
0.0008977878023870289
] |
[
0.9709675312042236,
0.026995211839675903,
0.0005175182595849037,
0.0015197310131043196
] |
en
| 0.999998 |
Patients were diagnosed and recruited at the outpatient department for immunodeficiencies at the Institute of Medical Immunology at the Charité - Universitätsmedizin Berlin. The diagnosis of ME/CFS was based on the modified Canadian Consensus Criteria (CCC) and a minimum of 14 h of PEM. 23 , 24 Inclusion criteria encompassed elevated β2 AR-AB at the time of screening and SARS-CoV-2 infection at the time of disease onset. All patients had to provide proof of SARS-CoV-2 infection by positive PCR, antigen test, or serology (SARS-CoV-2 nucleocapsid protein antibodies).
|
PMC11699797_p8
|
PMC11699797
|
Patients
| 3.995517 |
biomedical
|
Study
|
[
0.9951818585395813,
0.0045919641852378845,
0.00022606411948800087
] |
[
0.995922327041626,
0.003069056663662195,
0.0004280047432985157,
0.0005805737455375493
] |
en
| 0.999996 |
Patients were excluded from this study if they had relevant comorbidities, 25 pre-existing fatigue, evidence of organ dysfunction, or acute or chronic infections such as HIV or hepatitis. Additionally, patients who were unable to leave their homes due to the severity of their illness were also excluded.
|
PMC11699797_p9
|
PMC11699797
|
Patients
| 2.577512 |
biomedical
|
Study
|
[
0.9691125154495239,
0.029055573046207428,
0.0018318920629099011
] |
[
0.9748977422714233,
0.022203756496310234,
0.0010233334032818675,
0.0018751686438918114
] |
en
| 0.999997 |
All patients signed informed consent before study inclusion. The Ethics Committee of the Charité - Universitätsmedizin Berlin approved this study in accordance with the 1964 Declaration of Helsinki and its later amendments .
|
PMC11699797_p10
|
PMC11699797
|
Patients
| 1.191431 |
biomedical
|
Other
|
[
0.9683017134666443,
0.012578700669109821,
0.01911957748234272
] |
[
0.028316408395767212,
0.9674527645111084,
0.0007842120248824358,
0.003446615766733885
] |
en
| 0.999997 |
Five sessions of IA were administered at the Department of Nephrology at Charité - Universitätsmedizin Berlin. IA treatment was conducted in an outpatient setting over a ten-day period, with sessions spaced no more than two days apart. The TheraSorb® – Ig omni 5 adsorber (Miltenyi Biotech B.V. & Co. KG, Bergisch Gladbach, Germany) was used for removal of human lambda and kappa chains containing immunoglobulins IgG (subclasses IgG1-IgG4), IgA, IgM, IgE, and immune complexes as well as free lambda and kappa light chains from the plasma.
|
PMC11699797_p11
|
PMC11699797
|
Procedures
| 3.767353 |
biomedical
|
Study
|
[
0.9879012107849121,
0.011686135083436966,
0.00041269027860835195
] |
[
0.6936930418014526,
0.2945393919944763,
0.0017526898300275207,
0.010014846920967102
] |
en
| 0.999997 |
To ascertain the efficacy of IA, total serum immunoglobulin levels were assessed via immunoturbidimetry before, during, and after treatment. Antibodies against β1, β2, M3, and M4 receptors were determined using ELISA technology by CellTrend GmbH, Luckenwalde, Germany, both before and after treatment. Intra- and inter-assay coefficients of variation for the ELISAs provided by CellTrend were: b1 AR-AB 9.6%/12.0%, b2 AR-AB 4.2%/3.8%, M3 AchR-AB 5.9%/10.1%, and M4 AchR-AB 7.3%/12.5%. Pre- and post-treatment samples were analyzed in the same assay run. The upper normal levels of autoantibodies were determined based on validation studies of a healthy control group and defined as being larger than the 90th percentile of a healthy control group (>14U/l for β2 AR-AB).
|
PMC11699797_p12
|
PMC11699797
|
Procedures
| 4.125963 |
biomedical
|
Study
|
[
0.9993141889572144,
0.000505987205542624,
0.000179874652530998
] |
[
0.9992252588272095,
0.0003281179815530777,
0.00035905136610381305,
0.00008754415466682985
] |
en
| 0.999998 |
For patient-reported outcomes, questionnaires were filled out before, during, and after the treatment in monthly intervals and validated by physicians. Patients’ health-related quality of life was assessed using the 36-Item Short-Form Survey (SF-36), with scores ranging from 0 to 100, with 100 indicating no limitations. 26 Response to IA treatment was defined as a minimum increase in the SF-36 physical functioning domain (SF-36 PF) of 10 points from baseline to four weeks post IA, indicating a clinically relevant improvement. 27 Fatigue was evaluated using the Fatigue Severity Scale (FSS), ranging from 9 to 63, with a total score of 36 or more suggesting relevant fatigue. 28 Additionally, disease-related disability was scored according to the Bell score, rating the restriction in daily functioning on a scale from 0 to 100, with 100 indicating no restriction. 29 PEM was evaluated using the DePaul Symptom Questionnaire (PEM-DSQ), ranging from 0 to 20 for both severity and frequency, PEM duration was assessed ranging from 0 to 6, with higher values indicating higher PEM severity. 24 Further cardinal symptoms of both PCS and ME/CFS, including fatigue, muscle pain, immunological symptoms, and cognitive impairment, were scored on a numeric rating scale (NRS) from 1 to 10, with 10 indicating maximum symptom severity (not formally validated). Autonomic dysfunction was evaluated according to the Composite Autonomic Symptom Score (COMPASS31), ranging from 0 to 100, with 100 indicating maximum autonomic dysfunction. 30
|
PMC11699797_p13
|
PMC11699797
|
Procedures
| 4.223548 |
biomedical
|
Study
|
[
0.9954713582992554,
0.004232116509228945,
0.00029655126854777336
] |
[
0.9963616728782654,
0.0015697549097239971,
0.0017443085089325905,
0.00032419682247564197
] |
en
| 0.999998 |
Handgrip strength (HGS) of the dominant hand was measured using a digital hand dynamometer (EH101, Deyard, Shenzhen, China) in two separate sessions. Rest time between sessions was 60 min, in which no strenuous physical activity took place. Before starting the measurement, patients were shown two separate demonstrations of how the dynamometer should be used. Patients sat in an upright position facing a standard table during measurements of HGS. The forearm of the dominant hand was placed on the table in full supination holding the dynamometer. Under supervision and verbal motivation, the handle was pulled 10 times with maximum force for three seconds, followed by a five-second relaxation phase. The dynamometer displayed the highest value reached within these three seconds (measurement in kg), this single value was then recorded. The attempt with the highest reading out of ten repetitions was recorded as the maximum strength (Fmax), and the average strength (Fmean) of each session was calculated. 31
|
PMC11699797_p14
|
PMC11699797
|
Procedures
| 4.134043 |
biomedical
|
Study
|
[
0.9961814880371094,
0.0035340168979018927,
0.0002844806876964867
] |
[
0.9974218606948853,
0.0017112087225541472,
0.0004898995975963771,
0.0003771033661905676
] |
en
| 0.999998 |
Further, the Reactive hyperemia index (RHI), which is a measure for endothelial function, was assessed using a peripheral arterial tonometry device . The technology measures the pulsatile volume changes in the vascular beds of the finger using optical sensors. The subjects were in supine position for a minimum of 15 min before measurements, in a quiet, temperature-controlled room. Occlusion of the brachial artery was performed on the nondominant upper arm using a standard blood pressure cuff. The occlusion pressure was at least 60 mmHg above the systolic blood pressure. Upon release of the cuff, the resulting surge in blood flow causes vessel dilation. Each recording consisted of five minutes of baseline measurement, five minutes of occlusion measurement, and five minutes post-occlusion measurement. The post-occlusion dilation relative to pre-occlusion levels is calculated as the RHI. Endothelial dysfunction was defined as an RHI ≤ 1.67 based on previous cohort studies. 32
|
PMC11699797_p15
|
PMC11699797
|
Procedures
| 4.124345 |
biomedical
|
Study
|
[
0.9993601441383362,
0.0004759597941301763,
0.00016395763668697327
] |
[
0.9991100430488586,
0.00034672697074711323,
0.00044244443415664136,
0.00010072572331409901
] |
en
| 0.999997 |
Study data were collected and managed using the REDCap electronic data capture tools hosted at the Charité - Universitätsmedizin Berlin. 33 , 34
|
PMC11699797_p16
|
PMC11699797
|
Procedures
| 1.507173 |
biomedical
|
Study
|
[
0.9830827713012695,
0.002625375287607312,
0.014291906729340553
] |
[
0.6479333639144897,
0.34817278385162354,
0.002180699026212096,
0.0017131527420133352
] |
en
| 0.999996 |
Statistical analyses were conducted using R version 4.3.0 and RStudio version 2023.03.1. A linear mixed-effects model (LMM) was employed to assess changes in multiple outcome variables across different time points. The analysis was performed using the lmer function from the lme4 package (version 1.1-35.5), and ggplot2 (version 3.5.0) was utilized for data visualization. For each outcome variable, the LMM included time as a fixed effect and patient number as a random effect to account for within-patient correlation. The mixed model was fitted using restricted maximum likelihood (REML), and statistical significance was evaluated using t-tests with p -values approximated through Satterthwaite's method for degrees of freedom, implemented via the lmerTest package (version 3.1-3). Missing data were accounted for by using all available observations in the model, allowing for the estimation of fixed and random effects without listwise deletion, assuming data are missing at random.
|
PMC11699797_p17
|
PMC11699797
|
Statistical analysis
| 4.117046 |
biomedical
|
Study
|
[
0.9994174242019653,
0.00033341627568006516,
0.00024912803201004863
] |
[
0.9989062547683716,
0.0005734089063480496,
0.0004402822523843497,
0.00008015008643269539
] |
en
| 0.999998 |
For comparisons between groups the non-parametric Whitney-U test was used. Correlation analysis was performed using the nonparametric Spearman coefficient. A two-tailed p -value of <0.05 was considered to provide evidence of a statistically significant result.
|
PMC11699797_p18
|
PMC11699797
|
Statistical analysis
| 3.528713 |
biomedical
|
Study
|
[
0.9991284012794495,
0.0002839562948793173,
0.0005876421346329153
] |
[
0.9594087600708008,
0.038961973041296005,
0.0013536419719457626,
0.0002755201421678066
] |
en
| 0.999999 |
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
|
PMC11699797_p19
|
PMC11699797
|
Role of the funding source
| 0.978864 |
other
|
Other
|
[
0.06100447475910187,
0.0020385771058499813,
0.9369570016860962
] |
[
0.0030792111065238714,
0.9962848424911499,
0.00035098165972158313,
0.0002849063603207469
] |
en
| 0.999995 |
The β2 AR-AB levels of 402 patients, who met the CCC for post-infectious ME/CFS, were measured between June 2022 and March 2023. Out of these 402 patients, 189 (47%) had elevated β2 AR-AB levels. From this group, patients who planned IA treatment and fulfilled inclusion criteria were offered to participate in this trial and 23 were recruited for the study between September 2022 and October 2023. Three patients withdrew their consent to participate prior to the treatment due to concerns about the burden of study participation. 20 patients completed a six-month follow-up resulting in an 87% retention rate, suggesting that the protocol was generally acceptable to those who proceeded with the treatment.
|
PMC11699797_p20
|
PMC11699797
|
Results
| 3.869976 |
biomedical
|
Study
|
[
0.7545285224914551,
0.24121077358722687,
0.00426067179068923
] |
[
0.5374614596366882,
0.4499852955341339,
0.002224960830062628,
0.0103283217176795
] |
en
| 0.999998 |
The five IA treatment sessions were completed for all patients within a 10-day period in an outpatient setting. Sessions lasted between 4.5 and 9 h and were followed by a minimum of one day and a maximum of two days of rest. In five out of 20 patients, a Shaldon's catheter was required for vascular access; for the other patients peripheral venous puncture was sufficient. One patient experienced a thrombosis of the internal jugular vein as a side effect of the catheter. Otherwise, no severe side effects of IA treatment were reported.
|
PMC11699797_p21
|
PMC11699797
|
Results
| 3.599096 |
clinical
|
Study
|
[
0.391704797744751,
0.6061025857925415,
0.0021926178596913815
] |
[
0.7283121943473816,
0.16623328626155853,
0.004736384842544794,
0.10071811825037003
] |
en
| 0.999997 |
The treatment was generally reported as physically exhausting and frequently triggered PEM. To mitigate this, we aimed to minimize external stressors, ensured proper oral hydration, and offered lorazepam for up to three days as supportive therapy.
|
PMC11699797_p22
|
PMC11699797
|
Results
| 1.795682 |
clinical
|
Other
|
[
0.23960508406162262,
0.7541846632957458,
0.006210244260728359
] |
[
0.030207863077521324,
0.6614927053451538,
0.0031942243222147226,
0.30510520935058594
] |
en
| 0.999996 |
The median disease duration was 22 months (IQR: 15–31) at the time of inclusion. Seven patients were male and 13 were female with a median age of 40 (IQR: 36–51). All patients had a severe degree of disability with a median Bell score of 30 (range 20–40), corresponding to reduction of the functional state to 50% and being usually housebound. Individual patient characteristics are displayed in Table 1 . Table 1 Cohort characteristics and response to treatment as assessed by the SF36 PF. Patient Gender (M/F) Age (years) Time since COVID-19 (months) SF36 PF pre IA SF36 PF post IA (M1) ΔSF36 PF Responder to IA (yes/no) 1 F 36 39 15 70 55 Yes 2 M 41 25 25 70 45 Yes 3 F 56 15 25 65 40 Yes 4 F 37 21 45 85 40 Yes 5 F 52 23 45 80 35 Yes 6 M 59 31 35 65 30 Yes 7 F 51 38 15 35 20 Yes 8 F 31 19 40 60 20 Yes 9 F 59 32 20 35 15 Yes 10 F 50 31 15 30 15 Yes 11 F 36 10 15 25 10 Yes 12 M 36 9 40 50 10 Yes 13 M 46 32 20 30 10 Yes 14 M 57 14 50 60 10 Yes 15 M 33 23 25 30 5 No 16 F 36 15 25 30 5 No 17 F 44 14 5 5 0 No 18 M 33 39 60 60 0 No 19 F 37 15 30 25 −5 No 20 F 39 19 50 45 −5 No F: female; IA: immunoadsorption; M: male; M1: month 1 post immunoadsorption; SF36 PF: Short Form-36 physical functioning.
|
PMC11699797_p23
|
PMC11699797
|
Results
| 4.062853 |
biomedical
|
Study
|
[
0.970312774181366,
0.029216479510068893,
0.0004708107153419405
] |
[
0.9902218580245972,
0.006010659970343113,
0.0008047279552556574,
0.002962730824947357
] |
en
| 0.999994 |
There was a positive correlation between the immune score, which depicts the severity of the lymph node pain, throat pain, and flu-like symptoms, and the levels of antibodies against β1 AR ( r = 0.53, p = 0.017), β2 AR ( r = 0.46, p = 0.040), M3 AChR ( r = 0.60, p = 0.006), and M4 AChR ( r = 0.60, p = 0.006) at baseline. Otherwise, no significant correlation was found between the autoantibody levels and the clinical presentation.
|
PMC11699797_p24
|
PMC11699797
|
Results
| 4.063676 |
biomedical
|
Study
|
[
0.9995039701461792,
0.0003009490901604295,
0.0001950211590155959
] |
[
0.9994645714759827,
0.00018759109661914408,
0.00028657607617788017,
0.00006130913970991969
] |
en
| 0.999997 |
There was a mean increase in the SF-36 PF of 17.75 points ( CI : 13.41–26.16, p < 0.001) four weeks post IA. The corresponding Cohen's d was calculated as 1.19, indicating a large effect size. There were, however, four patients with an increase of 10 points, which is considered as a clinically meaningful but small effect. 27 As seen in Fig. 1 , though the SF-36 PF scores tended to decrease between three and six months post IA, at month six post IA a significant mean improvement of 12.81 points ( CI : 4.99–20.61, p = 0.002) remained. Fourteen out of 20 patients (70%) responded to the treatment as defined by an increase of at least 10 points in the SF-36 PF four weeks post IA suggesting a clinically meaningful improvement. Seven patients were non-responders according to this definition; however, two of these showed a delayed response at month 2. Fig. 1 Course of the mean 36-Item Short-Form Survey physical functioning domain (SF36 PF) over the study period. The duration of IA therapy is indicated by the green bar. A higher score indicates less restriction in physical functioning. Error bars represent 95% confidence intervals. Data were analyzed using a linear mixed-effects model fitted by restricted maximum likelihood (REML), with t-tests computed using Satterthwaite's method for degrees of freedom with significance levels indicated as ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001. From top to bottom, the panels display the trajectories of the SF36 PF for: a) the whole cohort ( n = 20), b) responders to the treatment defined by a ≥ ten-point increase in the SF36 PF at month 1 post IA ( n = 14), and c) non-responders to the treatment defined by a ≤ ten-point increase in the SF36 PF at month 1 post IA ( n = 7).
|
PMC11699797_p25
|
PMC11699797
|
Results
| 4.166182 |
biomedical
|
Study
|
[
0.9971204996109009,
0.0025395683478564024,
0.0003399105044081807
] |
[
0.9987671375274658,
0.0006108488305471838,
0.0004224258882459253,
0.00019956688629463315
] |
en
| 0.999997 |
There was no significant difference in age, symptom severity, disease duration, or level of β2 AR-AB between responders and non-responders. However, among female patients, responders had a significantly higher maximum HGS at baseline ( Mdn = 23.5 kg, IQR: 17.7–25.5 kg) compared to non-responders ( Mdn = 9.8 kg, IQR: 8.53–11.05 kg) ( z = −2.62, p = 0.006, r = 0.73).
|
PMC11699797_p26
|
PMC11699797
|
Results
| 4.103904 |
biomedical
|
Study
|
[
0.998970627784729,
0.0008058228413574398,
0.00022348591301124543
] |
[
0.9992934465408325,
0.0003511318936944008,
0.0002640446473378688,
0.00009124755160883069
] |
en
| 0.999997 |
Serum IgG, IgA, and IgM levels were collected from all patients at baseline, before each treatment, and after treatment. Compared to baseline, IgG, IgA, and IgM were significantly decreased during IA treatment ( p < 0.001) with a mean IgG reduction of 8.66 g/l ( CI : 8.06–9.26 g/l) (79%, CI : 73–84%), mean IgA reduction of 1.3 g/l ( CI : 1.2–1.51 g/l) (68%, CI : 63–78%), and mean IgM reduction of 1.1 g/l ( CI : 0.84–1.34 d/l) (76%, CI : 58–93%) at day five of the treatment. Fig. 2 a–c shows the course of immunoglobulin levels over time. β2 AR-AB decreased in parallel with the immunoglobulins with a mean reduction of 26.57 U/l ( CI : 20.11–33.02 U/l) (77%, CI : 58–95%). Fig. 2 Course of immunoglobulin and autoantibody levels over the study period ( n = 20), the duration of IA therapy is indicated by the green bar. Error bars represent 95% confidence intervals. Data were analyzed using a linear mixed-effects model fitted by restricted maximum likelihood (REML), with t-tests computed using Satterthwaite's method for degrees of freedom with significance levels indicated as ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001. From left to right, the panels display the trajectories of: a) immunoglobulin G (IgG), b) immunoglobulin A (IgA), c) immunoglobulin M (IgM), d) β1 adrenergic receptor autoantibodies (β1 AR-AB), e) β2 adrenergic receptor autoantibodies (β2 AR-AB), f) M3 acetylcholine receptor autoantibodies (M3 AchR-AB), and g) M4 acetylcholine receptor autoantibodies (M4 AchR-AB).
|
PMC11699797_p27
|
PMC11699797
|
Results
| 4.167166 |
biomedical
|
Study
|
[
0.9990924596786499,
0.0006756474613212049,
0.00023189815692603588
] |
[
0.9993392825126648,
0.0002739901829045266,
0.0002907867019530386,
0.00009586192027200013
] |
en
| 0.999998 |
Patients reported improvements in several key clinical symptoms at four weeks post IA. There were significant improvements in fatigue, as measured by the SF-36 energy/fatigue domain, and in pain, as measured by the SF-36 pain domain, following IA treatment. These improvements remained significant through month six. The maximal change was observed two months after IA, with a mean increase of 19 points ( CI : 11.61–26.39, p < 0.001) and 22.63 points ( CI : 13.28–31.96, p < 0.001) from baseline, respectively, as shown in Fig. 3 . Fig. 3 Clinical symptom progression over the study period ( n = 20). The duration of IA therapy is indicated by the green bar. Error bars represent 95% confidence intervals. Data were analyzed using a linear mixed-effects model fitted by restricted maximum likelihood (REML), with t-tests computed using Satterthwaite's method for degrees of freedom with significance levels indicated as ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001. From left to right, the panels display the trajectories of: a) 36-Item Short-Form Survey energy/fatigue domain (SF36 energy/fatigue), where a higher score indicates less fatigue, b) 36-Item Short-Form Survey pain domain (SF36 pain), where a higher score indicates less pain, c) post-exertional malaise (PEM) as assessed by the DePaul Symptom Questionnaire (DSQ-PEM), higher scores indicate more severe PEM, and d) Composite Autonomic Symptom Score (COMPASS31), where a higher score indicates more autonomic symptoms.
|
PMC11699797_p28
|
PMC11699797
|
Results
| 4.189101 |
biomedical
|
Study
|
[
0.9977774024009705,
0.001925236196257174,
0.00029734597774222493
] |
[
0.9987921118736267,
0.0005538722616620362,
0.0004864027432631701,
0.0001676584070082754
] |
en
| 0.999995 |
Furthermore, patients reported a lasting improvement in autonomic symptoms, as shown in Fig. 3 d. Improvements were most noticeable in the orthostatic, secretomotor, and gastrointestinal domains of the COMPASS31, which are shown in Figure S4 in the Supplement , as well as in the total score with a mean decrease of 12.23 points ( CI : 19.06–5.4, p = 0.001) at month one.
|
PMC11699797_p29
|
PMC11699797
|
Results
| 4.144843 |
biomedical
|
Study
|
[
0.9973512887954712,
0.0023761403281241655,
0.0002726589736994356
] |
[
0.998488187789917,
0.0007268941262736917,
0.0005869643646292388,
0.0001980144443223253
] |
en
| 0.999995 |
All patients experienced severe PEM lasting at least 14 h, as specified by the inclusion criteria. Both frequency and severity of post-exertional symptoms significantly decreased after IA according to the DSQ-PEM. The total score is shown in Fig. 3 c, remaining significantly decreased through month six.
|
PMC11699797_p30
|
PMC11699797
|
Results
| 3.405431 |
biomedical
|
Study
|
[
0.987441897392273,
0.011655731126666069,
0.0009023947059176862
] |
[
0.9953811168670654,
0.0033917624969035387,
0.0004454428271856159,
0.0007817232399247587
] |
en
| 0.999997 |
Additionally, there was a significant mean decrease of 4.9 points ( CI : 1.34–8.46, p = 0.009) in fatigue as assessed by the FSS at month one after IA as shown in Figure S3 in the Supplement . According to the symptom scores (NRS 1–10), there were also improvements in muscle pain, immunological as well as cognitive symptoms, that remained significant through month 6 with their maximum decrease between months two and three after IA as shown in Figure S1 in the Supplement .
|
PMC11699797_p31
|
PMC11699797
|
Results
| 4.115742 |
biomedical
|
Study
|
[
0.9985870122909546,
0.0011852503521367908,
0.00022771675139665604
] |
[
0.998783528804779,
0.0006311057368293405,
0.000453937886049971,
0.00013140258670318872
] |
en
| 0.999997 |
The improvement in the degree of disability according to the Bell score post IA reached statistical significance only at months two, four, five, and six, with a maximum mean increase of 5.18 points ( CI : 1.24–9.12, p = 0.013) at month two post IA as shown in Figure S2 in the Supplement .
|
PMC11699797_p32
|
PMC11699797
|
Results
| 4.078932 |
biomedical
|
Study
|
[
0.9987836480140686,
0.0009023537277244031,
0.0003139916225336492
] |
[
0.9991446733474731,
0.0004483311786316335,
0.0003138889151159674,
0.00009316507203038782
] |
en
| 0.999997 |
To further quantify physical improvement, we measured repeat HGS as an objective marker of muscle fatigue. There were improvements, especially in repeat HGS before and after treatment in female patients as shown in Fig. 4 . The mean HGS during the second measurement was significantly increased six months post IA by a mean of 20% ( CI : 2–39%, p = 0.042) indicating a better recovery of strength within the 60 min of rest time between HGS measurements. In female responders ( n = 9), both mean and maximum HGS were significantly increased as early as four weeks post-IA (not shown). Fig. 4 Course of mean handgrip strength (Fmean) in % in female patients ( n = 13) measured a) initially and then b) repeated after one hour over the study period. The duration of IA therapy is indicated by the green bar. Error bars represent 95% confidence intervals. Data were analyzed using a linear mixed-effects model fitted by restricted maximum likelihood (REML), with t-tests computed using Satterthwaite's method for degrees of freedom with significance levels indicated as ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001.
|
PMC11699797_p33
|
PMC11699797
|
Results
| 4.132555 |
biomedical
|
Study
|
[
0.9991175532341003,
0.0006496253190562129,
0.00023285717179533094
] |
[
0.999414324760437,
0.000202654191525653,
0.00028966981335543096,
0.00009340544056612998
] |
en
| 0.999997 |
As a measure of endothelial dysfunction, the reactive hyperemia index (RHI) was assessed using an EndoPAT device. Six patients, three responders and three non-responders, had a reduced RHI (<1.68). There was no significant change in the RHI at six months post IA.
|
PMC11699797_p34
|
PMC11699797
|
Results
| 3.956465 |
biomedical
|
Study
|
[
0.9970411658287048,
0.0026747258380055428,
0.0002840267843566835
] |
[
0.9980903267860413,
0.0013008038513362408,
0.0002893881464842707,
0.00031953692086972296
] |
en
| 0.999995 |
Responders to the first IA treatment were offered a second IA treatment within six to 12 months after completing the initial cycle, when their physical function or symptoms worsened again. The course of physical functioning according to the SF-36 PF in the seven patients receiving a repeat IA is shown in Fig. 5 . Symptoms improved again four weeks after the second IA treatment but then remained at a similar level as after the first IA treatment. Fig. 5 Course of 36-Item Short-Form Survey physical functioning domain (SF-36 PF) over the study period in patients who received a second cycle of IA therapy ( n = 7). The duration of IA therapy is indicated by the green bar. Error bars represent 95% confidence intervals. Data were analyzed using a linear mixed-effects model fitted by restricted maximum likelihood (REML) for each cycle, with t-tests computed using Satterthwaite's method for degrees of freedom with significance levels indicated as ∗ p < 0.05, ∗∗ p < 0.01, ∗∗∗ p < 0.001.
|
PMC11699797_p35
|
PMC11699797
|
Results
| 4.153617 |
biomedical
|
Study
|
[
0.993738055229187,
0.005829509813338518,
0.00043241659295745194
] |
[
0.9982767105102539,
0.000986036378890276,
0.00040898547740653157,
0.00032822569482959807
] |
en
| 0.999998 |
There is increasing evidence that autoantibodies, including those targeting β-adrenergic and muscarinic acetylcholine receptors, may contribute to the pathophysiology of PCS and ME/CFS. We here provide evidence from an observational study that depletion of autoantibodies by IA can lead to improvement in overall physical functioning, as well as the severity of several key symptoms, including PEM, fatigue, pain, immunological, cognitive, and autonomic symptoms in a subset of post-COVID ME/CFS patients.
|
PMC11699797_p36
|
PMC11699797
|
Discussion
| 4.086523 |
biomedical
|
Study
|
[
0.9994980096817017,
0.00036808574805036187,
0.00013396766735240817
] |
[
0.9988540410995483,
0.00041598634561523795,
0.0006321786204352975,
0.00009786762529984117
] |
en
| 0.999997 |
The clinical improvements observed after autoantibody removal via IA support the hypothesized involvement of these autoantibodies in the pathophysiology of ME/CFS and PCS in the responders. Meanwhile, a smaller group of patients did not show a response to the treatment. This highlights the potential diverse mechanisms underlying this condition, and indicates that autoantibodies may play a role only in a subgroup of patients.
|
PMC11699797_p37
|
PMC11699797
|
Discussion
| 3.917349 |
biomedical
|
Study
|
[
0.9994532465934753,
0.0003898973809555173,
0.00015689947758801281
] |
[
0.9961473941802979,
0.001550454879179597,
0.0021043065935373306,
0.0001979515509447083
] |
en
| 0.999997 |
IA has demonstrated clinical improvements in post-infectious ME/CFS patients in two small pre-pandemic trials conducted by our group. 19 , 20 Although in most patients symptoms worsened after a few months, IA can induce longer lasting improvement for more than 12 months in a subset as observed in our previous study in postinfectious ME/CFS. 20 In this study, clinical improvements generally peaked between months two and three, then gradually declined. However, even after six months, statistically significant improvements compared to baseline were still evident.
|
PMC11699797_p38
|
PMC11699797
|
Discussion
| 4.048442 |
biomedical
|
Study
|
[
0.9990398287773132,
0.0007571756723336875,
0.00020291507826186717
] |
[
0.9989168643951416,
0.000537533254828304,
0.00043984039803035557,
0.00010571764869382605
] |
en
| 0.999997 |
It is important to acknowledge that the observed improvement in SF36 physical functioning does not apply to all patients as there were several non-responders to the treatment and four patients had only a small improvement. Among these, some patients showed improvement only after a delay of two or three months, while others did not demonstrate any noticeable improvement. Thus, it is important to study the efficacy of autoantibody-depleting therapies in larger controlled trials. Further identifying factors predicting individual responses would support the clinical findings. To address this question, we are currently conducting several additional analyses to identify potential biomarkers for treatment response. These analyses include a comprehensive B cell subtyping using CyTOF analysis, the measurement of further autoantibodies, and markers of immune activation, hypoperfusion, microclots, and SARS-CoV-2 persistence. Although the main effect of IA is the depletion of autoantibodies, there is some evidence that memory B cells can be affected by IA. 19 A potentially important finding is that responders had a higher baseline maximum HGS, suggesting they have less severe muscular or mitochondrial impairment. 35 We could not identify any other significant differences in the clinical phenotypes of responders compared to non-responders. However, ME/CFS patients are a heterogeneous group, and there may be comorbid conditions, such as structural neuroanatomic abnormalities, that may have been overlooked in our patient cohort.
|
PMC11699797_p39
|
PMC11699797
|
Discussion
| 4.1257 |
biomedical
|
Study
|
[
0.9988114833831787,
0.00101560284383595,
0.0001728617789922282
] |
[
0.998908519744873,
0.0004718113341368735,
0.0004615710931830108,
0.00015808244643267244
] |
en
| 0.999997 |
Growing evidence suggests that SARS-CoV-2 can trigger autoimmune processes, contributing to long-term effects of COVID-19. Dobrowolska et al. summarized recent findings indicating that PCS can develop autoantibodies against a range of antigens, including those specific to the immune and cardiovascular systems, the thyroid, and rheumatoid-specific targets, G-protein coupled receptors, and more. However, the clinical significance of most of these autoantibodies remains unclear. 36 Several studies found elevated autoantibodies against β-adrenergic and muscarinic receptors in PCS patients and demonstrated an association between the levels of these autoantibodies with fatigue, neurological symptoms and pain. 9 , 10 , 11 , 12 , 13 , 37 , 38 Importantly, two recent studies by Chen et al. as well as Santos Guedes de Sa et al. were able to induce similar symptoms in mice by transferring IgG from PCS patients. 39 , 40 Remarkably, Chen et al. showed that patterns of transferred symptoms varied depending on the plasma proteome signature of the patients. IgG from those with neuronal or immune involvement induced pain, while IgG from those with muscular involvement impaired motion in the mice. 39 In the study by Santos Guedes de Sa et al., patients showed a broad pattern of autoantibodies reactive with neuronal and endothelial tissues. IgG from individual patients induced distinct symptoms such as pain, hypersensitivity or loss of coordination in mice. 40 These findings provide further evidence for the diversity of autoantibodies in PCS, possibly driven by prolonged inflammation, infection of various cell types and tissues, and reactivation of Epstein–Barr virus. Our IA study shows that removing autoantibodies generally led to disease improvement in a subset of patients; however, it remains unclear whether the benefits are primarily due to the removal of β2 AR-AB or other specific autoantibodies. Furthermore, decreases of β2 AR-AB and immunoglobulins were seen in all patients, independent of response.
|
PMC11699797_p40
|
PMC11699797
|
Discussion
| 4.338312 |
biomedical
|
Study
|
[
0.9993724226951599,
0.00043106498196721077,
0.00019651322509162128
] |
[
0.9984075427055359,
0.0002804552495945245,
0.0011765320086851716,
0.00013555180339608341
] |
en
| 0.999998 |
The clinical improvement observed after autoantibody removal via IA in a majority of patients supports the hypothesized role of these autoantibodies in the pathophysiology of PCS and ME/CFS in the responders. Although IA has a rapid and high clinical efficacy in a subset of patients, the clinical benefits of IA are in some patients temporary, and the procedure is strenuous. During our trial, one case of internal jugular vein thrombosis occurred as a side effect of the catheter. Although the patient experienced no long-term effects following temporary anticoagulation, the risk of such complications should be considered. Furthermore, it is a highly specialized procedure, available only in select medical centers with the necessary equipment and expertise. B-cell and/or plasma cell depletion thus emerges as a promising treatment option, addressing the urgent need for more effective sustained therapeutic strategies. B cell depletion with the CD20 monoclonal antibody rituximab proved effective in a subset of ME/CFS patients, and its efficacy was found to be associated with the depletion of β2 AR-AB. 41 However, the results from the phase II rituximab trials could not be confirmed in a multicenter trial, which had several limitations. 42 We are currently initiating a trial with inebilizumab in ME/CFS and PCS patients, a monoclonal antibody directed against CD19 on B cells and plasma blasts showing high clinical efficacy in neuromyelitis optica. 43 In this study, only responders to IA will be included in order to select patients with strong evidence of an autoantibody-mediated disease. Further novel treatment approaches are currently being tested in clinical trials for PCS and ME/CFS patients. These include targeting plasma cells by a monoclonal antibody to CD38, enhancing degradation of autoantibodies by Fc receptor inhibition, and neutralizing antibodies against G-protein coupled receptors with the aptamer BC007 .
|
PMC11699797_p41
|
PMC11699797
|
Discussion
| 4.272243 |
biomedical
|
Study
|
[
0.9957507848739624,
0.003973663784563541,
0.00027555611450225115
] |
[
0.9869711399078369,
0.008374026976525784,
0.003893387271091342,
0.0007615081849507987
] |
en
| 0.999998 |
Limitations of this study include the small sample size and non-controlled study design. The study was designed to detect larger effect sizes, smaller effects may not be captured with this sample size. Further studies are therefore required; we and two other sites in Germany are currently conducting randomized controlled trials of IA in PCS and ME/CFS with larger sample sizes. 44 Further, the outcomes are primarily patient-reported. The DSQ-PEM is designed for diagnostic purposes, and not validated for tracking changes in PEM in a clinical trial. While PCS encompasses a very heterogeneous patient population with presumably different pathomechanisms, our focus was solely on adult PCS patients meeting the ME/CFS criteria. Therefore, our findings may not be applicable to all PCS patients. Particularly our findings regarding the feasibility and safety of this procedure cannot directly be applied to the most severe, home bound patient group, since they were excluded from the study.
|
PMC11699797_p42
|
PMC11699797
|
Discussion
| 4.020514 |
biomedical
|
Study
|
[
0.9991651773452759,
0.000586054171435535,
0.00024885337916202843
] |
[
0.9993184804916382,
0.0002719995682127774,
0.0003207922854926437,
0.00008870872261468321
] |
en
| 0.999995 |
In conclusion, our study suggests that IA treatment may result in rapid clinical improvement in a subset of patients. Further trials with both more patients and clinical outcomes reported are needed to confirm our findings. Our study serves as proof of concept for the initiation of clinical trials using drugs specifically designed to target autoantibodies. Targeting B cells may offer a promising approach to long-term symptom relief by addressing the underlying mechanisms driving autoantibody generation.
|
PMC11699797_p43
|
PMC11699797
|
Discussion
| 4.079062 |
biomedical
|
Study
|
[
0.9984502792358398,
0.0013766048941761255,
0.0001730573712848127
] |
[
0.9972803592681885,
0.0015766029246151447,
0.0009072091197595,
0.00023582052381243557
] |
en
| 0.999998 |
ES conducted the main part of the study together with CK, KW, CS, and LK. RR helped with patient recruitment. CH prepared the figures of the report with input from LK and managed electronic data collection together with HF. CS did the conceptualization and provided resources and supervision. AK and MT managed IA therapy. FS managed laboratory analysis. LK wrote the first draft of the report and performed statistical analysis.
|
PMC11699797_p44
|
PMC11699797
|
Contributors
| 0.88312 |
other
|
Other
|
[
0.1408957988023758,
0.005273967981338501,
0.8538302183151245
] |
[
0.008968226611614227,
0.989346981048584,
0.0009331253240816295,
0.0007515763863921165
] |
en
| 0.999995 |
All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. CH and LK have accessed and verified the data.
|
PMC11699797_p45
|
PMC11699797
|
Contributors
| 0.953365 |
other
|
Other
|
[
0.00981215387582779,
0.0009304874110966921,
0.9892573952674866
] |
[
0.0015285281697288156,
0.9975425004959106,
0.0005035998183302581,
0.00042537806439213455
] |
en
| 0.999995 |
The data presented in this study will be available upon request from the corresponding author. Due to the sensitive nature of the data and the ongoing data collection and analysis, the data are not publicly available.
|
PMC11699797_p46
|
PMC11699797
|
Data sharing statement
| 0.912338 |
other
|
Other
|
[
0.4633254110813141,
0.00402929587289691,
0.5326452851295471
] |
[
0.027392785996198654,
0.9705954790115356,
0.001163227017968893,
0.0008485304424539208
] |
en
| 0.999997 |
Charité holds, together with CellTrend, a patent for the diagnostic use of autoantibodies against β2 AR-AB. CS has a consulting agreement with CellTrend and Berlin Cures. MT has received grants from the DFG, BMBF, Weidenhammer Zöbele Stiftung, Baxter, and Cytosorbents. MT has a consulting agreement with AstraZeneca and has received honoraria for lectures from Aey-Congress, AstraZeneca, Boehringer Ingelheim, Bayer, Baxter, Cytosorbents, DGK, DHL, Fresenius, Medical Tribune, MedPoint, Novartis, Pfizer, Sanofi, and Vifor. MT has also received support for attending meetings from AstraZeneca and Vifor. Additionally, MT serves on data safety monitoring or advisory boards for AstraZeneca, Boehringer Ingelheim, and Takeda. PG has received honoraria for lectures and travel support from Miltenyi Biotec GmbH. The other authors declare no conflict of interest.
|
PMC11699797_p47
|
PMC11699797
|
Declaration of interests
| 0.970641 |
other
|
Other
|
[
0.005648696329444647,
0.0014054443454369903,
0.9929459691047668
] |
[
0.0013837468577548862,
0.997312605381012,
0.0006585920928046107,
0.0006449848879128695
] |
en
| 0.999998 |
Head and neck cancer (HNC) refers to a group of heterogeneous tumors that originate, except for skin tumors, in the mucosa of the upper gastrointestinal tract, especially in the oral cavity, pharynx, and larynx . It ranks seventh in incidence and eighth in mortality estimates among the most prevalent cancers worldwide, excluding nonmelanoma skin cancer .
|
PMC11699980_p0
|
PMC11699980
|
1. Introduction
| 3.722425 |
biomedical
|
Other
|
[
0.9974946975708008,
0.0014354438753798604,
0.0010698222322389483
] |
[
0.022633032873272896,
0.861405074596405,
0.11443978548049927,
0.0015220950590446591
] |
en
| 0.999997 |
HNC is a multifactorial disease whose risk factors arise from the interaction between environmental influences and genetic inheritance . Among environmental factors, smoking has emerged as the greatest risk factor, followed by alcohol consumption. When consumed simultaneously, risk increases from 10 to 100 times [ 4 – 6 ].
|
PMC11699980_p1
|
PMC11699980
|
1. Introduction
| 3.619146 |
biomedical
|
Study
|
[
0.9995341300964355,
0.00017431833839509636,
0.0002915131626650691
] |
[
0.722540020942688,
0.08143282681703568,
0.19506897032260895,
0.0009581560734659433
] |
en
| 0.999997 |
As HNC affects regions directly related to the digestive tract (reducing food intake) and induces a hypercatabolic state, carriers show significant weight loss from the time of diagnosis . Such nutritional decline is consistently associated with nutritional impact symptoms (NISs). NISs are physiological alterations caused by cancer that can compromise oral intake, including pain, dry mouth, difficulty swallowing, reduced appetite, and vomiting, among others . Approximately 96% of the population with HNC show one or more NISs before starting treatment .
|
PMC11699980_p2
|
PMC11699980
|
1. Introduction
| 3.964516 |
biomedical
|
Study
|
[
0.9994945526123047,
0.00028872964321635664,
0.0002166847261833027
] |
[
0.8663425445556641,
0.016267944127321243,
0.11690333485603333,
0.0004861493071075529
] |
en
| 0.999997 |
Individuals with HNC and multiple NISs are more likely to experience reduced food intake, weight loss, functional capacity dysfunction, and decreased survival [ 12 – 14 ]. Systematic assessment and management of these symptoms before the start of treatment are crucial to prevent serious nutritional complications that often develop during antineoplastic therapy . An early approach allows for the implementation of appropriate nutritional and therapeutic strategies that can not only mitigate the progression of symptoms but also significantly improve the patients' quality of life. Furthermore, early treatment of NIS can prevent patients from reaching a state of severe malnutrition, which would further compromise the effectiveness of the treatment and survival .
|
PMC11699980_p3
|
PMC11699980
|
1. Introduction
| 3.891247 |
biomedical
|
Review
|
[
0.9978429079055786,
0.0016567487036809325,
0.0005003148689866066
] |
[
0.2988636791706085,
0.026721177622675896,
0.6733222007751465,
0.0010929570998996496
] |
en
| 0.999996 |
Therefore, early recognition (pretreatment) of patients with a higher burden of NIS is crucial and provides insights that can assist in appropriate therapy before the development of malnutrition and associated factors. This study aimed to analyze the presence and severity of NISs and their associated factors in individuals with HNC before treatment.
|
PMC11699980_p4
|
PMC11699980
|
1. Introduction
| 3.6975 |
biomedical
|
Study
|
[
0.9988705515861511,
0.0008035459322854877,
0.0003259266959503293
] |
[
0.9986333250999451,
0.0009032186935655773,
0.0003220170910935849,
0.00014145360910333693
] |
en
| 0.999995 |
This is an epidemiological, analytical, and cross-sectional investigation of individuals with HNC who were treated at a reference oncology hospital in Greater Vitória, Espírito Santo, Brazil. The data represent the baseline of a longitudinal study titled “Nutritional Indicators, Mortality, and Associated Factors: A Hospital-Based Study in Individuals with HNC.” The target population consisted of patients diagnosed with squamous cell carcinoma (mouth, larynx, oropharynx, and hypopharynx) of all sexes who were aged 18 years and above.
|
PMC11699980_p5
|
PMC11699980
|
2.1. Methodological Design and Study Population
| 3.94377 |
biomedical
|
Study
|
[
0.9991057515144348,
0.0005978992558084428,
0.00029634920065291226
] |
[
0.9994007349014282,
0.00034953138674609363,
0.00016668190073687583,
0.00008305083611048758
] |
en
| 0.999996 |
The study participants were invited to join after confirmation of their HNC diagnosis by the Head and Neck Surgery Medical Service at a cancer treatment reference hospital. The participants were patients receiving care through the Unified Health System (SUS), Brazil's public healthcare system. Following histopathological confirmation of the HNC diagnosis, all eligible individuals were invited by the researchers between September 2022 and January 2024. Participation was confirmed by signing informed consent forms that detailed the research. Data were collected by researchers who had undergone prior training in administering questionnaires and performing anthropometric measurements, including the standardization of measurement techniques to ensure data accuracy.
|
PMC11699980_p6
|
PMC11699980
|
2.2. Sampling and Selection
| 2.897177 |
biomedical
|
Study
|
[
0.9972299933433533,
0.0015463416930288076,
0.0012235766043886542
] |
[
0.9987778067588806,
0.0010027438402175903,
0.00011434040789026767,
0.00010515916801523417
] |
en
| 0.999997 |
To calculate the sample size, a sample universe of 200 patients was considered, corresponding to the average annual number of first consultation visits at the HNC outpatient clinic, a prevalence of 50% (to maximize the sample), a sampling error of 5%, and a confidence interval of 95%. The resulting minimum sample size totaled 132 individuals. The calculation was performed using Epi Info 7.2 software.
|
PMC11699980_p7
|
PMC11699980
|
2.2. Sampling and Selection
| 3.242578 |
biomedical
|
Study
|
[
0.9984387755393982,
0.0009421774884685874,
0.0006190602434799075
] |
[
0.9967228770256042,
0.0030189205426722765,
0.00013433799904305488,
0.00012382054410409182
] |
en
| 0.999998 |
Participants of all sexes who were aged 18 years or above, diagnosed with squamous cell carcinoma of the oral cavity, larynx, oropharynx, and hypopharynx, and without previous treatment, were included. Cases were confirmed by histology and classified according to the ICD-10-03 into the following topographies: base of tongue (C01), other and unspecified parts of tongue (C02), gum (C03), floor of mouth (C04), palate (C05), other and unspecified parts of mouth (C06), tonsil (C09), oropharynx (C10), pyriform sinus (C12), hypopharynx (C13), and larynx (C32).
|
PMC11699980_p8
|
PMC11699980
|
2.3. Inclusion and Exclusion Criteria
| 3.954034 |
biomedical
|
Study
|
[
0.9982975125312805,
0.0014064233982935548,
0.00029608234763145447
] |
[
0.9985034465789795,
0.0011475594947114587,
0.00021109468070790172,
0.00013796635903418064
] |
en
| 0.999996 |
Subsequently, the ICD codes were grouped into four topographic categories: oral cavity (C01, C02, C03, C04, and C05), oropharynx (C05.1, C09, and C10), larynx (C32), and hypopharynx (C12 and C13). Patients were excluded from the study if they had a diagnosis of recurrent squamous cell carcinoma, had previously received cancer treatment, presented with multiple tumors, or lacked the clinical and mental capacity to respond to the administered questionnaire.
|
PMC11699980_p9
|
PMC11699980
|
2.3. Inclusion and Exclusion Criteria
| 3.510175 |
biomedical
|
Study
|
[
0.9976071119308472,
0.0018425274174660444,
0.0005503383581526577
] |
[
0.9974888563156128,
0.0020387445110827684,
0.0002856982173398137,
0.00018664001254364848
] |
en
| 0.999998 |
A questionnaire was administered to evaluate patients' sociodemographic (sex, age, race/ethnicity, education, and income), lifestyle (smoking and alcohol consumption), and clinical data (tumor site and staging). It is worth noting that sociodemographic variables and lifestyle habits were self-reported. The Head and Neck Symptom Checklist (HNSC), a validated tool in individuals with HNC , was used to assess NIS. It consists of 17 symptoms assessed on a five-point Likert scale ranging from “1, not at all” to “5, very much.” For analysis, all 17 symptom scores were added, resulting in a total score that can range from 17 (no symptoms) to 85 (highest score for each symptom on the list) .
|
PMC11699980_p10
|
PMC11699980
|
2.4. Data Collection
| 4.042192 |
biomedical
|
Study
|
[
0.9986671209335327,
0.0010062850778922439,
0.00032651881338097155
] |
[
0.9992361068725586,
0.0004427309613674879,
0.00023832565057091415,
0.00008277734741568565
] |
en
| 0.999995 |
The Nutritional Risk Screening tool was used to assess nutritional risk. It is a validated instrument and is based on data on dietary intake in the previous week, body mass index (BMI), weight loss in the last three months, age, and disease severity. Patients are scored according to malnutrition and the severity of the underlying disease, classified for each variable as absent (0), mild (1), or severe (2). Patients with a score of three or more are classified as at nutritional risk, while those with a score below three should be reassessed . In addition, anthropometric measurements (weight and height) were collected by the researchers, and body composition measurements (appendicular skeletal muscle mass) were obtained using a portable InBody 120 bioimpedance device.
|
PMC11699980_p11
|
PMC11699980
|
2.4. Data Collection
| 4.111661 |
biomedical
|
Study
|
[
0.9984429478645325,
0.0014055166393518448,
0.00015153168351389468
] |
[
0.9969160556793213,
0.0018938331631943583,
0.0009581351187080145,
0.0002320241037523374
] |
en
| 0.999998 |
Data were evaluated on Research Electronic Data Capture , uploaded to the cloud of the Federal University of Espírito Santo, and organized and analyzed on R (4.3.1) for Windows. Absolute and relative frequencies were used to describe the categorical variables. Measures of central tendency (means and medians) and dispersion (standard deviations and interquartile ranges) were used to describe continuous variables. NIS scores (17–85 points) were used as the dependent variable. A multiple linear regression was performed to quantify the participation of independent variables (sex, age, staging, education, income, topography, race/color, smoking, alcohol consumption, nutritional risk, BMI, and ASMM) in the outcome. The significance level for all tests was set at 5%.
|
PMC11699980_p12
|
PMC11699980
|
2.5. Statistical Analysis
| 3.985972 |
biomedical
|
Study
|
[
0.9988498687744141,
0.0001859327167039737,
0.0009641836513765156
] |
[
0.9994875192642212,
0.0003174075100105256,
0.00016106553084682673,
0.00003391878635738976
] |
en
| 0.999996 |
This project was approved by the Research Ethics Committee of the Cassiano Antônio Moraes University Hospital under final opinion no. 6,241,277 and CAAE 56453322. 7.0000.5060. It complied with the ethical standards governing research involving human subjects.
|
PMC11699980_p13
|
PMC11699980
|
2.6. Ethical Aspects
| 1.01096 |
other
|
Other
|
[
0.31868812441825867,
0.003956183325499296,
0.6773556470870972
] |
[
0.0029913554899394512,
0.9963362216949463,
0.0002823825925588608,
0.0003900973533745855
] |
en
| 0.999996 |
The sample consisted of 132 participants, with a higher proportion of older adults (61%)—with a mean age of 61 years, men (77%), mixed-race people (54%), with less than eight years of education (71%), and a family income of less than or equal to two minimum wages (76%). In terms of lifestyle habits, most participants reported being former smokers (52%) and former drinkers (65%). However, even after diagnosis, 19% continued to consume alcohol. The most prevalent topography was in the oral cavity (45%), with stage IV tumors (53%). Although 43% of participants were overweight (showing overweight and obesity), 45% of the population were at nutritional risk according to the NRS at the time of diagnosis ( Table 1 ).
|
PMC11699980_p14
|
PMC11699980
|
3. Results
| 3.697648 |
biomedical
|
Study
|
[
0.9987587928771973,
0.0006949129165150225,
0.0005462294211611152
] |
[
0.9994396567344666,
0.00037383390008471906,
0.00012036747648380697,
0.00006612201104871929
] |
en
| 0.999994 |
Regarding NIS, 95% of participants showed one or more NISs ( n = 126), with the most recurrent symptoms being pain (68.93%), difficulty chewing (60.60%), thick saliva (59.84%), anxiety (58.33%), sore mouth (52.27%), and difficulty swallowing (50.0%) ( Table 2 ).
|
PMC11699980_p15
|
PMC11699980
|
3. Results
| 3.79487 |
biomedical
|
Study
|
[
0.9984121322631836,
0.0011852304451167583,
0.0004026060923933983
] |
[
0.9991040825843811,
0.000610123563092202,
0.0001825096842367202,
0.00010327131167287007
] |
en
| 0.999997 |
Table 3 shows the data on the association between sociodemographic, lifestyle, and clinical variables and the total score of NISs. Topography, smoking, and nutritional risk showed an association. Cancer in the larynx ( p =0.031) had an estimated reduction of 6.67 points in NIS scores in comparison to that in the oral cavity. Regarding smoking, former smokers ( p =0.019) showed an estimated reduction of 5.87 points in NIS scores than smokers. Finally, participants with nutritional risk ( p =0.009) have an estimated increase of 6.15 points in total NIS scores when compared to those without nutritional risks (see Table 4 ).
|
PMC11699980_p16
|
PMC11699980
|
3. Results
| 4.050092 |
biomedical
|
Study
|
[
0.9991998076438904,
0.00042154279071837664,
0.0003786710149142891
] |
[
0.9995275735855103,
0.0001520115474704653,
0.00026949227321892977,
0.00005094367588753812
] |
en
| 0.999997 |
This study evinced a high severity and quantity of NIS in its population. About 9 out of 10 participants reported one or more NISs before treatment, corroborating the findings by Farhangfar et al. , who observed that 94% of their HNC cohort had one or more NISs before antineoplastic therapy. NISs lead to a series of consequences for individuals, inducing an inflammatory response that limits energy and protein intake and contributes to increased stress and weight loss before and even during treatment . Additionally, NIS presence and severity tend to increase during treatment , which can impact treatment efficacy and sometimes necessitate treatment interruption until the specific symptom is reversed and the individual can resume therapy. Jin et al. showed that NIS worsened during radiotherapy early on, emphasizing the importance of managing these symptoms before starting therapy.
|
PMC11699980_p17
|
PMC11699980
|
4. Discussion
| 4.095107 |
biomedical
|
Study
|
[
0.9994738698005676,
0.00030617337324656546,
0.00021995858696755022
] |
[
0.9991292357444763,
0.00018748792354017496,
0.0006187367253005505,
0.00006459141877712682
] |
en
| 0.999998 |
The most recurrent symptoms included pain (68.93%), difficulty chewing (60.60%), thick saliva (59.84%), anxiety (58.33%), sore mouth (52.27%), and difficulty swallowing (dysphagia) (50.0%). Results showed symptom clusters similar to previous studies. Kubrak, Olson, and Baracos found that the most common symptoms before treatment were pain (33%) and dysphagia (29%). Farhangfar et al. reported that the most prevalent symptoms were pain (63.6%), anxiety (62.9%), and lack of energy (58.5%). Furthermore, Granstrom et al. showed that the highest NIS scores at baseline occurred for pain (96%), anxiety (96%), and sore mouth (95%). Despite the discrepancies in symptoms across studies, pain is commonly the most reported symptom, typically ranking first in proportions. This study may explain this fact by the predominant location (the oral cavity) and the advanced stage of the disease (stage IV).
|
PMC11699980_p18
|
PMC11699980
|
4. Discussion
| 4.086792 |
biomedical
|
Study
|
[
0.9992859959602356,
0.0003651413426268846,
0.00034886636422015727
] |
[
0.9986209869384766,
0.00014402499073185027,
0.0011720750480890274,
0.00006288271833909675
] |
en
| 0.999997 |
This study found an association between tumor location and NIS score before treatment. Individuals with HNC in the larynx had NIS lower quantity and/or severity than those with cancer in their oral cavity. These findings resemble those by Granstrom et al. , who found a higher NIS score in individuals with HNC in the oral cavity and oropharynx than in those with larynx cancer during and after treatment. The main signs and symptoms in laryngeal cancer include hoarseness, pain during swallowing, changes in voice quality, sensation of lumps in the throat, difficulty breathing, or even shortness of breath . Of these reported symptoms, the HNSC—the tool chosen for the study—includes only one: odynophagia (painful swallowing), with only 12% of the population reporting this type of NIS. Therefore, a partial explanation for a lower presence and/or severity of symptoms in laryngeal cancer may be due to the chosen tool ignoring the other characteristic symptoms of this type of cancer.
|
PMC11699980_p19
|
PMC11699980
|
4. Discussion
| 4.094824 |
biomedical
|
Study
|
[
0.9993477463722229,
0.00041582025005482137,
0.00023645299370400608
] |
[
0.9991140961647034,
0.0001879702613223344,
0.0006199704366736114,
0.00007799160812282935
] |
en
| 0.999995 |
Individuals who quit smoking had lower NIS presence and/or severity than those who still smoked. Smoking is a well-established direct risk factor in the literature, considered the primary risk factor in HNC development . Tobacco acts as a factor for tumor growth, and cigarette smoke acts as a mutagenic and DNA-damaging agent that drives tumor initiation in normal epithelial cells . Thus, individuals who continue smoking after diagnosis contribute to this entire cascade driving the tumor, which is consistently related to a higher burden or severity of NIS.
|
PMC11699980_p20
|
PMC11699980
|
4. Discussion
| 4.045579 |
biomedical
|
Study
|
[
0.9996159076690674,
0.00018115002603735775,
0.00020292871340643615
] |
[
0.9985752105712891,
0.00046496995491907,
0.0009004359599202871,
0.00005936736852163449
] |
en
| 0.999997 |
The presence of nutritional risk in individuals with HNC is relatively high from the time of diagnosis. Overall, 45% of the population in this study was at nutritional risk, agreeing with the findings by Wang et al. and by Bossi et al. , who found around 30.3% of the HNC population showing nutritional risk at the time of diagnosis. Furthermore, the presence of nutritional risk and total NIS scores showed an association. Individuals at nutritional risk had a higher presence or severity of NIS than those without nutritional risk. According to Wang et al. , NISs are positively correlated with nutritional risk in HNC patients in the perioperative period, resulting in higher scores according to the NRS-2002.
|
PMC11699980_p21
|
PMC11699980
|
4. Discussion
| 4.0519 |
biomedical
|
Study
|
[
0.9995021820068359,
0.0002705133520066738,
0.0002273347636219114
] |
[
0.9989332556724548,
0.00016388292715419084,
0.0008463654667139053,
0.00005657288420479745
] |
en
| 0.999997 |
As a possibility of bias, information bias was minimized due to training of all staff in data collection and management. In addition, selection bias was also a possibility; however, all individuals who were in the CCP outpatient clinic during the research period were invited to participate in the research. The refusal rate was low, at 2.1%, out of a total of 143 individuals.
|
PMC11699980_p22
|
PMC11699980
|
4. Discussion
| 2.113906 |
biomedical
|
Study
|
[
0.9898052215576172,
0.003149200463667512,
0.007045487407594919
] |
[
0.9914747476577759,
0.007971354760229588,
0.00024346222926396877,
0.00031043431954458356
] |
en
| 0.999998 |
This study has limitations. Its cross-sectional design implies an analysis of NIS at a single point in time, which affects causality. Additionally, a multicenter evaluation with a larger number of patients could provide more accurate assumptions. However, the findings in this study complement the literature and show that health education and nutritional monitoring should be provided to patients from the moment of diagnosis to help them understand the importance of nutritional treatment, ensuring adequate nutritional intake and improving their nutritional status.
|
PMC11699980_p23
|
PMC11699980
|
4. Discussion
| 3.93177 |
biomedical
|
Study
|
[
0.9994414448738098,
0.0003644120879471302,
0.00019403280748520046
] |
[
0.9986257553100586,
0.0005195256089791656,
0.0007607609149999917,
0.00009395867527928203
] |
en
| 0.999998 |
Individuals with HNC who smoke and have nutritional risk show higher estimates of NIS severity and quantity. However, those with tumors in their larynx have lower estimates of symptom severity than those with cancer in their oral cavity.
|
PMC11699980_p24
|
PMC11699980
|
5. Conclusion
| 2.406735 |
biomedical
|
Other
|
[
0.9966539144515991,
0.0007092833402566612,
0.0026367150712758303
] |
[
0.42863211035728455,
0.5575067400932312,
0.012734169140458107,
0.0011269524693489075
] |
en
| 0.999999 |
Treating patients with locally advanced or oligometastatic cancer using radiation therapy typically requires multiple targets to be irradiated simultaneously. However, treatment accuracy may be compromised due to differential motion between independently moving structures. 1 , 2 To compensate for relative motion between targets, large planning target volume (PTV) margins can be applied 3 , 4 to ensure each target receives the desired prescription dose, however, this is a suboptimal solution due to the resulting increase in dose to the healthy tissue. 5
|
39441205_p0
|
39441205
|
INTRODUCTION
| 3.934827 |
biomedical
|
Study
|
[
0.9956735968589783,
0.003682501148432493,
0.0006438886630348861
] |
[
0.5244158506393433,
0.36417344212532043,
0.10917069017887115,
0.002240058733150363
] |
en
| 0.999998 |
One patient subset requiring multi‐target treatment are those with locally advanced prostate cancer who can benefit from simultaneous prostate and pelvic node irradiation. 6 While the prostate can undergo motion of up to 15 mm, 7 this motion is largely uncorrelated with the pelvic nodes, 3 which remain approximately fixed to the pelvic vasculature. 8 Thus, when the patient is being aligned for radiation therapy treatment, a compromise must be made when aligning the radiation beam with the targets, and often the prostate is prioritized. 9 , 10 Decreases in dose coverage for the lymph nodes of 5%, 15%, and 25% have been seen when a patient is set up with 5, 10, and 15 mm prostate displacements respectively during intensity‐modulated radiation therapy treatment. 11 In addition to translational displacements relative to the prostate, variations in pelvic rotation may also be present, leading to further setup errors. Despite the potential for dosimetric consequences resulting from geometric displacements of the pelvis, the six‐degrees‐of‐freedom (6DoF) position of the pelvis is generally not monitored and cannot be accounted for during standard radiation therapy treatment without compromising the primary target.
|
39441205_p1
|
39441205
|
INTRODUCTION
| 4.138573 |
biomedical
|
Study
|
[
0.9984329342842102,
0.0012082564644515514,
0.00035879830829799175
] |
[
0.8569772243499756,
0.006237965542823076,
0.13613393902778625,
0.0006508164224214852
] |
en
| 0.999997 |
Treatment methods that account for interfraction displacements of the prostate and pelvic lymph nodes through online adaptation have been demonstrated. 12 , 13 However, online adaptive methods do not account for patient movement or internal prostate motion during treatment delivery which have shown considerable deviations in some patients. 7 , 14 To adapt to intrafraction motion of the targets, real‐time multi‐target MLC tracking has been proposed 15 , 16 which would require accurate intrafraction motion inputs for each target to be input.
|
39441205_p2
|
39441205
|
INTRODUCTION
| 3.966433 |
biomedical
|
Study
|
[
0.9992678761482239,
0.00027372274780645967,
0.00045842057443223894
] |
[
0.9818502068519592,
0.00234042014926672,
0.015666872262954712,
0.00014246325008571148
] |
en
| 0.999996 |
Existing tumor motion tracking systems such as the CyberKnife 17 and Radixact 18 have been designed to track tumor motion during radiation therapy delivery, however, are limited to adapting to single targets. Alternatively, Kilovoltage Intrafraction Monitoring (KIM) uses hardware on a standard linear accelerator to monitor tumor motion in real time by estimating 6DoF motion as observed in intrafraction kV images. 19 , 20 KIM has previously been implemented in clinical trials to treat prostate 21 and liver 22 cancer patients, and has demonstrated sub‐mm and sub‐degree geometric accuracy for monitoring the motion of fiducial markers implanted in the prostate. 23 So far, KIM has also been limited to monitoring the motion of a single target to guide motion adaptation.
|
39441205_p3
|
39441205
|
INTRODUCTION
| 3.995574 |
biomedical
|
Study
|
[
0.9991922974586487,
0.0003646467812359333,
0.00044314644765108824
] |
[
0.9085767269134521,
0.0013825128553435206,
0.08980035036802292,
0.0002404314000159502
] |
en
| 0.999994 |
The aim of this study was to enable multi‐target motion monitoring by developing and assessing a method to calculate the translation and rotation of the pelvic bone in intrafraction kV images as a surrogate for pelvic lymph node displacement. The resulting method could be integrated into a framework to enable simultaneous real‐time motion monitoring of both the prostate and pelvic lymph nodes and used to guide multi‐target treatment adaptation.
|
39441205_p4
|
39441205
|
INTRODUCTION
| 4.097562 |
biomedical
|
Study
|
[
0.998678982257843,
0.0010550571605563164,
0.00026601256104186177
] |
[
0.9986999034881592,
0.0008826663834042847,
0.0002903197892010212,
0.00012700694787781686
] |
en
| 0.999997 |
A method to track the pelvic bone translation ( T LR , T SI , T AP ) and rotation ( R LR , R SI , R AP ) in intrafraction kV images were developed and described in detail below. The method was tested retrospectively on images collected from 20 prostate cancer patients who were treated in the Trans‐Tasman Radiation Oncology Group (TROG) 15.01 Stereotactic Prostate Ablative Radiotherapy with KIM (SPARK) trial. 21 The anonymized patient images are publicly available. 24
|
39441205_p5
|
39441205
|
METHODS
| 3.875327 |
biomedical
|
Study
|
[
0.9984014630317688,
0.0012343417620286345,
0.0003641625808086246
] |
[
0.9974073767662048,
0.0021376481745392084,
0.00027315941406413913,
0.00018190147238783538
] |
en
| 0.999997 |
An outline of the multi‐target motion monitoring method is illustrated in Figure 1 . The method performed template matching to identify the position of the pelvic bone in the kV projections, requiring a set of reference images, and is described in detail below.
|
39441205_p6
|
39441205
|
The multi‐target motion monitoring method
| 3.162049 |
biomedical
|
Study
|
[
0.9940955638885498,
0.003839121898636222,
0.002065356820821762
] |
[
0.6087398529052734,
0.3872344493865967,
0.0017886492423713207,
0.0022370486985892057
] |
en
| 0.999996 |
To generate a template of the anatomy of interest, the pelvic bone on each patient's planning CT was contoured and used to mask the CT volume. The femurs were excluded from the contour. Digitally reconstructed radiographs (DRRs) were generated of the masked CT volumes using the open‐source Reconstruction Toolkit (RTK). 25 As the expected shape of the pelvic bone on the 2D treatment images would vary depending on the gantry angle, DRRs at a range of projection angles were generated to form a 6DoF library for each patient. DRRs were generated for angles around the superior‐inferior ( R SI ) axis ranging from 0° to 359.5° in increments of 0.5°. For each R SI angle, projections with the pelvic bone rotating out of the imaging plane ( R x ) were also generated, ranging from ‐6° to +6° in increments of 0.5°. The magnitude of the gradients for each DRR in the x and y directions were then computed so that the edges of the bony anatomy would form the dominant feature in each template.
|
39441205_p7
|
39441205
|
Pre‐treatment template generation
| 4.142459 |
biomedical
|
Study
|
[
0.9983782768249512,
0.0013741232687607408,
0.00024750945158302784
] |
[
0.9980736970901489,
0.0012747047003358603,
0.0004636874364223331,
0.00018788449233397841
] |
en
| 0.999995 |
Pelvic bone segmentation was performed on kV images acquired with a known gantry angle. The method implemented three‐frame temporal averaging and a median filter to reduce image noise, followed by a Gaussian bandpass filter to enhance the edges of the bony anatomy in the image. The fiducial markers implanted in the prostate for prostate motion monitoring were automatically masked in the kV images. The gradients of each kV image were calculated to generate an image that highlighted the edges of the bony anatomy, consistent with the method used for template generation.
|
39441205_p8
|
39441205
|
6DoF motion monitoring of the pelvic bone
| 4.086971 |
biomedical
|
Study
|
[
0.9989641904830933,
0.000861670239828527,
0.0001740966981742531
] |
[
0.9937900900840759,
0.005021250806748867,
0.0008941935375332832,
0.00029445948894135654
] |
en
| 0.999997 |
Template matching was performed by calculating the 2D normalized cross‐correlation of the template and the kV treatment image. The x and y values that corresponded to the maximum normalized cross‐correlation coefficient were used to determine the 2D displacement ( T x and T y ) of the pelvic bone during treatment from the planning CT. T x and T y were computed at a resolution consistent with the acquired image resolution. The search region for T x and T y was limited to within 1 mm of the last measured position in each direction between image acquisitions. This calculation was repeated for a selection of DRRs from the generated library, to check rotations close to the expected rotation of the pelvis in the R x and R y directions. Each template image was also rotated around the imaging axis to calculate the normalized cross‐correlation for varying R z rotations. The DRR and R z rotation that had the highest normalized cross‐correlation value were used to determine R x , R y , and R z . By finding the combination with the maximum normalized cross‐correlation coefficient, T x , T y , R x , R y , and R z were determined simultaneously. For the first treatment image, rotations ranging ± 6° from the planned pelvic bone position were tested, and for subsequent images rotations ranging ± 0.5° from the previous image were tested.
|
39441205_p9
|
39441205
|
6DoF motion monitoring of the pelvic bone
| 4.152921 |
biomedical
|
Study
|
[
0.9987670183181763,
0.0009766363073140383,
0.000256390223512426
] |
[
0.9988061189651489,
0.0006168262334540486,
0.0004441672354005277,
0.00013289813068695366
] |
en
| 0.999997 |
The final unresolved motion, translation along the imaging axis ( T z ), was calculated using a probability‐based method previously described by Poulsen et al. 26 This method assumes a 3D Gaussian probability density function (PDF) for the target position. An initial PDF was built using the position of the pelvis observed in the first 20 projections acquired using maximum likelihood estimation, and then updated with each incoming image. Then, the unknown position of the pelvis along the direction of the imager axis was estimated by finding the expectation value determined by the 1D Gaussian distribution along the imaging axis.
|
39441205_p10
|
39441205
|
6DoF motion monitoring of the pelvic bone
| 4.125031 |
biomedical
|
Study
|
[
0.9994646906852722,
0.00033223885111510754,
0.0002030741743510589
] |
[
0.9989042282104492,
0.0005885429563932121,
0.00042400319944135845,
0.0000832133591757156
] |
en
| 0.999998 |
Finally, a rotational transformation was applied to determine the pelvic bone displacement in the patient coordinates ( T LR , T SI , T AP and R LR , R SI , R AP ) with respect to the planning CT.
|
39441205_p11
|
39441205
|
6DoF motion monitoring of the pelvic bone
| 3.482375 |
biomedical
|
Study
|
[
0.994219183921814,
0.004436052404344082,
0.0013446928933262825
] |
[
0.9274053573608398,
0.07081621140241623,
0.0007152773905545473,
0.0010631096083670855
] |
en
| 0.999997 |
Prostate motion was monitored using KIM, which automatically segmented fiducial markers implanted in the prostate on the same kV image and estimated the 3D motion based on a 3D Gaussian PDF. Rotation of the prostate was then calculated using an iterative closest point algorithm for each marker to calculate a rotation matrix. 20 , 27
|
39441205_p12
|
39441205
|
6DoF motion monitoring of the pelvic bone
| 4.04802 |
biomedical
|
Study
|
[
0.99934321641922,
0.0005302885547280312,
0.00012649927521124482
] |
[
0.9957453608512878,
0.003251921385526657,
0.0008120230049826205,
0.0001907284458866343
] |
en
| 0.999998 |
To evaluate the geometric accuracy of the pelvic tracking method described above, the method was tested retrospectively on prostate patient data. The patients included in this study were treated using a Varian TrueBeam linear accelerator, at three different treatment institutions. Two‐dimensional images acquired using the onboard kV imaging system on the linear accelerator were tested for 20 patients, who were each treated in five fractions. Each patient was treated using stereotactic body radiation therapy (SBRT) guided by KIM which provided real‐time 6DoF motion of the prostate. 23
|
39441205_p13
|
39441205
|
Retrospective geometric accuracy analysis
| 4.074484 |
biomedical
|
Study
|
[
0.9976832866668701,
0.002008739160373807,
0.0003079661400988698
] |
[
0.9988075494766235,
0.0007669206243008375,
0.00023485020210500807,
0.00019074749434366822
] |
en
| 0.999997 |
Due to the limited field of view of the intrafraction KIM images, the multi‐target motion monitoring method was tested on 2D kV projections acquired for the pre‐treatment cone‐beam computed tomography (CBCT) image at the beginning of each treatment to guide the initial patient set‐up. These images were acquired over a 200° arc at a rate of 14 Hz, with an average of 470 full‐fan projections acquired per CBCT. The projections had an average angle separation of 0.4°. The imaging system had a source‐to‐axis distance (SAD) of 1000 mm and a source‐to‐detector distance (SDD) of 1500 mm. Each image was acquired with a resolution of 1024 × 774 pixels and a pixel size of 0.388 × 0.388 mm 2 , and then cropped to a field size of 180 × 180 mm 2 for pelvic motion monitoring.
|
39441205_p14
|
39441205
|
Retrospective geometric accuracy analysis
| 4.138352 |
biomedical
|
Study
|
[
0.9978347420692444,
0.0018476700643077493,
0.00031755544478073716
] |
[
0.9982241988182068,
0.001268582884222269,
0.00031963037326931953,
0.00018757424550130963
] |
en
| 0.999996 |
The ground truth offset between the pelvic bone displacement during CBCT acquisition and in the planning CT was evaluated by performing an automatic 6DoF rigid registration of the planning CT to the 3D reconstructed CBCT using the Elastix toolbox. 28 To ensure that the volumes were registered to the bony anatomy, the CT images were masked with the pelvic bone segmentations and registered to each CBCT. The planning CTs were acquired with 1.5, 2, and 2.5 mm slice thicknesses depending on the treatment institution. Both the translational and rotational displacements were calculated and compared to the output of the pelvic motion tracking method. The rationale for choosing this ground truth is that the mean of the real‐time 6DoF tracking during the image acquisition should equal the reconstructed image registration, assuming that the means from these two processes should be similar.
|
39441205_p15
|
39441205
|
Retrospective geometric accuracy analysis
| 4.114244 |
biomedical
|
Study
|
[
0.9988855719566345,
0.0008835067856125534,
0.0002308720286237076
] |
[
0.9988359808921814,
0.0005234578857198358,
0.0005184069741517305,
0.00012219847121741623
] |
en
| 0.999998 |
The overall geometric accuracy of the pelvic motion monitoring method with reference to the patients’ coordinate system is shown in Figure 2 . The mean and standard deviation geometric errors for the translational directions T LR , T SI , and T AP were 0.0 ± 0.1 mm, ‐0.5 ± 0.5 mm, and 0.1 ± 0.1 mm, respectively, and for the rotational directions R LR , R SI , and R AP were 0.3° ± 0.1°, 0.6° ± 0.4°, and 0.0° ± 0.3, respectively.
|
39441205_p16
|
39441205
|
6DoF pelvic motion monitoring accuracy
| 4.131774 |
biomedical
|
Study
|
[
0.9979560375213623,
0.0017658500000834465,
0.0002781508956104517
] |
[
0.9987710118293762,
0.0006482471944764256,
0.00041848557884804904,
0.0001621627452550456
] |
en
| 0.999998 |
The geometric accuracy of prostate motion monitoring using KIM for this cohort of patients has been previously reported to be sub‐mm for translation and within 1.4° for rotation. 23
|
39441205_p17
|
39441205
|
6DoF pelvic motion monitoring accuracy
| 3.77054 |
biomedical
|
Study
|
[
0.9987906813621521,
0.00091049779439345,
0.0002988485211972147
] |
[
0.9935401082038879,
0.005706813186407089,
0.0005099361296743155,
0.0002432123146718368
] |
en
| 0.999997 |
The distribution of relative displacements between the pelvic bone and prostate observed in the kV projections is shown in Figure 3 . The 5th and 95th percentiles for the relative motion between the prostate and pelvic bone were [‐0.8 mm, 1.4 mm], [‐6.2 mm, 3.6 mm], and [‐4.2 mm, 3.2 mm] for the T LR , T SI , and T AP directions, and [‐9.7°, 4.8°], [‐2.9°, 3.2°], and [‐2.4°, 1.8°] for the R LR , R SI , and R AP directions, respectively. The 3D relative displacement between the prostate and pelvic bone exceeded 2, 3, 5, and 7 mm for approximately 66%, 44%, 12%, and 7% of the time, respectively. The correlation of motion between the pelvic bone and prostate was small for both translation ( ρ < 0.3) and rotation ( ρ < 0.4) in all three directions. An example of the relative motion observed for one patient is shown in Figure 4 .
|
39441205_p18
|
39441205
|
6DoF multi‐target displacements
| 4.110065 |
biomedical
|
Study
|
[
0.9988337159156799,
0.0009217702317982912,
0.00024459653650410473
] |
[
0.9991921782493591,
0.00031079488690011203,
0.00037974907900206745,
0.00011724977230187505
] |
en
| 0.999997 |
After each CBCT scan was acquired during the patient's treatment, a translational couch shift was applied to set the patient up to correctly align the prostate to the isocenter for the beginning of treatment. Rotation was not corrected during patient setup. The resulting interfraction displacements of the pelvic bone for translation and rotation after patient setup for each patient across five fractions are shown in Figure 5 .
|
39441205_p19
|
39441205
|
6DoF multi‐target displacements
| 3.946747 |
biomedical
|
Study
|
[
0.9474238157272339,
0.05177770555019379,
0.0007985099218785763
] |
[
0.9308269619941711,
0.060994237661361694,
0.0014977909158915281,
0.0066810413263738155
] |
en
| 0.999999 |
This study presents an intrafraction pelvic motion monitoring method that would allow for simultaneous motion monitoring of the skeletal anatomy as a surrogate for the pelvic lymph nodes, and the implanted prostate markers using kV images acquired on a standard linear accelerator during treatment. A template matching method that utilized a pre‐generated library of DRRs containing projections of the pelvic bone simulating a range of projection angles to allow for estimation of the pelvic bone translation and rotation was developed and evaluated. The pelvic motion monitoring method was found to have a geometric accuracy and precision within 1 mm and 1° for images acquired for prostate cancer patients treated as part of the TROG 15.01 SPARK trial.
|
39441205_p20
|
39441205
|
DISCUSSION
| 4.131706 |
biomedical
|
Study
|
[
0.998763918876648,
0.0010321562876924872,
0.0002039476385107264
] |
[
0.9986938834190369,
0.0007633186178281903,
0.00039150871452875435,
0.00015121561591513455
] |
en
| 0.999998 |
Relative motion between the pelvic bone anatomy and the prostate was also reported. Relative translations between the pelvic bone and prostate were largest in the T SI and T AP directions, while rotations were largest around the R LR axis (pitch). This finding is consistent with previous observations of internal prostate motion. 7 , 29 , 30 The observed relative motions between the pelvic bone and prostate suggest that when motion management is based on the prostate, a 5 mm margin would be sufficient for the pelvic lymph nodes 88% of the time. However, it should be noted that this study was limited to measuring the relative motion between the prostate and pelvic lymph nodes within a short window throughout the acquisition of the pre‐treatment CBCT, and larger displacements could be observed when the entire fraction is considered. Tyagi et al. 31 similarly examined the relative differences between patient setups based on a fiducial match and bony anatomy match for 30 patients receiving SBRT to the prostate and pelvic lymph nodes. Larger translational shifts were observed in the study by Tyagi et al., where a 5 mm shift would have only covered approximately 75% of patients, and 19% of fractions would have seen a significant loss in dosimetric coverage to the pelvic lymph nodes. Pelvic bone rotations were also measured in the current study, with all pelvic rotations in the R SI and R AP directions being within 3°, and rotations in the R LR direction were within 6°. Larger rotations were seen for the prostate compared to the pelvis and were independent of the pelvic rotations.
|
39441205_p21
|
39441205
|
DISCUSSION
| 4.131558 |
biomedical
|
Study
|
[
0.9993128776550293,
0.0004513631865847856,
0.00023576922831125557
] |
[
0.999108612537384,
0.0001880789641290903,
0.0006247544079087675,
0.00007860054756747559
] |
en
| 0.999997 |
An alternative method of estimating 6DoF pelvic bone pose on 2D images has been demonstrated by Munbodh et al. 32 , 33 Their registration framework similarly relied on matching pelvic DRRs to a treatment image by finding the pelvic bone position that maximized a similarity measure. However, instead of relying on a library of DRRs with a predetermined set of pelvic rotations, 2D DRRs were computed after iteratively performing rigid spatial transformations of the CT, optimizing for the translation and rotation parameters using a gradient ascent search strategy. While this approach prioritized establishing a high registration accuracy, the computation time to achieve a single registration solution would not be compatible with real‐time intrafraction monitoring of the pelvic bone position. Similar methods relying on fast generation of DRRs have also been applied to verify the 6DoF position of other structures such as the spine 34 or cranium. 35 Registration of 2D to 3D images to verify patient setup has also been performed by acquiring orthogonal 2D projections, however the acquisition of images at separate gantry angles on a standard linear accelerator will involve a time delay. 36 The computational time of the method implemented in MATLAB (MathWorks, USA) in the current study was approximately 10 s per frame. This latency could be reduced considerably for clinical implementation using several strategies including utilizing high performance and parallel computing resources, implementing the method in a faster coding language, reducing the template size, and using gradient ascent search strategies to determine the translational and rotational parameters.
|
39441205_p22
|
39441205
|
DISCUSSION
| 4.160548 |
biomedical
|
Study
|
[
0.9994390606880188,
0.0002805905824061483,
0.0002803354000207037
] |
[
0.9987187385559082,
0.0002465370635036379,
0.0009720667148940265,
0.00006259800284169614
] |
en
| 0.999996 |
Subsets and Splits
SQL Console for rntc/test-pp-aa
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Returns a sample of 100 clinical case documents, providing a basic overview of the document type's content.