To investigate the temporospatial changes in sympathetic skin response (SSR) and electroencephalogram (EEG) under thermal stimuli and to draw a topographic map of SSR threshold temperature of the oral mucosa.A total of 40 healthy volunteers  were enrolled. Thermal stimuli were applied to the 35 partitions of oral mucosa starting from 36°C at the gradience of 1°C and the lowest temperature evoked SSR was defined as SSR threshold temperature. SSR and EEG signals at 45, 48, 51, and 54°C were then recorded synchronously.p < 0.05). Reduction in the alpha frequency band was observed after thermal stimuli, and there were statistical differences between baseline and thermal stimuli in all four degrees of temperatures (p < 0.05).The SSR threshold temperature increased from the anterior areas to the posterior areas. No significant difference between bilateral corresponding areas or between genders was observed. The SSR amplitude value increased from 45 to 54°C in the same area, while the highest value was recorded on the tip of the tongue and decreased backwardly from the anterior area. There were significant differences in latency of SSR between the tip of the tongue and the molar areas of the oral cavity  played important roles in thermal perception of oral mucosa and could be helpful for better understanding of pathological mechanism of burning mouth syndrome (BMS). Thermal perception is one of the essential senses. As the initial part of the digestion system, oral mucosa played a significant role in perception, protection, and secretion by acting as a major barrier . ThermalThe sympathetic skin response (SSR) was referred to as the process of a transient change in skin action potential upon receipt of external or internal stimulation . Hilz etElectroencephalogram (EEG) is a recording of typical physiological signals of the central nervous system , which cSympathetic skin response and EEG were often used as auxiliary methods to detect functional changes in autonomic and central nerves, which were helpful for the diagnosis and prediction of clinical nervous system diseases . HoweverTherefore, the aims of this study were to (1) investigate and map the SSR threshold temperature in the oral mucosa at various sites in healthy young adults, (2) measure the SSR and EEG triggered in different areas of the oral mucosa under various levels of thermal stimuli, (3) explore the potential relationship between SSR and EEG, and (4) provide a theoretical basis for diagnosis and treatment of patients with abnormal temperature perception or BMS.Forty healthy subjects from Tianjin Medical University were included in this study, including 24 men and 16 women, aged 19–28 years old, with a mean age of 23 ± 3 .The inclusion criteria were as follows: (1) participants who had complete dentition without any mucosal diseases or abnormal temperature sensation in the oral cavity; (2) participants without the intake of psychotropics or drugs inhibiting glandular secretion in the past 2 weeks, such as diazepam and atropine; (3) participants with normal cardiac function, without any heart-related diseases; and (4) participants who did not participate in other medical experiments or clinical trials in the past 2 months. Subjects, with psychiatric or neurologic disorders, or without written informed consent, were excluded from the study. In addition, participants whose waveform could not be obtained were excluded from the final analysis.This study was approved by the Ethics Committee of Tianjin Medical University (No. TMUhMEC20210201) and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Informed consent was obtained before the study. Participants were able to withdraw from this study at any time during the period of the study.The thermal stimulation instrument worked on the principle of intelligent temperature control (Chinese Patent No. ZL202121087859.2) . Hot temAn NDI-92 nerve/electromyogram evoked potential instrument  was used to test SSR. It was provided by the Stomatological Anatomy and Physiology Laboratory of the Stomatological Hospital of Tianjin Medical University.EEG signals were collected by a 32-channel Quik-Cap with a NuAmps amplifier .To make the results more representative and reliable, the oral mucosa in the labial area, gingival area, and anterior 2/3 of the tongue were fully measured. The authors distinguished the mucosa at the tip of the tongue and the central areas of the upper lip and lower lip as partitions 1–3, respectively. Then, according to the position of teeth, from the right maxillary third molar, the gingival mucosa was defined as area 4–35, in a clockwise direction .To compute global frequency changes, electrodes were selected and grouped into four main areas: the frontal, left parietal, right parietal, and occipital areas . The froPrior to the testing, participants were asked to have a rest in a supine position for 10 min, during which the procedures of testing were introduced, and participants were instructed on how to collaborate with the investigators. The testing was performed in a quiet, properly shaded room with an indoor temperature of 22–25°C between 3 and 5 pm.Two hydrogel electrodes were attached to the palm and the back of the non-dominant hand of the subjects, whereby the palmar electrode served as the recording electrode and the dorsal electrode as the reference electrode. The grounding wire was placed on the wrist. The bandwidth of the Butterworth bandpass filter was set between 0.5 and 30 Hz, and the sampling frequency of SSR was 120 Hz. The analysis time was 10 s, during which the temperature of the palm skin was above 32°C.First, participants were asked to gargle with water at 36°C which was the baseline temperature of the stimulus. The Peltier semiconductor chip was then placed on each area for at least 3 s. After that, the chip was removed from the testing area. If SSR could not be recorded, the temperature was set to increase by 1°C and the test was repeated. Then, the SSR threshold temperature was recorded until the SSR waveform was evoked . The lowThe value of SSR threshold temperature at each partition was tested twice. If the difference between these two values was significant , a third test would be performed. Two values that showed the smallest deviation were selected out of three results, and their mean value was defined as the final SSR threshold temperature. All partitions were tested in the same way . BetweenSympathetic skin response and EEG tests were conducted after the SSR threshold temperature test. Before the testing of SSR and EEG, 5-min EEG signals were recorded as a baseline EEG for each subject in a supine position with eyes closed.Electroencephalogram electrodes were placed in the testing areas according to the extended international 10–20 system. The sampling frequency of EEG was 1,000 Hz, and the contact resistance between the electrode and scalp was less than 5 kΩ. To simultaneously perform SSR and EEG tests, a trigger device was designed and used by the researchers to synchronize the acquisition of signals. The onset of each thermal stimuli automatically excited the trigger operation, which allowed the synchronized acquisition of the SSR and EEG signals.There were four different levels of temperature stimuli in SSR and EEG tests. A temperature of 45°C was identified as the initial temperature for the tests, and the temperature gradient was set to 3°C. Therefore, the stimulation temperatures were 45, 48, 51, and 54°C, respectively. Each testing area received four different levels of temperature stimuli.Considering the physiological nature of the oral cavity, some representative areas were selected for the SSR and EEG tests, including (1) the central areas of incisors, premolars, and molars in maxillary and mandibular dentition, (2) the central area of the inner side of the upper and lower lip, and (3) the tip of the tongue. Since the SSR threshold temperatures were with no significant difference in premolar and molar areas, the authors, therefore, grouped these adjacent areas and irregular time intervals and non-adjacent stimulation areas were used to reduce the habituation. Each stimulation lasted for 3–5 s. Each area was tested three times, and the mean value was taken. All areas were tested in the same way.The participants were asked to rate their pain intensity on a visual analog scale (VAS). The scores were summed across categories and can range from 0 to 10. 0 points represented no pain; a score of 1–3 represented mild pain; a score of 4–7 represented moderate pain; and a score of 7–10 represented severe pain. The rating was obtained at the end of each recording in SSR and EEG tests.There were many essential parameters in the analysis of SSR, such as latency, amplitude, and waveform . The latElectroencephalogram processing and analysis were also performed in MATLAB. The recorded data were bandpass-filtered (0.05–100 Hz). The line noise of 50 Hz was suppressed by a notch filter. The eye movement and muscle artifacts were corrected by independent component analysis (ICA) using EEGLAB (version 13.6.5b). Spectral analysis was performed for each data segment by the periodogram method . Next, tStatistical analysis was performed using SPSS statistics version 25.0 . All data were tested for normality using the Shapiro–Wilk normality test. The SSR threshold temperature values were analyzed by a one-way ANOVA. The relationship between gender and SSR temperature threshold was analyzed using a generalized estimation equation (GEE), in which SSR temperature threshold was defined as the dependent variable, while partitions and gender were covariables. The SSR and EEG data were analyzed by a two-way repeated-measures ANOVA. The Bonferroni test was used when the variances were homogeneous, while Dunnett’s T3 test was used when the variances were not homogeneous. Correlational analysis was performed using Pearson’s correlations.P < 0.001). In contrast, partition 1 was the most sensitive area to heat stimuli, with an SSR threshold temperature value of 36.13 ± 1.95°C, and there was a significant difference between the SSR threshold temperature of partition 1 and that in other areas (P < 0.001). These results reflected that the sensitivity of SSR threshold temperature of oral mucosa gradually decreased from the anterior areas to the posterior areas. However, there was no significant difference between the SSR threshold temperature of symmetrical areas on either side, such as partition 8 (46.20 ± 1.65) and partition 15 (45.88 ± 1.91) (P = 0.65). In addition, the sensitivity of the SSR threshold temperature of the oral mucosa showed a tendency to gradually decrease from the midline backward to both sides. The SSR threshold temperature of the oral mucosa was not affected by sex since there was no significant difference between male and female volunteers . Finally, the map of the SSR threshold temperature of the oral mucosa was formed by the data obtained from the study , and the difference between the SSR threshold temperature of partition 6 and that in other areas was significant , temperature , and a significant area × temperature interaction on SSR amplitude  (P < 0.001), while SSR amplitudes recorded in premolar and molar areas were lower. In addition, the second and third highest values of SSR amplitude were detected in the region of the upper lip and the lower lip, respectively. In gingival areas, the first highest value of the SSR amplitude was obtained in the maxillary incisor area with significant statistical difference (P < 0.001). However, there was no statistical difference between the SSR amplitude obtained in the premolar and molar areas (P > 0.05). At the temperature of 54°C, no significant statistical difference was observed between the values of the SSR amplitude in the tip of the tongue, lips area, and the maxillary incisor area. However, compared with SSR amplitudes in the premolar or molar areas, there were significant differences between these areas (P < 0.001)  . At stim< 0.001) . The cha< 0.001) .P < 0.001). Comparing the values of the area of SSR at different temperatures, significant differences (P < 0.001) were observed except at 45 and 48°C, and at 51 and 54°C. In addition, the statistical results showed that the amplitude and the area of SSR were both positively related to the intensity of temperature stimuli  (P > 0.05).There were significant differences in the latency of SSR between the tip of the tongue and molar areas of the oral cavity at different degrees of temperatures (< 0.001) . HoweverF = 23.25, P < 0.001), theta band , alpha band , and beta band . However, neither the areas  nor the interaction effect (area × temperature) affected the average power of all four bands (P > 0.05) (P = 0.01) and 48°C (P = 0.01) in the frontal area, while in the left and right parietal area, only between baseline and 45°C (P < 0.001). Theta band: Compared to the baseline, the theta power decreased at each degree of thermal stimuli in all four brain areas. In the frontal region, there were statistical differences between baseline and 45°C (P < 0.001) and 48°C (P < 0.001), while in the occipital area, and left and right parietal area, only between baseline and 45°C (P < 0.001). Alpha band: Compared to the baseline, the alpha power also decreased at each degree of thermal stimuli in all four brain areas. There were statistical differences between baseline and thermal stimuli at all four degrees in all four brain areas (P < 0.001). Beta band: Compared to the baseline, the beta power also decreased at each degree of thermal stimuli in all four brain areas except 51 and 54°C in the occipital area. Statistical difference was observed in the frontal, left, and right parietal areas between baseline and 45°C (P < 0.001).To observe and analyze the changes in the EEG of healthy subjects in two states , the average power of the baseline and four degrees of temperatures in each frequency band were calculated in each of the four areas of the brain . A two-w > 0.05) . Delta bP < 0.001)  . To test< 0.001) .In terms of innervation, the areas of maxillary labial, buccal, and gingival mucosa were mainly innervated by the maxillary nerve, while the areas of mandibular labial, buccal, and mandibular gingival mucosa were primarily innervated by the mandibular nerve . The antThe differences in the sensitivity to heat among the oral partitions are caused by a series of factors, including differences in receptor location or type within the oral mucosa, diversities in innervation density, and variables related to the thermal conductivity of the oral mucosa . For insIn addition, the degree of keratinization and physiological function of the oral mucosa were different. Compared with the lining (lip) and the specialized mucosa (tongue), the masticatory mucosa (gingiva) contacted food more frequently; therefore, its degree of keratinization was higher, leading to a higher SSR threshold. According to the findings in this study, sex had no significant effect on the SSR threshold temperature of the oral mucosa. This may relate to the small sample size, and larger samples for verification will be needed in the future. The SSR threshold temperature of oral mucosa with a high degree of keratinization was also high. Furthermore, we found that people with unilateral chewing habits had a higher tolerance to heat temperature on the preferred side than on the non-preferred side, which was more sensitive to heat. However, in this study, we observed that the SSR could not be evoked in five subjects, which did not result from the equipment, experimental process, or environmental factors, thus requiring further investigation.The tolerance of heat in different areas of oral mucosa was different. In general, the oral cavity mucosa could tolerate higher temperatures than the lip, and a temperature below 60°C will not cause harmful results. Forty-five degrees Celsius was defined as the baseline temperature in the SSR test based on the pre-experiment. In the pre-experiment, the stimulation temperature started at 36°C and increased by 1°C each time. First, it was noted that SSR began to appear frequently only after temperature stimuli of 43°C. However, SSR could not be evoked stably until each temperature stimuli was applied at approximately 45°C. Therefore, a temperature stimuli of 45°C was used to ensure that the SSR could be evoked every time and that the waveform of the SSR was stable. The authors compared the efficacy of temperature gradients of 3 and 1°C. Eventually, the gradient of 3°C was determined as ideal to test the minimum difference of SSR under different stimulation temperatures, and great differences between the amplitudes obtained at different temperatures could be observed and the areas of SSR showed the same trend. Furthermore, this study suggested that the amplitudes and the areas of SSR were positively correlated with the intensity of stimulation . At the However, under 54°C stimulation, the amplitude of the SSR in the tip of the tongue was close to that in the upper and lower lip areas as well as the maxillary incisor area. These results further supported the idea that nociceptors could be activated at higher temperatures and subsequently initiate an extraordinary stress response . TherefoHowever, there were no significant differences in the latency of SSR between four degrees of temperatures, and the reason for differences in the latency of SSR between areas was that these areas were innervated by different nerves and the nerve conduction rate was different. Although the latency was one of the most essential factors of SSR. However, in this study, the participants were healthy young adults and the differences in latency were not obvious. Moreover, this study focused more on the relationship between SSR and EEG. Therefore, the study of latency was only a small fraction, and we will further study the difference between healthy people and patients with BMS.Delta waves (0.5–4 Hz) were the slowest waves. The waveform used in the sleep assessment was the 0.5–2 Hz band. These waves were commonly found in the frontal lobe and have a relatively large amplitude of activity, normally 75 μV or even greater, with no fixed waveform duration, and were more pronounced during deep sleep or coma. Theta waves (4–8 Hz) were often found in the central region, with no fixed amplitude range, mostly in areas of the brain unrelated to hand function, and were easily detected during the shift from relaxation to sleep. Alpha waves (8–13 Hz) often appeared in the parieto-occipital region, and normal alpha waves were synchronized and symmetrical in the cerebral hemispheres and were easily detected in the state of quiet, awake, relaxed, and eyes closed resting. Beta waves (13–30 Hz) were commonly found in the frontal and central regions and were often present in states of positive thinking, concentration, anxiety, tension, and agitation. Beta waves were decreased during deep sleep, reappear during rapid-eye-movement sleep, and vary in amplitude in both hemispheres which should exceed 50% .The observed decrease in alpha power during painful stimulation was a robust finding that previous studies have also repeatedly found. Our results showed that the decreasing trend of alpha power in all four brain areas became less obvious as the temperature of thermal stimuli increased. There was no doubt that the psychological state of the subjects at rest was relaxed, as indicated by the maximum alpha power at baseline. However, there were only statistical differences between baseline and certain temperature stimuli, and no statistical differences between temperatures. In addition, previous studies often used much larger differences between thermal stimulus intensities, and the stimulation sites were different from our study . TherefoPhysiological studies have confirmed that during the transmission of human oral temperature stimuli from the periphery to the center, the oral cavity received oral internal temperature and cold sensory stimuli through mucosal receptors and converged to the caudate nucleus of the bilateral trigeminal spinal tract nucleus through the tympanic cord nerve fibers, trigeminal nerve, and lingual nerve fibers. Then, the caudate nucleus of the spinal trigeminal nucleus further transmitted the warm pain information to the ventroposteromedial nucleus and ventroposterolateral nucleus of the thalamus  and thenThese findings, including ours, bear testimony to the fact that the CNS and the ANS are structurally linked. The degree of keratinization of the oral mucosa was related to many influencing factors such as age, dietary type, and chewing habits. There were certain differences in the degree of keratinization of the oral mucosa among people of different ages . In addiSympathetic skin response can be used to assess the activity of the sympathetic nervous system. However, the biggest limitation was the habituation of this procedure. The essence of habituation was unclear. For SSR, with the increase in the number of stimuli at the same stimulation site, the amplitude decreased in a short period and could recover soon . The habThe SSR threshold temperature of the oral mucosa varied greatly in different areas. The anterior area of the oral mucosa was the most sensitive to temperature, while the posterior area of the oral mucosa was less sensitive, which was consistent with the pattern of food intaking function of the oral cavity. The topographic map of the oral mucosa SSR threshold temperature summarily elucidated the physiological characteristics of the thermal perception pattern as well as the mechanisms of thermal habituation and protection from harmful stimuli. The action potential of SSR evoked by thermal stimuli was an objective parameter reflecting the activity of the autonomic nervous system; in this study, we hypothesized that thermal stimuli aroused SSR existed extensively over the human body than limited to the oral cavity.Our study tried to transform the subjective perception of oral mucosa to thermal stimuli into a relatively objective and accurate quantitative description, which was helpful for us to have a deeper understanding of the neurophysiological mechanism of temperature perception of oral mucosa from a new point of view. In this study, through the perception of thermal temperature in oral mucosa, we further explored the activities, mechanisms, and influencing factors of the ANS and CNS, to better understand and diagnose BMS.Measurement of synchronous activities of the CNS by EEG average power level indicated that both the autonomic and central nervous system played important roles in thermal perception. Further application of multiple channels of electrophysiological parameter analysis could be helpful to better understand the interrelationship between the CNS and ANS.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of Tianjin Medical University (No. TMUhMEC20210201) and have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. The patients/participants provided their written informed consent to participate in this study.HZ was responsible for study conception and design, device design, and assemble. SH was responsible for volunteer recruitment, data analyses, and drafted the manuscript. ZW contributed to the data interpretation. XL contributed to the data interpretation and critical revision of the manuscript. GC and SW contributed to the study conception and design, data interpretation, critically reviewing the manuscript, and crucial guidance in the study. All authors have given final approval and agreed to be responsible for all aspects of this study to ensure accuracy and integrity.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The glucocorticoid receptor (GR) promotes resistance to androgen receptor (AR)-targeting therapies in castration-resistant prostate cancer (CRPC) by bypassing AR blockade. However, the clinical relevance of evaluating GR expression in patients with CRPC has not been determined. The present study investigated the association of relative GR expression in CRPC tissue samples with treatment response to AR-targeting therapy.GR, AR-FL, and AR-V7 mRNAs were measured in prostate cancer tissue from prospectively enrolled CRPC patients who were starting treatment. Patients were divided into groups with high and low AR-V7/AR-FL ratios and with high and low GR/AR-FL ratios. The primary endpoint was prostate-specific antigen (PSA) response rate to treatment.Levels of Evaluation of 38 patients treated with AR-targeting therapies showed that the PSA response rate was significantly higher in patients with low than high AR-V7/AR-FL ratios  and in patients with low than high GR/AR-FL ratios . Patients with low GR/AR-FL ratios had higher rates of PSA progression-free survival , radiologic progression-free survival , and overall survival  than patients with high GR/AR-FL ratios. The association of GR/AR-FL ratio with PSA response to AR-targeting therapy remained significant in multivariable models. Evaluation of the 14 patients who received taxane chemotherapy showed that PSA response rates did not differ significantly in those with low and high AR-V7/AR-FL and GR/AR-FL ratios, although no definitive conclusions can be drawn due to the small number of patients.Relative GR expression is associated with sensitivity to AR-targeting therapy and survival in patients with CRPC. Large-scale prospective validation and liquid biopsy-based studies are warranted. AR mRNA has emerged as an important mechanism in CRPC progression and resistance to the AR-targeting agents enzalutamide and abiraterone (Androgen receptor (AR)-dependent mechanisms are the main pathways for development of castration-resistant prostate cancer (CRPC). Specifically, alternative splicing of raterone . Increasraterone . AR-V7 iraterone . Assessmraterone  showed traterone –9.AR bypass signaling is another mechanism implicated in resistance to AR-targeting therapy. The glucocorticoid receptor (GR), another member of the steroid receptor superfamily of ligand-regulated transcription factors, has structural and functional properties similar to those of AR . ImportaSixty men with CRPC starting AR-targeting therapy  or taxane chemotherapy (docetaxel or cabazitaxel) between January 2016 and December 2018 were prospectively enrolled. Men lacking cancerous lesions in the tissue samples (n=4), those not treated after biopsy (n=2), and those from whom mRNA could not be extracted from the biopsy sample (n=2) were excluded. The control group included men with benign prostate hyperplasia (BPH) and those with hormone-naïve prostate cancer. The study protocol was approved by the institutional review board of Asan Medical Center (no. 2014-0957).After providing informed consent, all patients underwent transrectal ultrasonography-guided prostate biopsy. Six biopsy cores from each patient were evaluated pathologically to confirm the presence of cancer cells, and two additional cores from target lesions most likely to be cancerous were used in mRNA analysis. AR-FL, AR-V7, and GR mRNA levels were analyzed by real-time quantitative reverse transcription PCR, and AR-FL, AR-V7, and GR protein levels were analyzed by western blotting, as detailed in The choice of treatment was determined by the treating physician, who was blinded to the results of tissue-based mRNA analysis. Follow-up included measurements of serum concentrations of prostate-specific antigen (PSA) levels monthly, and abdominopelvic CT and bone scanning every 3 months. All treatments were continued until PSA progression, radiologic progression, or severe treatment-related adverse events occurred.The primary endpoint was PSA response rate. The PSA response was defined as a ≥50% reduction from baseline in serum PSA concentration lasting more than 4 weeks. The best PSA response was defined as percent maximal decrease in serum PSA from baseline . SecondaCategorical variables were reported as numbers and frequencies, whereas continuous variables were reported as means and standard deviations (SDs). Correlations between levels of mRNA expression were assessed using Pearson correlation coefficients. PSA response rates between groups were assessed using Fisher’s exact tests. Survival outcomes were evaluated by the Kaplan–Meier method and compared by log-rank tests. Factors significantly associated with survival were assessed by multivariable analysis using the Cox proportional hazard model. To avoid overfitting due to the limited number of patients and events, each multivariable model included only three or four variables. Covariates were selected based on previous findings , 4. To eAll statistical tests were two-tailed, with a significance level of 0.05. All statistical analyses were performed using R version 3.5.1 software .AR-FL, AR-V7, and GR mRNAs in tissue samples from individual patients with CRPC , BPH (n=2), and hormone-naïve cancer (n=6) is shown in AR-V7 mRNA was detected in 86.5%, and GR mRNA was detected in 98.1% of patients with CRPC. Western blot analysis revealed that the levels of AR-FL, AR-V7, and GR proteins were consistent with those of AR-FL, AR-V7, and GR mRNAs  or GR  mRNA expression, and GR mRNA expression did not correlate significantly with AR-FL mRNA expression .The median AR-V7/AR-FL ratios were 0.9%  in hormone-naïve cancers and 1.2%  in CRPC, whereas the median GR/AR-FL ratios in these two groups were 35.6% (12.5–128.9%) and 21.8% , respectively. Evaluation of the 14 patients who received taxane chemotherapy showed that PSA response rates did not differ significantly in those with low and high AR-V7/AR-FL  and GR/AR-FL  ratios. The best PSA responses in patients treated with taxane chemotherapy, as shown by AR-V7/AR-FL and GR/AR-FL ratios, are shown in Of the 38 patients with CRPC starting AR-targeting therapy, including 32 (84.2%) who had not received any prior treatments, 24 (63.2%) were treated with enzalutamide and 14 (36.8%) were treated with abiraterone. The demographic and clinical characteristics of the patients in the CRPC group are summarized in The overall PSA response rate in patients treated with enzalutamide or abiraterone was 50.0% (19 of 38). Analysis of patients receiving AR-targeting therapy showed that the PSA response rate was significantly higher in patients with low than high AR-V7/AR-FL ratios , who were excluded from analysis. The tissue biopsy approach also has the advantage of a higher In summary, the present findings support an association between relative GR expression and resistance to AR-targeting therapy and survival in patients with CRPC. Large-scale prospective validation and liquid biopsy-based studies are warranted.The original contributions presented in the study are included in the article/The study protocol was approved by the institutional review board of Asan Medical Center (no. 2014-0957). The patients/participants provided their written informed consent to participate in this study.SP and HA designed the study, performed the data analysis, and drafted the manuscript. SYP performed statistical analysis. SP, JS, YK, YC, HA participated in the data acquisition. HA supervised the project. All authors discussed the results and commented on the manuscript. All authors contributed to the article and approved the submitted version.This study was supported by a grant (W17-012) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Delayed fluorescence(DF) by triplet–triplet annihilation(TTA) is observed in solutions of a benzoperylene-imidoester mesogenthat shows a hexagonal columnar mesophase at room temperature in theneat state. A similar benzoperylene-imide with a slightly smallerHOMO–LUMO gap, that also is hexagonal columnar liquid crystallineat room temperature, does not show DF in solution, and mixtures ofthe two mesogens show no DF in solution either, because of collisionalquenching of the excited triplet states on the imidoester by the imide.In contrast, DF by TTA from the imide but not from the imidoesteris observed in condensed films of such mixtures, even though neatfilms of either single material are not displaying DF. In contrastto the DF from the monomeric imidoester in solution, DF of the imideoccurs from dimeric aggregates in the blend films, assisted by theimidoester. Thus, the close contact of intimately stacked moleculesof the two different species in the columnar mesophase leads to aunique mesophase-assisted aggregate DF. This constitutes the firstobservation of DF by TTA from the columnar liquid crystalline state.If the imide is dispersed in films of polybromostyrene, which providesan external heavy-atom effect facilitating triplet formation, DF isalso observed. Organic light-emitting diodes (OLEDs) devices incorporatingthese liquid crystal molecules demonstrated high external quantumefficiency (EQE). On the basis of the literature and to the best ofour knowledge, the EQE reported is the highest among nondoped solution-processedOLED devices using a columnar liquid crystal molecule as the emittinglayer. Consequently,the molecular order in the intracolumnar packing is fundamental forhigh charge mobility.21 Furthermore, ColLCs have a propensityto self-healing of structural defects within the stack originatingfrom their local fluidity. This property leads to a better chargetransport, as such structural defects appear as a limiting factorof organic semiconductors.22 The abilityto control molecular order and macroscopic alignment of ColLCs permitsa significant improvement in device properties, because uniform anisotropicalignment of the molecular dipoles of the emissive layer may promotebetter light extraction in OLEDs and thus improved external quantumefficiency (EQE). Additionally, an improvement in charge transportproperties can be obtained as the molecular alignment may induce asignificant increase in charge mobility.25Liquidcrystals (LCs) have dominated display technology since the1970s.30 For this reason, the ColLC studied in this work consists of a planarπ-conjugated core based on a perylene derivative and alkyl esterand imide groups forming the periphery of the conjugated disk. A moredetailed discussion about the design of these molecules can be foundin the original works.32Aromaticsystems based on perylene derivatives are particularlyinteresting as they are easily functionalized, are thermally and chemicallystable, and have high photoluminescence quantum yields.29 In this situation,only singlet states are able to decay radiatively, and the other 75%of excited states remain unused (dark), leaving only25% as upper limit for the internal quantum efficiency (IQE). Thedesign of molecules exhibiting efficient phosphorescence,33 thermally activated delayed fluorescence (TADF),35 or delayed fluorescence (DF) from triplet–triplet annihilation(TTA) has emerged as a strategy to harvest dark triplet states.36 Phosphorescent OLED emitters often contain aheavy metal atom in their structure, which through inducing spin–orbitcoupling strongly accelerates phosphorescence radiative rates.37 TADF molecules have a small energy gap betweenthe lowest excited singlet and triplet states, enabling thermal up-conversionfrom the triplet state to the singlet manifold.39 TTA, alongside TADF, is an important triplet harvesting processin OLEDs. TTA molecules are able to achieve IQE of up to 65.2% inOLEDs.38 This mechanism involves the collisionof two triplet excitons, which can fuse to give one singlet exciton.As a result of up-conversion of triplet excited states into singlets,delayed fluorescence (DF) can be observed. Efficient triplet diffusionand a high exciton concentration are very important for TTA to occur.40 Many materials exhibit TTA, among them polycyclicaromatic hydrocarbons, of which the best-known is pyrene.41 P-type delayed fluorescence is an older termfor TTA and originates from its discovery in pyrene. To the best ofour knowledge, DF by TTA has never been observed in liquid crystalforming molecules.OLED efficiency is limitedbecause of spin statistics, as tripletand singlet excited states form in a 3:1 ratio as a result of chargecarrier recombination.42 DF is generally observedonly either in solution, where collisions between fluorescent chromophoresleading to radiationless triplet de-excitation are limited, or inthe crystalline or glassy amorphous solid state, where intramolecularmotions and collisions leading to radiationless de-excitation arefrozen out. The observation of DF by TTA in the viscous fluid condensedmesophase indicates that the columnar state of the emitter mixtureallows at the same time anisotropic chromophore alignment and bimolecularDF.The aim of this work was to combine two perylene-basedColLCs toinvestigate their photophysical properties and evaluate their potentialapplication in OLEDs. To our surprise, we observed a first exampleof a ColLC mesogen exhibiting delayed fluorescence in solution whichmanifestly occurs via the TTA mechanism. Even more significantly,we observed TTA DF also in thin liquid crystalline films of mixturesof the two mesogens, which is to our knowledge the first time thatDF by TTA is observed in the columnar liquid crystalline state ofmatter, whereas TADF has recently been reported with columnar liquidcrystalline carbazole-substituted terephthalonitriles bearing alkoxyphenylsubstituents.22.1Steady-state absorption andemission spectra in solution and thin film were acquired using anOcean Optics spectrophotometer (Model USB4000) and a Hitachi fluorescencespectrophotometer (Model F-7000), respectively.Time-resolvedspectroscopy was performed using time-correlated single photon counting(TCSPC) and time-gated acquisition (iCCD) techniques. For TCSPC, aPicoquant modular fluorescence spectrometer (Model Fluotime 200) wasused. The samples were excited using a 401 nm pulsed laser diode withrepetition rates varying from 5.0 to 20 MHz. Lifetimes were obtainedfrom a fluorescence decay by fitting with a multiexponential functionusing FluoFit 2.0 software. Time-resolved photoluminescence spectrawere recorded using an ultrafast 4 PICOS iCCD camera (Stanford ComputerOptics) with a pulsed (10 Hz) Nd:YAG laser (EKSPLA-SL312) excitationsource at 355 nm.2.2N,N′-bis(1-hexyldecyl)benzo[ghi]perylene-3,4:11,12-tetracarboxdiimide (ColLC-A)31 and benzo[ghi]perylene-1,2,4,5,10,11-hexacarboxylic 1,2-bis(2-ethylhexyl)ester4,5:10,11-bis(undec-4-yl)imide (ColLC-B),32 have been reported previously. Their chemicalstructures are shown in ColLC-B  molecule has been published elsewhere.24Thesynthesis and characterizationof the two room-temperature columnar liquid crystals (ColLCs) investigatedin this work, 2.345 and visualized usingAvogadro 1.2.0.47 Ground state geometry and molecularorbital (MO) iso surfaces were calculated using the B3LYP49 functional and the 6-31G**50 basis set.Excited state geometries were optimized with time-dependent densityfunctional theory (TD-DFT) with Tamm-Dancoff approximation (TDA) usingthe same combination of functional and basis set. All optimized geometrieswere confirmed to be energetic minima through frequency calculation.All MO iso surfaces were rendered with an iso value of 0.03 if notstated otherwise. In order to simplify calculations, long alkyl chainswere reduced to isopropyl or ethyl groups.DFT calculations wereperformed using Orca 4.2.1 software2.4–1, and mixtures were produced in differentratios of ColLC-A:ColLC-B .For measurements in solution, the stock solutions were diluted toachieve concentrations of 0.17 mg mL–1 and 0.017mg mL–1. Degassed solutions were obtained by 4 freeze–pump–thawcycles to remove all dissolved oxygen.51 Neat and blend thin films of ColLC-A/B were producedfrom 10 mg mL–1 solutions and deposited by spincoating on glass or sapphire substrates at 2000 rpm for 30 s, followedby annealing at 50 °C for 30 min. Films in a polymer matrix werefabricated by spin-coating on sapphire substrates at 1000 rpm for60 s. Films of ColLC-A/B in the two polymer matricespoly(4-bromostyrene) (4BrPS) and Zeonex52 were produced with 1% and 10% w/w concentrations of emitter fromchloroform (4BrPs 100 mg mL–1) and toluene (Zeonex100 mg mL–1) solutions, respectively.Stock solutionsof individual compounds were prepared in chloroform with a concentrationof 10 mg mL33.1ColLC-A and ColLC-B showa planar configuration of the aromatic central unit in both compounds.The planarity of the aromatic core of the molecules is favorable forthe formation of the columnar liquid crystal mesophase, made of disorderedstacks of disk-shaped molecules. HOMO and LUMOs are generally localizedon the aromatic π-conjugated core with contributions from imideunits in both compounds. The HOMO → LUMO transition shows apredominant π–π* character, which is typical forthis class of molecules.54The calculatedground-state geometries 2 of ColL1 → S1 up-conversionpathway, the excited state energy landscape has been analyzed at theT1 geometry. The flat structure of both ColLC-A and ColLC-B does not leave room for significant changesin structural geometry of the molecule at different electronic states;thus, the T1 geometry can reasonably be considered similarto that of other excited states.To understand the TColLC-A and ColLC-B, both the excitationsto S1 and T1 involve the HOMO → LUMOtransition, thus giving them a π–π* character.In ColLC-A the S1 is at 2.25 eV and T1 is at 1.42 eV, giving a singlet–triplet energy gapΔEST of 0.83 eV at the T1 geometry. In ColLC-B S1 is at 2.65 eV andT1 is at 1.49 eV, giving a ΔEST of 1.16 eV . These results are consistent with theexpected behavior of such highly conjugated polycyclic diimides.55In  1.16 eV 3. The ca1 to T1 is forbidden, as both states present the same orbital geometry.The large ΔEST of these compoundssuppresses intersystem crossing; thus, low triplet formation yieldsare to be expected. These conditions are disallowing TADF occurringas a T1 → S1 up-conversion process becausethe ΔEST is large.39 Similarly, a large T2-T1 energy gap of 0.80–0.95eV in both ColLC-A and ColLC-B disqualifiesTADF mechanisms involving upper triplet states as intermediates. Onthe other hand, the S1 energy is less than double the T1 energy in both of the molecules, allowing for triplet up-conversionvia TTA.In both systems, the direct transition from S3.23.2.1ColLC-A and ColLC-B, photophysical characteristicswere investigated at two concentrations in chloroform: 0.017 mg mL–1 and 0.17 mg mL–1 which correspondto molar concentrations of ≈10–5 M and ≈10–4 M. We use the acronyms ColLC-A and ColLC-B to identify the two liquid crystal-forming moleculesthroughout the manuscript, including in solution, even though theydo not present liquid crystal properties there. Steady-state absorptionand emission spectra at concentration 0.017 mg mL–1 are shown in Figure S3. The mixturesshow predominant characteristics of ColLC-B in both absorptionand emission spectra as it has a higher extinction coefficient . Excited-state lifetimes for ColLC-A and ColLC-B in chloroform solution at0.017 mg mL–1 were obtained from TCSPC measurements.The photoluminescence of ColLC-A and ColLC-B decays monoexponentially with lifetimes of 11.0 and 2.3 ns, respectively. Moreover, both individualmolecules, ColLC-A and ColLC-B, presentedrelatively high photoluminescence quantum yield (PLQY) of 64% and60%, respectively, in chloroform solution. –1. Emission contributionsin mixture solutions follow the trend in the ratio of emitters. Aclear isoemissive point shows that the emission of the two materialsare dependent on each other: The increasing quenching of the ColLC-B emission is accompanied by a proportional increaseof the ColLC-A emission, as the amount of the latteris increased in the mixture. This quenching occurs because of Försterresonant energy transfer (FRET) between the two materials, as theabsorption spectrum of ColLC-A overlaps with the fluorescencespectrum of ColLC-B .To evaluate the concentrationdependence in the luminescent systems ColLC-A and ColLC-B in 0.17mg mL–1 solutions. The decay curves of both moleculesshow biexponential behavior in the prompt fluorescence regime, indicatingemission from two different species. The data also show a longer lived(delayed) emission for ColLC-B with a lifetime of around58 μs . The longer livedemission is only present in degassed solution, but not in aeratedsolution. This DF is not observed in solutions of mixtures of ColLC-A and ColLC-B  which suggests that ColLC-A interferes withthe triplet excited states of ColLC-B in solution .ColLC-B wasnot observed in a more dilute solution, which indicates that the DF mechanism is bimolecular .56 This is in agreement with calculations,as the modeled value of ΔEST = 1.16eV in ColLC-B impedes TADF at room temperature. At lowconcentration, the ColLC-B molecules are further apart,thus reducing chances for collision of two triplet excited stateswith formation of the excited singlet state—TTA is thus unlikelyin these conditions. However, TADF as an intramolecular process wouldnot be suppressed by a low emitter concentration. In conclusion, wehave demonstrated the TTA mechanism by varying the concentration ofthe emitter. TTA is highly dependent on emitter concentration as theimportant part of the mechanism involves intermolecular collisions—therefore,it should be present at high and absent at low concentrations. Thisapproach is equivalent to recording power dependence at a fixed concentration.DF of ColLC-A, where a gradualredshift is observed in the nanosecond time regime. An isoemissivepoint in the time-resolved area-normalized emission spectra  indicates that the redshift observedis due to two emissive species (monomer and dimer) decaying independentlyof each other. Time-resolved spectra of a degassed solution of ColLC-B show a triexponential decay (57 Emission spectra in the third (microsecond) time regime, 25.1 to112.2 μs, are depicted in the inset of ColLC-B showed DF in solution. This might indicatethat the different types and locations of the peripheral substituentsmay influence the modes of the intermolecular interaction and consequentlyaffect radiationless decay from T1. spectra S9 indica spectra S9 indica spectra S9 indica3.2.2Figure S3a) and in condensed state spectra is observed, indicatingdimer formation in the films. In the condensed state, the blendedfilms presented simple sums of the absorption spectra of neat filmsof ColLC-A and ColLC-B .A clear change in the absorption onsetbetween the individual materials in solution S3a and iColLC-A:ColLC-B blends, we studied the liquidcrystal propertiesof the mixtures. The differential scanning calorimetry (DSC) traces show only one phase transition,which we interpret as clearing point from the columnar mesophase tothe isotropic liquid state. The occurrence of only one phase transitionin DSC of the mixtures indicates a full miscibility between ColLC-A and ColLC-B with the formation of a uniquemesophase. In addition, the mesophase is stable down to room temperaturein all cases. The type of the mesophase was confirmed by polarizingoptical microscopy (POM) ,which revealed typical textures of the hexagonal columnar mesophaseformed by the two LCs at room temperature. The columnar order of themesophase was verified by X-ray diffraction  from the appearance of the (10) and (20) peaks of thehexagonal columnar lattice. As discussed to DSC, the X-ray diffractogramsalso show no crystallization peak upon cooling down the clearing temperatureto room temperature. The mesomorphic characterization of the blendssuggests that the two ColLCs are fully miscible. This is in a goodagreement with efficient FRET in the blends as the mechanism dependson the proximity of the two chromophores and therefore only remainsactive at relatively short distances. Furthermore, the liquid crystallinecharacter of the blends persists at room temperature, being desirablefor optoelectronic applications.In order to understand the high efficiency of FRET in ColLC-A presents a small redshiftin emission over time delay , no DF is observed in neat films of either material. This confirmsthat in the condensed state, dimer formation quenches TTA in ColLC-B molecules. Probably because of the lower T1 energy, dimers appear to be quenching monomer triplet states, whiledimer triplet states undergo accelerated nonradiative decay. On theother hand, in solution, TTA seems only to occur in monomer speciesby a collision-driven mechanism.Time-resolved spectra for thesingle-component and blend filmsare shown in me delay 6a, indicelay −1, 4c. As seColLC-A dimer emissionenergy. At later times, the wavelength of maximum emission does notchange, even in the microsecond time scale. There is also a smallcontribution from monomer emission of ColLC-A in thenanosecond regime in the wavelength range of 400–525 nm. However,in the 1:2 and 1:3 blend films .nd films 6e,f, thiFigure S16 and Table S3) was used to fit the photoluminescencedecay in the films. The average lifetime of DF of the blend filmsis in the range of ≈2–3 μs. The lifetimes arelonger when the contribution of ColLC-B in the blendincreases, and a maximum of 3.33 μs is obtained for the 1:2ratio. This suggests that by increasing the contribution of ColLC-B molecules in the blend, the available triplet populationincreases, which favors TTA. However, a higher proportion of ColLC-B molecules leads to suppression of dimer formationbetween two ColLC-A molecules. As neither ColLC-A nor ColLC-B undergo TTA on their own in pristine films,and as ColLC-A does not show TTA on its own in solution. Consequently, the combinationof both compounds in the blend films provides the necessary requirementfor TTA to occur: elevated triplet formation yield in ColLC-A due to Dexter transfer from ColLC-B and dimer formationof ColLC-A. ColLC-B however does not showTTA in films, likely due to faster decay of its dimer triplets comparedto its monomer triplets. It is worth noting here that only the ColLC-B monomer shows TTA in solution, but the dimer formdoes not, confirming that the exciton migration mechanism is differentin the condensed state. The two pure materials and their mixturesare shearable between two glass plates at room temperature . These shearing experiments demonstratethat the condensed state retains fluidity of the mesophase at roomtemperature. This indicates that the residual mobility of the moleculesin the film enables the TTA mechanism that relies on molecular encounters,while the viscosity hinders collision-induced radiationless de-excitation.The decay curves for both the neat and blend films are presentedin ColLC-A and ColLC-B doped in polymer matrices at two different concentrations: 1% wt.and 10% wt. Zeonex and poly(4-bromostyrene) (4BrPS) were chosen astwo polymer matrices. Zeonex as an aliphatic (light atoms only) polymercan be considered neutral, while 4BrPS is a polymer bearing bromineatoms, thus inducing an external heavy atom effect. The 4BrPS waspreviously used to increase the triplet formation yield.58 An external heavy atom effect originating fromthe bromine atom is responsible for the increase in the intersystemcrossing rates of the dopant molecules, thus it leads to an increasedpopulation of triplet states originating from optical excitation.The results of this study are presented in the Supporting Information . Only ColLC-A in4BrPS at 10% concentration shows a delayed fluorescence component,while no DF is observed in any of the other seven films. This behavioris in line with the properties in ColLC-A:ColLC-B blend films described above. In contrast to its liquid solution, ColLC-B does not show TTA on its own in 1% loaded polymerfilms, presumably because the molecules are restricted and show lowmobility, thus reducing chances of intermolecular interactions. Onthe other side, at 10% load ColLC-A exhibits dimer emission,while ColLC-B dimers were already shown not to presentTTA. Consequently, ColLC-A only shows TTA in conditionswhich provide both: small distances between molecules facilitatingdimer formation and provision of triplet states. These conditionsare present in the 10%-loaded 4BrPS film.In order to further probe the origins of delayed fluorescence inblend films, an additional investigation was made using polymer hostsblended with either of the columnar materials. Time-resolved measurementswere performed in the films of Figure S20 and S21). Electroluminescence spectraare shown in Figure S21d. Results and additionaldiscussion of OLED performance are given in Supporting Information. Nondoped OLED devices using ColLC-A as the emitterpresent a high EQE of 1.8% with its electroluminescence maximum at646 nm. This unexpectedly high EQE might be an indication of the TTAmechanism being at work in the ColLC-A OLED device asthe initial triplet populations originating from electrical excitationare considerably larger than in optical measurements. On the basisof the literature and to the best of our knowledge (see Table S5 for details), we believe this EQE figureto be the highest among nondoped solution-processed OLED devices usingcolumnar liquid crystal as the emitting layer. The OLEDs are stillsubject to optimization in the future; however, they providea proof of concept for the feasibility of such systems in luminescentdevices.To evaluate the potentialapplication of the TTA phenomenon inColLCs, OLEDs comprising blend films were fabricated  for TTA to appear on its own. ColLC-B provides triplet states for TTA to occur, but itsdimers/excimers do not display TTA on their own. The combination ofthe two molecules in blends yields TTA from ColLC-A dimersfueled by the triplet population on ColLC-B dimers. Likewise,the external heavy atom effect of a bromopolymer matrix fuels emissionfrom ColLC-A. The observation of delayed fluorescencein the condensed viscous fluid state of liquid crystal materials,where molecules can be uniformly oriented by annealing, opens up thepossibility to use such materials as emissive layers of organic light-emittingdiodes to enhance light outcoupling as well as charge and excitontransport.At alow concentration in solution, both individual compounds showphotoluminescence from their monomer species. At an elevated concentration,dimer/excimer emission occurs because of strong intermolecular π–πinteractions. In concentrated solution,


Implementing evidence-based recommendations with the option of patient-individualised and situation-specific adaptations in telerehabilitation may increase adherence with improved clinical outcome.As part of a registry-embedded hybrid design (part 1), digital medical device (DMD)-usage in a home-based setting was analysed in a multinational registry. The DMD combines an inertial motion-sensor system with instructions for exercises and functional tests on smartphones. A prospective, single-blinded, patient-controlled, multicentre intervention study (DRKS00023857) compared implementation capacity of the DMD to standard physiotherapy (part 2). Usage patterns by health care providers (HCP) were assessed (part 3).2 = 44.9, p<0.001). Intention-to-treat-analysis (part 2) revealed DMD-users to have significantly higher adherence to the rehabilitation intervention compared to the matched patient-control-group . DMD-users performed recommended exercises at home with higher intensity (p<0.05). HCP used DMD for clinical decision making. No adverse events related to the DMD were reported. Adherence to standard therapy recommendations can be increased using novel high quality DMD with high potential to improve clinical rehabilitation outcome, enabling evidence-based telerehabilitation.Registry raw data  were analysed from 604 DMD-users, demonstrating clinically expected rehabilitation progression post knee injuries. DMD-users performed tests for range-of-motion, coordination and strength/speed enabling insight to stage-specific rehabilitation (χ Telerehabilitation refers to rehabilitation programmes delivered by electronic services such as medical apps. This technology can facilitate health care access and improve individual adherence to recommendations in a home-based setting, especially in the early phases of rehabilitation. We investigated key aspects of a sensor-guided medical app used for knee rehabilitation after surgery in three separate studies. We compared usage patterns, clinical effectiveness, and safety from 604 nationwide users and found that the sensor and medical app are able to measure correct values in the rehabilitation progress when used only by patients at home. Using the tests suggested by the app was safe. Patients with the app in the home environment were more likely to stick to recommendations of exercises given by doctors and physiotherapists and train harder compared to those only undertaking physiotherapy. Doctors and physiotherapist used sensor data and the medical app to decide what type of exercise a patient should perform. Our data show that telerehabilitation, and medical apps in particular, may become a game-changer for individualised and functional approaches to orthopaedic rehabilitation programmes. Telerehabilitation has a high potential to improve adherence and clinical outcomes in guideline-based rehabilitation programmes. Implementing evidence-based rehabilitation recommendations with individualised and situation-specific adaptations may increase adherence to health care providers’ recommendations at home with subsequent improved clinical outcomes . In orthFurther, telemedical applications may ensure correct performance of exercises. Validated sensors  that areIn the initial phase of rehabilitation after acute knee joint injuries and/or after surgical interventions, active and passive knee joint mobility becomes relevant, while later functional stability, coordination, and strength become necessary before dynamic and speed exercises will be possible –10.Adherence is the degree to which a person’s behaviour meets the agreed-upon recommendations of a health care provider . There iWe here present three different perspectives of the first DMD for knee rehabilitation. First, we sought to determine the usage patterns, measurement of clinical effectiveness and safety of the DMD in real-life from registry data. Next, we tested the prespecified hypothesis of its effect on clinical efficacy (adherence) and safety. Finally, we present the usage patterns and requirements of health care providers for a DMD as add-on to standard rehabilitation. All data stem from a registry-embedded hybrid design.ORthelligent telematic rehabilitation System OutcoME” study, ORSOME-study, DRKS00023857) on patients after surgical intervention for knee injuries. The prespecified primary endpoint of superiority of adherence to rehabilitation was quantified from a score deducted from a beforehand validated adherence questionnaire (ADREHA-score) and compared to a similar patient control group who received standard physiotherapy. In the third part, involved health care providers were requested to provide feedback on usage, adherence, and clinical outcome in patients using the telerehabilitation.A registry-embedded hybrid design of DMD in rehabilitation in German-speaking countries in real life was performed. Approval was obtained by the local ethics committee prior to trial commencement . In the first part, a systematic data analysis of primary raw data of all users of a DMD-registry was conducted. This was followed by a prospective, single-blinded, patient-controlled, and formally multicentre study  is a validated Class I medical device . It consFrom January 2018 to September 2020, 33,057 records of 604 patients who used a DMD-system for any indication were stored in a comprehensive multinational registry . After plausibility-driven  data cleanings, the remaining 10,311 values were further analysed. To exclude intra-week fluctuations and repetitively performed tests in order to record best individual measurements at acquisition dates, only the best value per week was considered for further analysis.After performance of each test, demographic data, medical history, usage data, measurement results of each test performed, and information about sensation of pain on the injured leg were recorded. Pain was quantified by a visual analogue scale ranging from 0–10  . InformaBetween December 2020 and February 2021, consecutive patients (n = 308) from the registry, who had received a knee orthosis, received a one-time invitation to participate in an online survey to give information on their individual 6 months rehabilitation after knee surgery. This procedure was in accordance with the corporate policy, EU-GPDR and individual consent to data usage and protection prior to using the DMD. Diagnosis data coded according to the International Classification of Disease (ICD) were available for all patients, and diseases were classified accordingly. 30 responded to the survey and gave their digital informed consent. The study was approved by the local ethics committee (Eth-53/20).Inclusion criteria for analysis were: DMD-usage (≥ 1 test) or usage of knee orthosis treated within 6 months post-surgery, and informed consent. Exclusion criteria for analysis were: total and /or plausible answers <80%, or DMD-usage in the patient control group. The dataset retrieved from the prospective ORSOME-study contains all patients who made an assignment to one of the two treatment groups after surgical treatment of a knee joint injury or for knee joint damage or instability in an intention-to-treat-analysis (ITT).The following questionnaires were used:- Medical history and preinjury level of sports activity: International Knee Documentation Committee (IKDC) forms  - activity and return to activities of daily life: PAQ 50+  - restrictions related to knee injury: ACL-RSI Knee Score   and subj- QoL: KOOS QoL items - adherence: ADREHA , give their actual condition and the time interval since intervention.Health care providers (HCP) listed in the company’s data bank as prescribers or professional users of any of the company’s products received a one-time invitation to participate in an anonymised digital survey regarding the DMD. Fields of interest were: individual background, usage patterns, current and future indications, subjective assessment of the DMD, their judgement on area of application, perception of patients’ adherence and clinical outcomes and to document the benefits. All ratings by HCP were given on a scale from 0–10.As there are no measurement instruments available for assessing adherence to rehabilitation for the target population of a cohort of patients undergoing rehabilitation after knee joint injuries or for chronic knee injuries in German-speaking countries and the corresponding cultural area, a standardised adherence score was derived from existing and validated components in German language. The questionnaire was tested and internally validated following the COSMIN guideline  accordinData was collected and analysed in a GCP-compliant manner, in accordance with the ethical principles of the Declaration of Helsinki and in compliance with all EU regulations and German legislation.Statistical analyses of the register data bank (part 1) were performed blinded from the database used for exploratory analysis. A range data plausibility check was performed for all independent and dependent outcomes; data was cleaned accordingly. Measurement results of the affected leg were analysed in the pre- and postoperative rehabilitation course for each test only for patients who provided their—planned or actual—date of intervention. Data of patients, who performed the corresponding test postoperatively with at least one repetition during the first 12 weeks, were evaluated for individual temporal courses. Missing or unclear values were not replaced. A minimum of 80% data completeness for key variables was prerequisite for subsequent analysis.Data from the ORSOME study (part 2) were analysed in an ITT-analysis with the prespecified endpoint of increased adherence in the treatment group compared to the patient control group measured by the previously validated ADREHA-score. For details, please see 2) was used to estimate the relative chance of usage and 95% CIs are given. To analyse the frequency of use with respect to time to usage, “time to 50% of patients” (t50) and “time to 75% of patients” (t75) were analysed. Statistical significance is assumed if the null hypothesis can be rejected with a significance level of p ≤ 0.05. IBM SPSS Statistics  was used for analysis.For part 1–3, all continuous variables were examined for normal distribution using Q-Q plots. All metric data is non-normally distributed, presented as median with corresponding quartiles , and compared with Mann-Whitney-U tests. Bivariate non-parametric correlation (Spearman) was used to examine the internal validity of the individual questions used for the ADREHA-score in relation to each other and in relation to the ADREHA-score. Cumulative start to usage of the test categories during follow-up time was univariately evaluated by Kaplan-Meier analysis (log-rank test) and time to test for the earliest test within a category was chosen for analysis. Likelihood ratio chi-square , whereas 20% (n = 122) of the DMD-users were treated only conservatively. Patients started using the DMD at three different time periods related to surgical interventions in home-based settings: (I) 1 year to 8 weeks pre-operatively, (II) peri-operatively (immediately pre- and up to 8 weeks post-surgery), and (III) >3 months post-operatively , range of motion was used by nearly all patients see .2 46 for group comparison, p<0.001, log-rank, Patients started with tests for ROM in the earliest rehabilitation phase, followed by coordination after intervention, whereas strength / speed were started significantly later  or 75% of patients (t75) had used single tests in the early rehabilitation phase (16 weeks), a much more differentiated pattern can be observed with regards to patient heterogeneity. For tests of ROM and coordination, t50 was 1 week and t75 was 2 weeks, similarly for coordination (t50: 2 weeks and t75: 4 weeks), indicating a rather homogenous rehabilitation progress for all patients for these tests. Interestingly, for the dynamic challenges (strength and speed) a different pattern (t50: 3 weeks and t75: 6 weeks) was observed, indicating that a small patient group had performed these tests safely at unexpectedly early timepoints. More than a quarter had not even performed dynamic tests up to 16 weeks.Range of motion objectively quantified with the DMD increased during the course of postinterventional rehabilitation , mainly for the dynamic tests  at the beginning and after 6 weeks . No adverse events were related to the DMD.Of 31 patients consented to participate in the survey regarding adherence to health care providers’ recommendations, 30 patients answered the questionnaires. After the exclusion of 3 patients , 27 data sets were available for analysis  of the DMD-users confirmed the benefit of monitoring their rehabilitation outcome as positive feedback to increase motivation. No adverse events related to DMD-usage in a cumulative 104 months DMD-usage period confirmed the safety of home-based use.Making an appointment with their physical therapist was rated as rather hard  for all joints of the lower extremity  with appr. 20 (5–50) DMD-prescriptions / HCP during the last year. DMDs had been prescribed or recommended from adolescents (13–17 years) up to elderly (> 65 years) patients. The settings were postoperatively (48% of HCP), perioperatively (48% of HCP), and merely conservatively (4%) as home-based use, 43% had been for acute and 19% for chronic orthopaedic conditions, as well as for neurological (n = 3) or muscular disease (n = 6). 45% of HCP already used the ORS and 57% saw the potential for research to generate objective quantifiable data  or as instrument to influence clinical decision making , whether patients can return to work or sports (90% of HCP), optimising individual therapy schedules (81% of HCP), identifying further therapy needs (67% of HCP) and taking influence on patients’ rehabilitation , “Orthelligent” offers the additional possibility of intraindividual comparison  and interindividual comparison to healthy individuals of an amateur or competitive level and to patients in different stages of rehabilitation.Choice of different exercises and testing options of the DMD vary depending on the period before or after surgical intervention, or mere conservative treatment. The pattern presented here clearly shows that the individual tests of the Orthelligent are adequately used by patients at home, depending on their respective individual situation. Furthermore, data of this study support the relevance for an individualised and functional rather than time-dependent rehabilitation programme as currently implemented due to lack of large-scale real-world data. In conclusion, digital medical devices offer the opportunity to serve as a fact-based game-changer for optimal guidelines in rehabilitation programmes.Digital medical device-usage was predominantly pain-free and safe in-home use. This is in line with similar results about the safety of other digitally supported rehabilitation programmes in orthopaedics ,37. One Since the exercises guided by and the test values assessed by the DMD are not specific to rehabilitation after ACL reconstruction, it is not surprising to find health care providers applying the DMD for patients with acute and chronic conditions. The DMD was used predominantly for clinical indications for all joints of the lower extremity, for postoperative, conservative, or preoperative indications, and acute or chronic joint disease, as well as for neurologic or muscular diseases. Health care providers used the ORS in children, adolescents, adults, and also elderly patients (> 65 years). Furthermore, specialised service providers see the benefit of DMD and already use it for a larger group of indications, which goes far beyond the exemplary patient collective shown here .The DMD with measurement functions used in this study offers the potential for a) objective quantitative monitoring of lower extremity function and rehabilitation progress, relevant for health care providers in clinic and research, b) decision making in adjusting rehabilitation measures or giving fact-based recommendations, or c) quality assurance of certain rehabilitation programmes. Planning and controlling the implementation of evidence-based rehabilitation steps are preconditions for individual function- and ability-based control of rehabilitation progress instead of rigid time-based rehabilitation protocols and would constitute a major step forward. This may lead to an adaptation of rehabilitation phases by supporting well-trained and proficient or hesitant and anxious patients. At the same time the risk of a too fast and therefore risky rehabilitation can be avoided, and the rehabilitation programme can be adapted to the individual needs / requirements.We here present a new validated tool (ADREHA-score) for quantification of adherence to rehabilitation recommendations for the middle European culture in German, automatically calculating individuals’ adherence score. Further research is needed to test its validity for other indications and settings or its individual scoring in clinic or research.The data set provided from the server of the DMD shares the strength and limitations of raw data sets primarily intended for non-scientific purposes. The data of more than 30.000 data sets from 604 patients used for originally intended use (post ACL-reconstruction rehabilitation in athletes) as well as other indications  and extended user circles (adolescents and the elderly) show the potential of DMD-usage as an add-on to standard physiotherapy in real life examined in a study population representative of the target population . This fiHowever, no assumptions can be made regarding individuals, who for any reason did not consider usage of this DMD suitable or helpful, or discontinued usage for any reason, be it discomfort or fast rehabilitation. Furthermore, response rate was relatively low in one study part. It is not clear from the evaluation whether and to what extent the patients may have already had pain prior to testing or, if applicable, whether testing was not performed in the case of pre-existing pain. Although designed as a prospective, blinded and controlled study with a prespecified primary endpoint and meticulous attention to confounding variables, an improved clinical outcome as a result to increased adherence can be deducted from clinical experience and is supported by the body of evidence. Still, the underlying causal relation has not been proven in this study and will need to be determined in a large-scale RCT considering sufficient numbers of different indications to confirm our first findings on increased adherence in a relatively small number of patients. Furthermore, prospective trials will be needed to clarify to which extent telerehabilitation might replace, essentially modify, or reduce the frequency of classic standard rehabilitation.Well-designed digital medical devices increase adherence to health care providers’ recommendations regarding rehabilitation programmes and are safe to use. Additionally, valid and reliable mobile measurement tools for quantification of complex functional movements offer substantial value for different health care provider groups. Implementing novel digital technologies may well be a key solution for functional rehabilitation protocols and programmes in the future.S1 FileFig A: Flowchart registry data analysis (part 1) and ORSOME study (part 2); n, number of patients; ITT, intent-to-treat. Fig B: Begin of use at three different time periods related to surgical interventions: (I) 1 year to 8 weeks pre-operatively, (II) peri-operatively (immediately pre- and up to 8 weeks post-surgery), and (III) >3 months post-operatively. Fig C: Kaplan-Meier curve for begin of usage of the DMD for rehabilitation within 16 weeks after knee surgery by test categories (A-C). CI, confidence-interval; n, number of patients. Fig D: Postoperative progression of FIT-Index after surgical intervention in 113 patients. Table B: ADREHA-Score, patient assessment of adherence score elements. Main components of ADREHA-score in arbitrary units (in %) on a scale of 0–10; median [IQR]. Fig E: Benefit of DMD for A) patients and B) health care providers from health care providers perception(DOCX)Click here for additional data file.S1 ADREHA Questionnaire(DOCX)Click here for additional data file.


Patients with endocrine therapy resistance and chemotherapy insensitivity have poor prognosis. Androgen receptor (AR) is widely expressed in breast cancer, but there is no clear conclusion about its function and correlation with prognosis in luminal B breast cancer. Further research is needed to reveal the role of AR in luminal B (HER–2 negative) breast cancer. (2) Methods: Retrospectively analyzed patients with early–stage luminal B breast cancer. The correlation between AR and its associated indexes with long–term survival was determined. (3) Results: A total of 985 patients were included with 143 treated by neoadjuvant therapy. Of these, 83.5% of the patients had AR expression ≥65%. High AR expression was associated with good disease–free survival (DFS) and overall survival (OS). In the neoadjuvant population, AR/estrogen receptor (ER) > 1.06 and residual tumor Ki67 > 23% had significantly worse DFS. (4) Conclusion: Low AR (<65%) expression is associated with poor prognosis in luminal B (HER–2 negative) breast cancer patients. High AR/ER and residual tumor Ki67 were associated with poor DFS in neoadjuvant group with a cutoff value of AR/ER > 1.06 and residual tumor Ki67 > 23%. Hormone receptor (HR)–positive breast cancers account for about 75% of all breast cancers ,2,3. TheThe systemic treatment of breast cancer can be classified as neoadjuvant or adjuvant therapy, depending on its timing. Neoadjuvant therapy plays a vital role in the treatment of breast cancer, not only to reduce the extent of surgery, and obtain information on treatment responsiveness and prognosis, but also to adjust subsequent treatments based on the treatment response to improve the survival of patients in non–pathological complete response (non–pCR) patients. In HER–2–overexpressing breast cancer and triple–negative breast cancer (TNBC) patients, the rate of pCR can reach 40–50% with neoadjuvant treatment, and the long–term survival of patients achieving pCR is significantly better. Luminal B (HER–2 negative) breast cancer lacks HER–2 targets, and the current standard neoadjuvant treatment regimen is chemotherapy; neoadjuvant endocrine therapy is still being investigated. Luminal B (HER–2 negative) breast cancer has poor sensitivity to neoadjuvant therapy, with a pCR rate of 5–10%, and the predictive value of pCR for long–term prognosis is not as high as that for HER–2 positive breast cancer and TNBC. Therefore, there is a need to find novel indicators to predict the efficacy of neoadjuvant therapy and outcomes for luminal B (HER–2 negative) breast cancers. The literature suggests that Ki–67 can be used to evaluate the efficacy of neoadjuvant endocrine therapy in patients with luminal B (HER–2 negative) breast cancer. However, the cutoff values and predictive sensitivities in different reports vary widely, and its predictive ability lacks validation in neoadjuvant chemotherapy.The androgen receptor (AR) is widespread across various breast cancer subtypes, and over 70% of HR–positive breast cancers express AR. Most retrospective studies have found that positive AR expression is associated with a better long–term prognosis of breast cancer ,5. HowevIn this single–center study, cases of luminal B (HER–2 negative) breast cancer at the Peking University First Hospital were retrospectively analyzed to investigate the correlation between AR and survival and neoadjuvant treatment outcomes in luminal B (HER–2 negative) breast cancer, and to determine AR cutoff values with clinical value.Patients with early–stage luminal B (HER–2 negative) breast cancer admitted to the Peking University First Hospital Breast Center between January 2013 and December 2019 were retrospectively analyzed. The inclusion criteria were patients with luminal B (HER–2 negative) breast cancer diagnosed using core needle biopsy (CNB) and treated by surgery at our hospital. The exclusion criteria were patients who had the following: (1) first diagnosis of stage IV breast cancer; (2) AR expression level missing from pathology report and inability to retest; and (3) underwent excisional biopsy or ultrasound–guided vacuum–assisted breast biopsy (VABB) prior to admission . The hosPreparation of CNB and surgically resected specimens was as described in the 2007 American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) guidelines . SpecimeIHC for ER, PR, HER–2, AR, and Ki67 was performed for all included cases. In this study, ER , PR , AR , and Ki67  staining was performed using a fully automated IHC stainer (Dako Autostainer Link 48), and HER–2  staining was performed using a fully automated IHC stainer . In this study, ER, PR, and HER–2 were tested in accordance with the 2010 ASCO/CAP Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors (ER/PgR) in Breast Cancer  and the 2 intravenous infusion once every 3 weeks or albumin–bound paclitaxel 200–260 mg/m2 intravenous infusion once every 3 weeks; ② A: pirarubicin 50 mg/m2 intravenous infusion once every 3 weeks. Response evaluation was performed every two cycles in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and patients underwent surgical treatment after completing neoadjuvant therapy. The pathological response was evaluated using the Miller–Payne system. According to the recommendations of the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) international working group, pCR was defined as the absence of invasive cancer in the breast and axillary nodes irrespective of ductal carcinoma in situ (ypT0/is ypN0) [Among the included patients undergoing neoadjuvant therapy, neoadjuvant chemotherapy and neoadjuvant endocrine therapy were allowed. The first choice for the neoadjuvant chemotherapy regimen was 6–8 cycles of taxanes + anthracycline (TA), with the specific drugs being ① T: docetaxel 75 mg/mis ypN0) . The dect–test for independent samples was used for continuous variables, Pearson’s χ2 test or Fisher’s exact probability test was used for categorical variables, and the Mann–Whitney U test was used for ranked variables. The odds ratio (OR) for a pathological response was calculated using a binary logistic regression model. The hazard ratio (HR) for long–term survival was calculated using Cox analysis. In both binary logistic regression and Cox analysis, continuous variables were analyzed by groups according to clinical practice and experience. DFS was defined as the time from the surgery date to recurrence and metastasis, death, or last follow–up. Overall survival (OS) was defined as the time from the surgery date to death or last follow–up. DFS/OS was analyzed using the Kaplan–Meier method, and differences between subgroups were tested using the log–rank test. Diagnostic tests were analyzed using ROC curve analysis. The selection of the best threshold is based on the boundary point when the Youden index is the maximum value. Differences with p < 0.05 were considered statistically significant. All tests were two–sided. All statistical analyses were performed using the IBM SPSS Statistics .For comparisons of clinicopathological characteristics between groups, the A total of 985 patients, including 978 women and 7 men with a median age of 56 years, were included in the study. Patients were divided into neoadjuvant and non–neoadjuvant therapy groups based on the treatment modality, with 143 patients  in the neoadjuvant therapy group and 842 patients  in the non–neoadjuvant therapy group. Most patients in the neoadjuvant therapy group (88.1%) underwent neoadjuvant chemotherapy containing anthracycline and taxanes, and nine (6.3%) underwent neoadjuvant endocrine therapy. Seven patients achieved pCR for a pCR rate of 4.9%. The median follow–up time was 42 months (range: 4–101 months), with 37 DFS events and 10 OS events in the neoadjuvant therapy group and 46 DFS events and 19 OS events in the non–neoadjuvant therapy group during follow–up. The baseline characteristics of the overall population were shown in Table 1Compared to patients in the non–neoadjuvant therapy group, patients in the neoadjuvant therapy group were mostly young and non–menopausal, in late clinical stage, and had a high histological grade, low ER, PR, and AR expression levels, and high Ki67 expression levels; the differences between the two groups were statistically significant. There were no statistically significant differences in body mass index (BMI) or HER–2 expression levels between the two groups.p = 0.032).Eleven patients (7.7%) in the neoadjuvant therapy group were AR–negative before treatment, 39 (27.3%) had AR expression levels of 1–64%, 21 (14.7%) had AR expression levels of 65–89%, and 72 (50.3%) had AR expression levels above 90%. Eleven patients (1.3%) in the non–neoadjuvant therapy group were AR–negative before treatment, 101 (12.0%) had AR expression levels of 1–64%, 196 (23.3%) had AR expression levels of 65–89%, and 534 (63.4%) had AR expression levels above 90%; the differences between the two groups were statistically significant .AR/ER and AR/PR were calculated as AR expression level/ER expression level and AR expression level/PR expression level, respectively. In cases of PR negativity, the AR expression level was used as AR/PR. Overall, 14.7% of patients had AR/ER > 1.00 and 55.1% had AR/PR > 1.00; the difference between the two groups was not statistically significant (AR/ER p = 0.003).Ki67 expression before treatment was higher than 30% in 95 patients (66.4%) in the neoadjuvant therapy group and 207 patients (24.6%) in the non–neoadjuvant therapy group; the difference between the two groups was statistically significant  had a residual tumor Ki67 over 20%. The ΔKi67 was calculated as ΔKi67 = residual tumor Ki67 − CNB Ki67, with “substantial decrease” defined as a decrease of at least 40%, “moderate decrease” defined as a decrease of 20–39%, “small decrease/no change” defined as a decrease of 0–19%, and “elevation” defined as a higher residual tumor Ki67 than CNB Ki67. A total of 31 patients (21.7%) exhibited a substantial decrease, and 15 patients (10.5%) exhibited elevation of Ki67 levels compared to preoperative levels. Details of the neoadjuvant therapy group are summarized in A multifactorial survival analysis was performed on the overall luminal B (HER–2 negative) breast cancer population using backward regression. Age, baseline T–stage, baseline N–stage, histological grade, baseline ER, PR, HER–2, Ki67, AR, AR/ER, AR/PR levels, and whether neoadjuvant therapy was administered as the factors initially included. A total of seven steps were performed, with age, baseline T–stage, baseline N–stage, histological grade, baseline AR, and whether neoadjuvant therapy was administered as the factors included in the end. The results of steps 1 and 7 are presented in OS multifactorial survival analysis was also performed using the same backward regression with the same included factors as for DFS and a total of 8 steps. The factors included in the end were baseline T stage, baseline N stage, histological grade, CNB HER–2, and CNB AR. The results of steps 1 and 8 are presented in p < 0.001; OS p < 0.001), with a poor DFS and OS in patients with AR < 65%. In order to further determine whether AR is a prognostic factor independent of ER, we compared the ER expression levels between groups of AR < 65% and ≥65%. The results showed that there was a significant difference in the expression of ER between the two groups. The expression of ER was relatively lower in the subgroup with low AR expression . This conclusion is consistent with the finding that expression of ER and AR was related in the overall population.In this study, the AR cutoff value was selected as 90% based on clinical experience. Multifactorial survival analysis suggested that AR ≥ 90% was a protective factor for patient prognosis. To further investigate the optimal AR cutoff value associated with long–term prognosis, the ROC curve of AR for predicting recurrent metastatic events was plotted a, and thAmong the neoadjuvant therapy patients, seven achieved pCR, with one DFS event and no OS events during the follow–up period. A total of 136 patients did not achieve pCR, with 36 DFS events and 10 OS events during the follow–up period. The differences in DFS and OS between the pCR and non–pCR groups were not statistically significant .p = 0.105). In the ER high expression group, DFS of the population with AR/ER > 1.00 showed a trend of benefit, but there was also no statistical difference (p = 0.213). OS multifactorial survival analysis was not performed due to the small number of OS events.To further investigate the prognosis–related factors in the neoadjuvant therapy population, DFS multifactorial survival analysis was performed on the non–pCR population of luminal B (HER–2 negative) breast cancer who underwent neoadjuvant therapy. Patients were screened using a backward regression, with age, baseline T–stage, baseline N–stage, histological grade, CNB ER, PR, HER–2, Ki67, AR, AR/ER, AR/PR levels, residual tumor TN stage, residual tumor ER, PR, HER, Ki67, and ΔKi67 as the factors initially included . Late bap = 0.003) with no significant difference in OS (p = 0.222), and patients with residual tumor Ki67 > 23% had significantly worse DFS than patients with residual tumor Ki67 ≤ 23% (p = 0.003) with no significant difference in OS (p = 0.148).In this part of the study, an AR cutoff value of 65% was selected, AR/ER and AR/PR cutoff values of 1.00 were selected, and a residual tumor Ki67 cutoff value of 20% was selected. Multifactorial survival analysis suggested that AR/ER > 1.00 and residual tumor Ki67 > 20% were risk factors for DFS events. To further investigate the prognosis–related optimal AR/ER cutoff value, the ROC curve of AR/ER for predicting DFS events was plotted a, and thThe 2011 St. Gallen International Expert Consensus proposed classifying breast cancers based on molecular expression markers. Those with positive ER expression and low PR expression or high Ki67 expression were defined as luminal B breast cancer, which accounted for approximately 50–60% of all breast cancers. The systemic treatment of luminal B (HER–2 negative) breast cancer primarily involves endocrine therapy and chemotherapy. The 8–year DFS of patients with luminal B (HER–2 negative) breast cancer is 78.9% . Some paAR is a widespread molecular marker across various breast cancer subtypes, and approximately 70–90% of luminal–type breast cancers express AR ,20. In EA total of 985 patients with luminal B (HER–2 negative) breast cancer were enrolled in this study, with a median follow–up of 42 months. There were a total of 83 DFS events and 29 OS events, and the 3–year DFS was 97.3%, 3–year OS was 98.7%, 5–year DFS was 93.5%, and 5–year OS was 97.4%. In the SOFT trial, the 5–year DFS of patients ranged 84.7–86.6% , and in In this study, over 60% of patients had AR expression levels above 90%, and only 2.2% did not express AR. In the literature, the definition of negative and positive AR expression is not consistent, with 1%, 10%, or more, or the Allred score all being used. It is generally accepted that 70–90% of patients with luminal–type breast cancer are positive for AR expression. The high percentage reported in this study may be associated with the difference between Chinese and Western populations and using an AR cutoff value of 1%. The inconsistency of AR cutoff values in the literature affects the comparability of the study results. It informs the need for finding AR prognosis–related cutoff values. The literature reports that male breast cancer patients represent approximately 1% of the patient population, and almost all are ER+ AR+ . A totaln = 219) and a validation cohort (n = 418) to determine AR expression cutoff values. Their findings revealed that although most studies selected 1% or 10% as cutoff values, these were not the best cutoff values to differentiate between patients with different outcomes, and they suggested that a positivity cutoff value of 78% had better sensitivity (57.1%) and specificity (75.0%). Patients with AR > 78% had better survival, and those with positive ERα and AR > 78% had the best outcomes. Yang et al. [Multifactorial analysis of survival in the overall population suggested that age above 40 years was a protective factor for DFS events. Late T stage, axillary lymph node metastasis, and high histological grade were risk factors for DFS events. In this study, over 60% of patients had at least 90% AR expression levels, and the median AR level of the overall population was 90%. Therefore, a preliminary analysis was performed using an AR expression level of 90% as a cutoff value, and it was observed that the AR expression level correlated with DFS and OS. Further analysis showed that when patients were grouped using an AR of 65% as a cutoff value, there were significant differences in DFS and OS between the two groups, and patients with AR ≤ 65% had significantly worse survival. Recciardelli et al.  reviewedg et al.  studied In the population of patients who underwent neoadjuvant therapy, 37 DFS events occurred, with a relapse rate of 25.9%. pCR was achieved in only seven individuals in this study, for a pCR rate of 4.9%. Prognostic analysis grouped by pCR or non–pCR suggested that pCR did not correlate with long–term survival. Therefore, further investigation of prognostic correlates in the neoadjuvant therapy population is needed. Currently, there have been few studies on AR in neoadjuvant therapy for breast cancer, and some studies have suggested that AR positivity may be associated with poor neoadjuvant outcomes in TNBC. Witzel et al.  reviewedp = 0.023). Further investigation of the cutoff value showed that the optimal AR/ER cutoff value was 1.06, and patients with AR/ER >1.06 accounted for 15.4% of the population who underwent neoadjuvant therapy. Kaplan–Meier analysis suggested that patients with high AR/ER had significantly worse DFS and no significant difference in OS when classified using an AR/ER cutoff value of 1.06. However, the follow–up period of this study was short, and the OS results were incomplete.The present study investigated the prognostic, predictive value of AR/ER and AR/PR. Most patients had high AR and ER expression, with a median and mode AR/ER of 1.00. Overall, 14.7% of patients had AR/ER > 1.00, and 31 patients had AR/ER ≥ 2.0, accounting for 3.1% of the study population. There were no statistically significant differences in AR/ER and AR/PR between the neoadjuvant and non–neoadjuvant therapy populations. In the neoadjuvant therapy population, the risk of recurrence was 5.381 times higher in patients with high AR/ER than in those with low AR/ER  and disease–specific survival . In a study by Rangel et al. [The literature shows that AR/ER and AR/PR correlate with endocrine resistance and survival. The study by Cochrane et al.  includedl et al. , 402 patl et al.  performel et al.  reviewedl et al.  reviewedIn luminal–type breast cancers, high AR expression is associated with a good prognosis, and low ER expression is associated with a poor prognosis. Therefore, further investigation is required to determine whether AR/ER is an indirect manifestation of low ER expression. The role of AR in HR–positive breast cancer is controversial, particularly with regard to the relationship between AR and resistance to endocrine therapy. Cochrane et al.  found thKi67 expression levels are predictive of breast cancer prognosis, with higher Ki67 expression levels indicating worse survival. In hormone receptor–positive breast cancer, Ki67 is an important molecular marker to distinguish between luminal A and B breast cancers.A multifactorial survival analysis of non–pCR patients who underwent neoadjuvant therapy revealed that high residual tumor Ki67 expression was a risk factor for recurrence and metastasis, whereas changes in residual tumor ER, PR, and Ki67 before and after neoadjuvant therapy were not correlated with prognosis. Using the ROC curve, we found that the optimal residual tumor Ki67 cutoff value for distinguishing prognosis was 23%. Non–pCR patients with residual tumor Ki67 < 23% had significantly better survival . Among nThe advantage of the present study is that it is an early and large population–based, single–center study of the relationship between AR and related indicators and survival among the luminal B breast cancer population in China, and the number of included cases is larger than most foreign studies. This is the first study of the correlation between AR/ER and AR/PR with survival in China. The number of cases far exceeds that of foreign studies related to AR/ER. Moreover, this is the first study of neoadjuvant therapy and AR, AR/ER, and AR/PR in China, and it is also a less studied and novel research topic internationally. The limitations of the study are that it is a single–center, retrospective study that lacks further testing of gene transcription levels; therefore, its results should be validated in a large–sample, prospective study, and gene–level and translational studies are needed to investigate the mechanism.Luminal B breast cancer has a relatively good overall prognosis. However, a few patients still exhibit endocrine resistance, early recurrence, and low neoadjuvant chemotherapy pCR rates. Novel prognostic and response–related biomarkers can help screen patients with poor prognoses and may serve as a therapeutic target. In this study, we found that AR influenced the long–term survival of patients with luminal B (HER–2 negative) breast cancer, with an optimal cutoff value of 65%. Patients had significantly worse DFS and OS when AR < 65%. In patients with luminal B (HER–2 negative) breast cancer who underwent neoadjuvant therapy, AR expression level alone was not an influencing factor for prognosis, whereas AR/ER > 1.06 and residual tumor Ki67 > 23% were risk factors for DFS. The study contributes to the early screening of patients with a poor prognosis of luminal B (HER–2 negative) breast cancer and provides a basis for studies on AR–targeted therapies. More extensive and in–depth studies are further needed to address the relationship between luminal B breast cancer and AR.