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Methods | PMC10504081 | |||
Patients and study design | spasticity, cognitive impairment, contracture, upper-extremity hemiparesis, ischemic stroke | SECONDARY, EVENT, ISCHEMIC STROKE | Eligible individuals suffered a first-time, unilateral, ischemic stroke in the middle cerebral artery territory that spared the diencephalon and basal ganglia 12–36 months before surgery. Individuals with persistent moderate-to-severe upper-extremity hemiparesis as defined by an FM-UE score of ≤42 and sufficient upper-extremity motor ability to engage in rehabilitation (that is, a score of ≥1 on the FM-UE elbow flexion, elbow extension or finger mass flexion or extension) were included. Exclusion criteria included excessive spasticity or contracture of the upper-extremity muscles (that is, Modified Ashworth Scale = 4), severe cognitive impairment (Mini Mental State Examination < 24), as well as surgical, imaging or transcranial magnetic stimulation-related contraindications as detailed in the Candidates were enrolled in an open-label, non-randomized, single-arm trial with a target enrollment of 12 individuals. Participation spanned 20–24 months, with monthly assessments performed to record safety data and secondary metrics (Fig. The study protocol and subsequent amendments were approved by the Food and Drug Administration (investigational device no. G150237; 12/2015) with local approval established by the Institutional Review Board (IRB) of the Cleveland Clinic. Written informed consent was obtained before study-specific testing and re-consent to protocol changes was obtained when applicable. The informed consent process was actively monitored by two neuroethicists (P.F. and L.S.) and an independent Data Monitoring Committee (DMC). The DMC was composed of two neurosurgeons experienced in DBS and one physical medicine and rehabilitation physician. The DMC had the authority to halt the study in case of an unanticipated event or terminate the study in case of a second unanticipated event that did not have an acceptable etiology or resolution. | PMC10504081 |
Rehabilitation | The rehabilitation protocol was focused on highly repetitive, challenging and salient upper-extremity task practice administered by a physical therapist or assistant | PMC10504081 | ||
Deep brain stimulation | PMC10504081 | |||
Surgical implantation and programming | movement disorders | MOVEMENT DISORDERS | Participants underwent stereotactic implantation of a single DBS lead in the area of the cerebellar DN contralateral to the lesioned cerebral hemisphere using a frame-based technique similar to that used in DBS for movement disorders (Supplementary Fig. Between the rehab-only and the DBS + rehab phases, participants underwent up to 16 programming visits. First, a traditional monopolar review was performed to characterize stimulation-related side effects for each of the eight contacts of the DBS lead and delineate the upper limit of the parameter space. Thereafter, the acute effects of DN-DBS on motor task execution and task-related electroencephalography were examined according to specified combinations of electrode polarity, pulse frequency, pulse width and pulse amplitude. | PMC10504081 |
DBS + rehab phase | At the end of programming, participants had their devices activated for a period of 4 to 8 months with continued rehabilitation. With a single exception, all had their device programmed for 30-Hz stimulation, consistent with our preclinical work | PMC10504081 | ||
Outcome measures | upper-extremity impairment | ADVERSE EVENTS, SECONDARY | The primary end point was safety as measured by the incidence of serious adverse events during study participation. Among the secondary measures, the first motor outcome metric for characterization of the effects of the investigative treatment on upper-extremity impairment was the FM-UE, as it was the measure that determined the participant’s eligibility for the study under the inclusion and exclusion criteria. Additional secondary measures included indices of distal motor FA and quality of life as well as metabolic changes characterized by | PMC10504081 |
Adverse events—primary outcome | death, illness or injury, birth defect, illness or injury or permanent impairment, congenital abnormality | FETAL DISTRESS, ADVERSE EVENTS, ADVERSE EVENT, DISEASE, EVENT, FETAL DEATH, ADVERSE EVENT, EVENTS | Adverse events, including serious safety events, device-related events and unanticipated events were actively monitored in scheduled and unscheduled visits by the research team. The definitions for adverse events and serious adverse events followed the US Food and Drug Administration guidelines where adverse events were defined as any untoward medical occurrence, unintended disease or injury or any untoward clinical signs (including an abnormal laboratory finding) in participants, users or other persons whether or not related to the investigational medical device. Adverse events included all hospitalizations and events related to the investigational device or the comparator. This included events related to the procedures involved (any procedure in the clinical investigation plan). For users or other persons, this was restricted to events related to the investigational medical device. Adverse events did not include conditions preexisting to the participant’s enrollment. Preexisting conditions were not reported as adverse events unless the condition had an increased occurrence or intensity. Serious adverse events were defined as adverse events that (a) led to a death; (b) led to a serious deterioration in health that resulted in a life-threatening illness or injury, resulted in a permanent impairment of a body structure or a body function, required in-patient hospitalization or prolongation of existing hospitalization, resulted in medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function, or resulted in a substantial disruption in ability to conduct normal life functions; (c) led to fetal distress, fetal death or a congenital abnormality or birth defect; (d) when the event did not fit the above outcomes, but the event may have jeopardized the patient and may have required medical or surgical intervention (treatment) to prevent one of the other outcomes. It did not include in-patient hospitalization for a planned study procedure. Serious adverse events included device deficiencies that might have led to a serious adverse event if (a) suitable action had not been taken or (b) intervention had not been made. A planned hospitalization for preexisting conditions, or a procedure required by the Clinical Investigation Plan, without a serious deterioration in health or to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function, was not considered to be a serious adverse event. Adverse events were reviewed by the principal investigator and DMC, and recorded in accordance with Good Clinical Practice and Food and Drug Administration Code of Federal Regulations for Medical Devices guidelines. Source documentation was provided to the study sponsors. Monthly checks of DBS hardware integrity were established by recording electrical impedance values. | PMC10504081 |
Efficacy assessment—unblinded | Anxiety, spasticity, anxiety, depression, Depression | SECONDARY | All efficacy assessments were performed, unblinded and in person, as secondary measures for this phase 1 trial. Data were collected monthly from the presurgical baseline through 4 months after the DBS + rehab phase (Fig. Several other secondary measures were collected as part of this initial phase I exploration, including the Nine-Hole Peg Test, the Bilateral Box and Block Test, the Bimanual Grip Test, the Modified Ashworth Scale, the Short Form Health Survey (SF-12), the EQ-5D, the Beck Anxiety Inventory and the Beck Depression Inventory. These additional secondary metrics were included to monitor for any possible (then unknown) effects of DN-DBS on non-motor domains, including effects on spasticity, anxiety and depression; however, no significant changes were observed in this limited sample. A complete listing of secondary endpoints is provided in the Supplementary Table | PMC10504081 |
Brain imaging | BRAIN | Brain imaging included T1-weighted volumetric MRI of the head (Magnetom Prisma; Siemens Healthineers) performed before implantation of the DBS lead. FDG PET/CT studies were performed (Biograph TruePoint; Siemens Healthineers), adding physical therapy to the routine clinical protocol for cerebral metabolic imaging. After fasting at least 4 h, | PMC10504081 | |
Statistical analysis | pre-DBS + | SECONDARY | Change scores for each secondary outcome measure were calculated individually across five separate time periods: pre-surgery versus post-surgery (month 1 minus consent), pre-rehab-only versus post-rehab-only (month 3 minus month 1), pre-DBS + rehab versus post-DBS + rehab (month 8–12 minus month 4), pre-rehab carryover versus post-rehab carryover (month +2 minus month 8–12) and post-DBS + rehab to end of long-term follow-up (month ‘+10’ versus month 8–12). Due to skewed distributions, change scores are summarized using medians with interquartile ranges. Wilcoxon signed-rank tests were used to test for a significant change at each time period by comparing change scores for each phase to zero. Descriptive statistics with confidence intervals, for the full sample and for the sample stratified by functional preservation at baseline, are presented in the Statistical analyses of PET data focused on the effect of therapy and its correlation with change in arm function per the AMAT (version 13). Linear mixed-effects models | PMC10504081 |
Reporting summary | Further information on research design is available in the | PMC10504081 | ||
Online content | Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02507-0. | PMC10504081 | ||
Supplementary information |
Supplementary Figs. 1–3, Tables 1–4, study protocols 1–2 with summary of changes, DMC charter, summary of screen failures, detailed inclusion/exclusion criteria and surgical procedure details.Reporting Summary | PMC10504081 | ||
Extended data | PMC10504081 | |||
Extended data | is available for this paper at 10.1038/s41591-023-02507-0. | PMC10504081 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41591-023-02507-0. | PMC10504081 | ||
Acknowledgements | BRAIN | We thank all study participants who devoted time to our research and trusted us with their health in a clinical trial that involved an experimental neurological intervention. We thank all research personnel who dedicated time and effort to the success of the clinical trial including physical and occupational therapists, nurses in the neurological units of Cleveland Clinic, colleagues and caregivers in the Anesthesiology Institute of Cleveland Clinic, all nurses and caregivers in the operating rooms as well as colleagues in the Cerebrovascular Center and Department of Physical Medicine and Rehabilitation at Cleveland Clinic, Department of Neurology at University Hospitals of Cleveland and Department of Physical Medicine and Rehabilitation at MetroHealth who helped us identify potential candidates for the study. We thank M. Pierre (at Enspire DBS) for support regarding the investigational device exemption and regulatory compliance throughout the study. This study was supported by the National Institutes of Health Brain Research Through Advancing Innovative Neurotechnologies Initiative under grant number UH3NS100543 (to A.G.M. and K.B.B.) as well as by Enspire DBS, a spin-off company of Cleveland Clinic. | PMC10504081 | |
Author contributions | All authors contributed extensively to the work presented in this paper. The rationale for stimulating the cerebellothalamocortical pathway to promote motor recovery was provided previously by A.G.M. and K.B.B. A.G.M. and K.B.B. supervised the project, while A.W. and M.S. helped conduct the trial. A.G.M. and S.N. performed surgeries, and S.N., K.B.B. and R.G. were responsible for programming the DBS devices. A.B.R., F.B. and S.D. were responsible for conducting and prescribing physical therapy. C.C., J.O., A.W. and D.F. collected participant data. P.J.F. and L.S. participated as consent monitors. J.C., X.H., F.P.D. and S.E.J. helped with capturing and analyzing imaging data. D.C., J.C. and E.B.P. assisted in the collection of electrophysiological data. O.H. conducted data analysis. S.L.W. contributed to study design, reviewing data and critiquing draft phases of manuscript draft development. | PMC10504081 | ||
Peer review | PMC10504081 | |||
Data availability | Raw data related to safety and feasibility, the primary endpoints of the study, can be shared upon request and review by Cleveland Clinic and the study sponsors. Secondary endpoint data and PET imaging data, analyzed or raw, may also be shared. Depending on the data that are requested, we will need to consult with the IRB and sponsors before sharing. Cleveland Clinic has regulations related to data sharing, in particular data that could be used as identifiers. The investigators and the IRB will need to verify that data sharing would be acceptable and within policy for patient protection and within the limits of the informed consent provided by participants when enrolling in the study. The investigators will also have to consult the sponsors before data sharing. Patient-related information not included in this report was collected as part of a clinical trial and may be subject to patient confidentiality.Given the restricted study population and small sample size, even though any dataset will be stripped of identifiers before release for sharing, we believe that there remains the possibility of deductive disclosure of participants by unique combinations of characteristics. Therefore, we will make the data and associated documentation available to users only under a data-sharing agreement that provides for a commitment to: (1) using the data only for research purposes and not to identify any individual participant; (2) securing the data using appropriate computer technology; and (3) destroying or returning the data after analyses are completed.Requests for data can be sent to A.G.M. All requests will be answered within 4 weeks. We anticipate that data will be shared, if there are no risks or low risks to the participants. | PMC10504081 | ||
Competing interests | SECONDARY | A.G.M. serves as Chief Medical Officer and Chair of the Scientific Advisory Board for Enspire DBS Therapy and is paid with stock options. As the inventor, A.G.M. will receive portions of commercialization and/or Cleveland Clinic Foundation stock revenue and payments through Cleveland Clinic Foundation with fees deducted. B.H. serves as a paid member of the DMC for the corresponding phase I/II study (RESTORE). S.L.W. serves as a member of the Scientific Advisory Board and is a paid consultant to Enspire DBS Therapy. J.C. also serves as a paid consultant, but the agreement is with MetroHealth, and J.C. is their designated representative. J.C. is also a member of the Scientific Advisory Board. K.B. serves on the Scientific Advisory Board and is paid with stock options. In addition, A.B.R. is a paid consultant to Enspire DBS Therapy. Enspire DBS Therapy partially sponsored the study and had access to the safety, feasibility and secondary outcome measures. The company had no role in the drafting or editing of this manuscript. | PMC10504081 | |
References | PMC10504081 | |||
Background | pancreatic cancer | METASTASIS, PANCREATIC CANCER | Lymph node metastasis (LNM) is a critical prognostic factor in resectable pancreatic cancer (PC) patients, determining treatment strategies. This study aimed to develop a clinical model to adequately and accurately predict the risk of LNM in PC patients. | PMC10465378 |
Methods | 13,200 resectable PC patients were enrolled from the SEER (Surveillance, Epidemiology, and End Results) database, and randomly divided into a training group and an internal validation group at a ratio of 7:3. An independent group ( | PMC10465378 | ||
Result | A total of six risk predictors (including age at diagnosis, race, primary site, grade, histology, and T-stage) were identified and included in the nomogram. The areas under the curves (AUCs) [95% confidential interval (CI)] were 0.711 (95%CI: 0.700–0.722), 0.700 (95%CI: 0.683–0.717), and 0.845 (95%CI: 0.749–0.942) in the training, internal validation and external validation groups, respectively. The calibration curves showed satisfied consistency between nomogram-predicted LNM and actual observed LNM. The concordance indexes (C-indexes) in the training, internal, and external validation sets were 0.689, 0.686, and 0.752, respectively. The DCA curves of the nomogram demonstrated good clinical utility. | PMC10465378 | ||
Conclusion | pancreatic cancer | PANCREATIC CANCER | We constructed a nomogram model for predicting LNM in pancreatic cancer patients, which may help oncologists and surgeons to choose more individualized clinical treatment strategies and make better clinical decisions.
| PMC10465378 |
Keywords | PMC10465378 | |||
Introduction | malignancy | GASTROINTESTINAL CANCERS, LYMPH NODE METASTASIS | PC is the most aggressive and lethal malignancy in gastrointestinal cancers. The overall 5-year survival rate is less than 10%, with few significant improvements for years (Ansari et al. The nomogram model has been widely used in the prediction of lymph node metastasis. However, there is a lack of nomograms for predicting LNM in resectable PC patients preoperatively. In this study, the clinical characteristics of cases diagnosed with PC were analyzed, and a nomogram for predicting LNM was developed, which contributes to providing personalized guidance for resectable PC patients. | PMC10465378 |
Materials and methods | PMC10465378 | |||
Data collection | death, pancreatic cancer | PANCREATIC CANCER | In our study, patients diagnosed with pancreatic cancer from 2000 to 2019 were collected from the SEER database. The exclusion criteria were as follows: diagnosed confirmation with clinical diagnosis only, radiography without microscopic confirm, direct visualization without microscopic confirmation or unknown; more than 2 primaries; SEER cause-specific death unknown; survival months equal to zero or unknown; grade unknown; stage or Patients enrollment and exclusion process in the SEER databaseA total of 62 patients diagnosed with PC from December 2018 to February 2022 in The First Affiliated Hospital of Xinxiang Medical University were used to further validate the constructed nomogram externally. The inclusion and exclusion criteria were the same as the training set. The time of the last follow-up was March 2023. This study was approved by the institutional review board of our hospital. | PMC10465378 |
Statistical analysis | NRI | REGRESSION | The median (IQR), frequency (proportions), Mann–Whitney U tests, independent t-tests, Pearson’s chi-square test, Fisher’s exact test, and univariate and multivariate binary logistic regression analysis were calculated by SPSS (SPSS Inc., Chicago, USA). Nomograms, ROC curves, calibration plots, the nutrition risk index (NRI), integrated discrimination improvement (IDI), DCA curves, and Kaplan–Meier plots, were conducted by R software (version 4.2.2). | PMC10465378 |
Construction, validation, and clinical usefulness of the nomogram | REGRESSION | Univariate and multivariate logistic regression analyses were utilized to find the independent factors in predicting LNM and the minimum Akaike’s information criterion (AIC) was performed to choose the optimal model parameters and construct a nomogram for evaluating the risk of LNM. The predictors include age at diagnosis, race, primary site, grade, histology, and | PMC10465378 | |
Results | PMC10465378 | |||
Patient characteristics | pancreatic cancer | PANCREATIC CANCER | A total of 13,200 resectable pancreatic cancer patients were enrolled in our research between 2000 and 2019 according to the screening flowchart from the SEER database and randomly divided into a training group (Clinicopathological characteristics in resectable pancreatic cancerNote: OthersOthers | PMC10465378 |
Univariate and multivariate logistic regression results | REGRESSION, LYMPH NODE METASTASIS | The clinicopathological factors associated with LNM were revealed by the univariate and multivariate logistic regression analysis. Univariate logistic regression analysis showed that age at diagnosis, race, primary site, grade, histology, and T-stage were significant factors for LNM in PC patients (Table Risk variables for lymph node metastasis determined by univariate and multivariate logistic regression analysesNote: Asian, Asian or Pacific Islander; OthersOthers | PMC10465378 | |
Construction and validation of the nomogram based on predictors of lymph nodes metastasis | pancreatic cancer, NRI | PANCREATIC CANCER, LYMPH NODE METASTASIS | The minimum Akaike’s information criterion (AIC) was used to select the optimal model parameters and construct a nomogram for assessing the risk of LNM (Arunajadai The nomogram for the risk of lymph node metastasis in resectable pancreatic cancer patientsROC of the nomogram for the training cohort (The calibration plots of the training cohort (The clinical application value was determined by DCA which calculates the net benefits at different risk threshold probabilities. The net benefit of the nomogram was the largest in comparison to the grade and T-stage, which indicated the nomogram was a reliable clinical tool for predicting LNM in PC patients who underwent surgical resection (Fig. Nomogram decision curves (DCA) for the training cohort (Additionally, the accuracy of the nomogram compared with the T-stage was demonstrated by the NRI and IDI. The NRI was 0.370 (95%CI: 0.329–0.411) and the IDI was 0.044 (95%CI: 0.039–0.048, The Kaplan–Meier overall survival curves of training and internal/external validation groups are plotted in Fig. The Kaplan–Meier overall survival (OS) analysis of lymph node metastasis in the training set ( | PMC10465378 |
Discussion | cancers, tumor, cancer death, adenocarcinoma, pancreatic head cancer | CANCERS, TUMOR, ADENOCARCINOMA, LYMPH NODE METASTASIS, LIVER METASTASIS, PANCREATIC NEUROENDOCRINE NEOPLASM | PC is one of the most lethal of all cancers with high mortality, which is the seventh leading cause of cancer death worldwide (Sung et al. In our study, a total of six clinicopathological factors were considered as risk factors associated with LNM in PC patients, including age at diagnosis, grade, histology, T-stage, primary site, and race, which was largely consistent with previous analyses (Huang et al. Various studies demonstrated that race was related to lymph node metastasis and prognosis (Oweira et al. The correlation between grade and LNM in PC patients has been revealed in previous studies widely. Harimoto Norifumi et al. shows that lymph node metastasis was significantly associated with higher tumor grade in pancreatic neuroendocrine neoplasm (Harimoto et al. The histological type is commonly considered an important predictor of the prognosis in PC patients. Bi-Yang Cao et al. found that adenocarcinoma was the independently associated risk factor for poor prognosis in patients with liver metastasis in PC patients (Cao et al. The nomogram for evaluating the risk of LNM in PC patients was developed by easily available clinicopathological factors, including age at diagnosis, race, grade, histology, T-stage, and tumor location. The AUC and the calibration curves demonstrated excellent discrimination and consistency of this nomogram model. The risk of LNM in PC patients could be conveniently and accurately calculated by those accessible variables. Furthermore, DCA curves were utilized to estimate the clinical utility, which shows good net benefit. In summary, the risk of LNM in preoperative PC patients can be easily and accurately predicted by the newly established nomogram model.Although the nomogram model had good accuracy for predicting the risk of LNM in PC patients, there are several limitations to this study. First of all, the selection bias could not be avoided due to the nature of retrospective analyses. For example, patients with missing data were excluded from our study, which may cause selection bias. Secondly, variables such as age, tumor size, leucocyte, albumin, and lymphocytes/monocytes have been identified as independent predictors of LNM in pancreatic head cancer (Guo et al. | PMC10465378 |
Conclusion | In summary, the nomogram for predicting the preoperative LNM in PC patients was developed based on the SEER database, which shows good performance and clinical application.
| PMC10465378 | ||
Acknowledgements | All the researchers and staff of the SEER program should be highly appreciated. | PMC10465378 | ||
Author contributions | HC, XX, XK, and QZ designed this research and revised the manuscript. HC and JX collected the data. Statistical analysis was conducted by HC and XX. Figures and tables were generated by HC, XX, and JX. HC wrote the original manuscript. XX, XK, and QZ supervised this study. All authors contributed to this article and approved the final manuscript. | PMC10465378 | ||
Funding | The article received support from the fund from the Joint Project of Henan Province and Ministry (LHGJ20200516, and LHGJ20200500). | PMC10465378 | ||
Data availability | The data of this study are available for all authors. | PMC10465378 | ||
Declarations | PMC10465378 | |||
Conflict of interest | All authors declare no conflict of interest. | PMC10465378 | ||
Ethical approval | Data from our hospital have been approved by the Ethics Committee of the First Affiliated Hospital of Xinxiang Medical University. While, data from the SEER database were in no need of informed consent and medical ethics review. | PMC10465378 | ||
References | PMC10465378 | |||
Methods | subarachnoid block | It is a Prospective Randomized Double-Blind Study. It includes 68 patients undergoing urological procedures under subarachnoid block. Group LD: Patients will receive 3.5 ml of Isobaric Levobupivacaine 0.5% + Dexmedetomidine 10 µg (0.1ml) Group RD: will receive 3.5ml of Isobaric Ropivacaine 0.5% + Dexmedetomidine 10 µg (0.1ml) | PMC9987288 | |
Results | Time taken for onset of sensory and motor block is significantly more in ropivacaine while duration of block is more in levobupivacaine. | PMC9987288 | ||
Conclusions | Addition of Dexmedetomidine to Isobaric Levobupivacaine significantly prolongs the duration of analgesia and anaesthesia compared to Ropivacaine and maintains stable hemodynamics. Ropivacaine is a suitable drug for day care whilst levobupivacaine is an excellent agent for longer surgeries. Dexmedetomidine is an effective non-opioid adjuvant which improves effectiveness of block without increasing the risk of side effects. | PMC9987288 | ||
Results | REGRESSION, REGRESSION | There is a significant difference in Onset of Sensory Block {T10} between study group. {P value < 0.001}. There is a significant difference in Time for onset of motor block between study group. {P value 0.016}. The mean time for complete block {in minutes} was 8.03 ± 2.53 in Group LD and it was 9.18 ± 1.8 in Group RD. There is a significant difference in time for complete block {in minutes} between study groups {P value 0.035}. There is a significant difference in time taken to achieve T8 and T6 {in minutes} between study groups {P value < 0.05}. There is a significant difference in Duration of motor Blockade between study groups {P value < 0.001}. There is a significant difference in Time of two segment regression from highest sensory level between study groups {P value < 0.001}. There is a significant difference in Regression of Sensory level {up to T10} between study groups {P value 0.002}. There is a significant difference in Time for First Rescue Analgesia between study groups {P value < 0.001}. | PMC9987288 | |
Acknowledgements | Sensory Block | REGRESSION | Immeasurable appreciation and deepest gratitude are extended to all our colleagues whose help and support contributed in making this study possible. We thank our families for their unwavering support of our academic and professional endeavors. Above all, we are forever thankful to Father Almighty for providing us with physical and mental strength.Comparison of mean of Onset of Sensory Block (T10), time taken to achieve sensory level of T8 and T6 and the Mean of Time of Two Segment Regression from Highest Sensory Level between study group (N=68)Comparison of mean of time for onset and mean duration of motor block between study group (N=68) | PMC9987288 |
Design | Cluster randomized control trial. | PMC10389722 | ||
Setting | The intervention was conducted in the primary care setting in the province of BC between December 2010 and February 2012. | PMC10389722 | ||
Participants | We randomized 4 833 FPs by geographic location into an Early intervention arm (n = 2 417) and a Delayed control arm (n = 2 416). | PMC10389722 | ||
Intervention | The Education for Quality Improvement in Patient Care (EQIP) program mailed to each FP in BC, a ‘portrait’ of their individual prescribing of antibiotics to women with UAC, plus therapeutic recommendations and a chart of trends in antibiotic resistance. | PMC10389722 | ||
Main outcome measures | Antibiotic prescribing preference to treat UAC. | PMC10389722 | ||
Results | SAID | Implementing exclusion criteria before and after a data system change in the Ministry of Health caused the arms to be unequal in size–intervention arm (1 026 FPs, 17 637 UAC cases); control arm (1 352 FPs, 25 566 UAC cases)–but they were well balanced by age, sex and prior rates of prescribing antibiotics for UAC. In the early intervention group probability of prescribing nitrofurantoin increased from 28% in 2010 to 38% in 2011, a difference of 9.9% (95% confidence interval [CI], 9.1% to 10.7. Ciprofloxacin decreased by 6.2% (95% CI: 5.6% to 6.9%) and TMP-SMX by 3.7% (95% CI: 3.1% to 4.2%). Among 295 FPs who completed reflective surveys, 52% said they were surprized by the | PMC10389722 | |
Data Availability | A minimal dataset underlying the primary result has been made available as a | PMC10389722 | ||
Introduction | infections | INFECTIONS | Indicators show that infections caused by antimicrobial resistant organisms continue to increase in Canada [In 2010, as part of a collaboration between the British Columbia (BC) Ministry of Health and the BC Medical Association, an initiative known as Education for Quality Improvement of Patient care (EQIP) mailed family physicians (FPs) confidential feedback portraits of their individual prescribing of antibiotics for UAC. In 2012, after the portrait was distributed, the Ministry abruptly terminated the EQIP initiative and access to the original EQIP data [ | PMC10389722 |
Methods | PMC10389722 | |||
Study design and setting | The intervention was conducted in the primary care setting in the province of BC between December 2010 and February 2012. FPs were identified through the College of Physicians and Surgeons of British Columbia registrant directory containing public information on individuals currently registered and licensed with the College. The EQIP portrait was a cluster randomized control trial. The unit of randomization was the practice community (n = 116). Pairs were matched based by size and rural vs urban location using the same method used in a prior cluster randomized control trial [ | PMC10389722 | ||
Randomization | BLIND | Active FPs during 2009 in the province were eligible to receive the UAC portrait intervention. Physicians were included in the study if they met all of the following criteria: did not opt out of the program via their registration package; had evidence of medical practice in the form of Medical Services Plan billings in the most recent quarter of data available; were available in the BC Ministry of Health database with a valid, encrypted, and linkable MSP billing number; and were categorized as a ‘Private Practice General Practitioner” in the MSP Registration & Billing information system. Pairs of practice community locations were randomized into two groups using a random number generator. Blind to this allocation, the EQIP Working Group Chair flipped a coin to determine which group received the early intervention and which received the delayed intervention. Physicians in both groups who had zero patients diagnosed with a UAC in the prior year, resulting in an empty prescribing graph on the portrait, were sent a sample portrait with the delayed mailing, but excluded from the evaluation. | PMC10389722 | |
Personalized portrait intervention | infection | INFECTION, DISEASE | An interdisciplinary team with expertise in antimicrobial resistance, infection disease, primary care, pharmacoepidemiology, and public health developed an educational portrait aimed to improve the quality of antimicrobial prescribing for UAC in primary care. The EQIP UAC portrait (The EQIP portrait was a two-page personalized colour document containing: 1) a vignette describing a common clinical encounter, 2) | PMC10389722 |
Databases | DISEASE | Prescription records were obtained from a linked administrative database at the BC Ministry of Health. The database contains records of all prescriptions dispensed at community pharmacies with the exception of patients who were federally insured at the time (e.g., Veterans, Royal Canadian Mounted Police, and First Nations and Indigenous People). The prescription records were linked to physician services and hospitalizations using anonymous client identifiers. The physician and hospital databases contained diagnostic codes (International Classification of Disease (ICD) 9 | PMC10389722 | |
Prescribing endpoints | Women with visits indicating UAC were identified from MSP billing records in which the first 3 digits of the ICD-9 diagnosis code in the record indicated | PMC10389722 | ||
Statistical analysis | REGRESSIONS | We measured the percentages of women coded with UAC who received any antibiotic during the 12-month post-intervention window (Dec 3, 2010 to Dec 3, 2011) in the Early and Delayed arm, as well as the FPs’ preferences for each type of antibiotic. We compared the preferences both by calculating differences with 95% confidence intervals (CI), and by estimating preference odds ratios (OR) via logistic regressions in which the ratio of change in the intervention group between the pre-intervention period to the post-intervention period was compared to the same ratio of change (or non-change) in the delayed control group [ | PMC10389722 | |
Results | PMC10389722 | |||
Physician demographics | The target population was 4,832 family physicians from British Columbia. 2,416 physicians did not meet the eligibility criteria, and 39 physicians opted out of the program ( | PMC10389722 | ||
Study physician flow diagram. | PMC10389722 | |||
Physician characteristics. | PMC10389722 | |||
Primary and secondary outcomes | Tables | PMC10389722 | ||
Prescribing outcomes, 12 months pre and post intervention. | PMC10389722 | |||
Prescribing outcomes, 3 months pre and post intervention. | REGRESSION | Logistic regression models, accounting for clustering of patients by physician, showed the preference odds for a nitrofurantoin prescription following a UAC diagnosis increased by 57% in the 12 months after the intervention (relative risk (RR) = 1.57, 95% confidence interval (CI): 1.43–1.71). The increase in nitrofurantoin preference was offset by a 33% decrease in treatment with ciprofloxacin (RR = 0.67, 95% CI: 0.52–0.83) and a 32% decrease in TMP-SMX (RR = 0.68, 95% CI: 0.50–0.86). The intervention was not associated with a change in treatment with other antibiotics or a change in UAC followed by no treatment. The 3 month pre-and-post intervention sensitivity analysis yielded similar results. The intervention was associated with a 37% increase in nitrofurantoin prescribing (RR = 1.37, 95% CI: 1.20–1.54) in the early physician group relative to the delayed group. Likewise, both ciprofloxacin and TMP-SMX were associated with a 26% decrease in treatment (RR = 0.74, 95% CI: 0.56–0.91) and (RR = 0.74, 95% CI: 0.54–0.94), respectively. | PMC10389722 | |
Physician feedback | There were 295 physicians who completed and returned a reflective activity form ( | PMC10389722 | ||
Physician reflective survey results. | cystitis | CYSTITIS | With regards to all the information in the portrait, 222 (75%) agreed their prescribing data accurately reflected their first-line prescribing for cystitis. 153 (52%) reported being surprised by the rates of | PMC10389722 |
Discussion | cystitis | CYSTITIS | Our study described the impact of a personalized prescribing portrait intervention on antibiotic use for UAC in the primary care setting of BC. The prescribing impact from the UAC portrait was greater than previous portraits implemented by the EQIP initiative [FPs were asked to complete a reflective survey where they were asked questions pertaining to the quality of evidence, accuracy of data, and potential for changing their personal treatment decisions for patients with UAC. The responses were overwhelmingly positive, with the majority of physicians indicating they learned something new and described their individual prescribing data as accurate. Less than 2% of the physicians reported being dissatisfied with the content of the portrait. The large sample of physician responses was novel, and offered important feedback and support for the future development of personal prescribing portraits. However, the physicians responding to the survey were not a random sample, and therefore careful interpretation of the results is warranted.Several government programs in BC have aimed at reducing antimicrobial use, including educational campaigns [A systematic review and meta-analysis of audit and feedback interventions calculated an overall adjusted risk difference of 10% improvement in the intervention groups after adjusting for baseline difference [Our intervention had several strengths that may have contributed to the high magnitude of impact. First, comprehensive medication dispensing data was used to twice mail up-to-date personalized prescribing charts, with actionable evidence-based prescribing targets, and peer comparison, to over 2,000 active family physicians. The components of the intervention have been shown to be highly effective [Our study had data limitations that warrant discussion. The use of administrative health claims data is subject to data quality issues. This evaluation relies on the accuracy of diagnosis coding in the MSP database, particularly the use of the ICD-9 code 595 for cystitis. Patient visits for cystitis that were incorrectly coded would not have been included in the evaluation. Another limitation of our study was the randomization of physicians by community. This created baseline geographic imbalances between the intervention and control groups that could be related to antibiotic preference for the treatment of UAC. However, this is very unlikely to explain the magnitude of impact. | PMC10389722 |
Conclusion | ACUTE CYSTITIS | Our analysis showed the educational intervention was effective at increasing use of nitrofurantoin and decreasing use of ciprofloxacin and TMP-SMX for treatment of uncomplicated acute cystitis. This intervention demonstrated that high quality educational interventions with clearly stated recommendations for action, supported by robust evidence and individualize prescribing pattern comparisons, have the potential to significantly change family physician prescribing patterns in the primary care setting. Physician feedback was overwhelmingly positive towards the quality of evidence and accuracy of data, with over half indicating they learned something new. Further educational interventions with well documented methods will assist future studies identify key factors that improve evidence-based prescribing changes. | PMC10389722 | |
Supporting information | PMC10389722 | |||
CONSORT 2010 checklist of information to include when reporting a randomised trial*. | (DOC)Click here for additional data file. | PMC10389722 | ||
Uncomplicated acute cystitis sample portrait. | (PDF)Click here for additional data file. | PMC10389722 | ||
Cystitis complicating factors, case definitions. | (PDF)Click here for additional data file. | PMC10389722 | ||
Continuing Medical Education credit reflective exercise. | (PDF)Click here for additional data file. | PMC10389722 | ||
References | PMC10389722 | |||
Subject terms | Toxicities, SD, TRAEs, DLBCL | SOLID TUMOUR, PROLIFERATION, ADVERSE EVENTS, DISEASE, SOLID TUMORS, SECONDARY, DIFFUSE LARGE B-CELL LYMPHOMA | Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months’ duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8–33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0–8.6) and a CBR of 31.7% (95% CI, 18.1–48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents.Bromodomain and extraterminal proteins (BET) are reported as targets for anticancer therapy. Here, the authors report the final results of a phase I clinical trial of the BET inhibitor trotabresib in patients with solid tumours and diffuse large B-cell lymphoma. | PMC10011554 |
Introduction | DLBCL | SOLID TUMORS | Bromodomain and extraterminal proteins (BET) are epigenetic readers that bind to acetylated lysine residues on histones in chromatinTrotabresib (CC-90010; BMS-986378) is an orally administered, potent, reversible inhibitor of BET family members. CC-90010-ST-001 is a phase I, multicenter, open-label study to assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of trotabresib in patients with advanced or unresectable solid tumors or relapsed/refractory (R/R) DLBCL. The dose escalation (part A) of this trial evaluated a wide range of doses and treatment schedules, with the intention of optimizing the treatment-free interval in each treatment cycle to improve the tolerability of the dose selected for further evaluation in the expansion cohortsHere, we report long-term follow-up of safety and efficacy from the dose escalation (part A) and, for the first time, present results from the dose-expansion cohorts (parts B and C), including evaluation of food effects on trotabresib safety and PK. | PMC10011554 |
Results | PMC10011554 | |||
Patients and treatment | aggressive tumors, DLBCL | SOLID TUMORS | Patients were enrolled at 11 study sites in France, Italy, Japan, and Spain. Patient enrollment in part A took place between July 31, 2017 and November 12, 2018, with a total of 69 patients enrolled and treated, of whom 67 had advanced or unresectable solid tumors and two had R/R DLBCL. Patient enrollment in part B began on June 18, 2019, and was ongoing at the time of the data cutoff; the last patient enrolled at the time of the data cutoff was enrolled on January 11, 2021. In total, 23 patients with R/R DLBCL were enrolled and treated in part B, of whom 19 received trotabresib 45 mg/day 4 days on/24 days off and four received an alternate RP2D dose and schedule of trotabresib 30 mg/day 3 days on/11 days off. The alternate RP2D was investigated further because it had comparable tolerability to 45 mg/day 4 days on/24 days off, delivered the same cumulative dose over a 28-day treatment cycle, and was potentially more suitable for the treatment of patients with aggressive tumors such as R/R DLBCL, due to more constant exposure and target engagement. Patient enrollment in Part C took place between October 21, 2019 and July 27, 2020, with a total of 41 patients with advanced solid tumors enrolled to evaluate the effects of food on the PK and safety profile of trotabresib 45 mg/day 4 days on/24 days off.Details of patient disposition are shown in Fig. | PMC10011554 |
Safety | Safety and tolerability were the primary endpoints of the study. Safety results for part A at the most recent follow-up were consistent with the preliminary analysis reported previously | PMC10011554 | ||
Treatment-related adverse events reported in ≥10% of patients in the overall study population, or in ≥2 patients at grade ≥3 severity. | pneumonia, TRAEs, leukopenia, syncope, lymphopenia, inappropriate antidiuretic hormone secretion, presyncope, any-grade, hypokalemia | PNEUMONIA, FEBRILE NEUTROPENIA, ESSENTIAL HYPERTENSION, LEUKOPENIA, DIABETES MELLITUS, LYMPHOPENIA, ABDOMINAL INFECTION, SKIN HEMORRHAGE, HYPERAMYLASEMIA, INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION | Grade 3 essential hypertension, hypokalemia, lipase increased, liver function test abnormal, presyncope, skin hemorrhage, and grade 4 blood creatinine phosphokinase increased, diabetes mellitus, and inappropriate antidiuretic hormone secretion were reported in one patient each in the overall part A population. Grade 3 abdominal infection, blood bilirubin increased, pneumonia and grade 4 blood creatinine increased, febrile neutropenia, leukopenia, and lymphopenia were reported in one patient each in the part B R/R DLBCL population. Grade 3 gamma-glutamyl transferase increased, hyperamylasemia, and syncope were reported in one patient each in the part C population. Source data are provided as a source data file. Details of TRAEs and all-cause TEAEs occurring at any-grade and grade 3–5 severity are shown in Supplementary Tables | PMC10011554 |
Efficacy | DLBCL | SECONDARY | Preliminary efficacy was a secondary endpoint of the study. Response rates in part A were unchanged from those previously reportedOf the 23 patients with R/R DLBCL treated in part B, 15 (65.2%) were evaluable for response (Fig. | PMC10011554 |
Summary of antitumoral activity. | Source data are provided as a source data file. | PMC10011554 | ||
Pharmacodynamics | BLOOD | The pharmacodynamic effects of trotabresib in peripheral blood were assessed as an exploratory endpoint. Blood C-C motif chemokine receptor 1 ( | PMC10011554 | |
Discussion | tumor, high-grade astrocytoma, DLBCL, malignancies, glioblastoma, tumors | TUMOR, THROMBOCYTOPENIA, MINOR, SOLID TUMORS, DISEASE, BRAIN TUMOR, ADVANCED CANCER, MALIGNANCIES, GLIOBLASTOMA, TUMORS, DIFFUSE ASTROCYTOMA | Effective new treatments for patients with advanced malignancies are urgently needed, particularly for those patients who have tumor types with limited treatment options or whose tumors are refractory to currently available therapies. BET inhibitors have a mechanism of action that differs from existing marketed drugs, and have demonstrated anticancer activity across a broad range of tumor types in preclinical models and patients with various solid and hematological malignanciesTrotabresib is a next-generation BET inhibitor with properties that provide potent and selective inhibition of BRD family proteins, as well as a PK profile that allowed evaluation of a range of dosing schedules in part A. Preliminary results of this study were encouraging, with trotabresib showing high oral bioavailability and a comparatively long tLonger follow-up of the dose escalation (part A) and data from parts B and C confirmed that trotabresib was generally very well tolerated in heavily pretreated patients with advanced, unresectable solid tumors and R/R DLBCL. Most TRAEs were mild or moderate and were easily manageable with dose modifications and/or treatment interruption. The most frequent grade 3/4 TRAE was thrombocytopenia, which is a class effect of BET inhibitorsBiomarker analysis using blood levels of The preliminary efficacy of trotabresib monotherapy in patients with heavily pretreated advanced solid tumors and R/R DLBCL was supportive of antitumor activity, with one CR and one PR reported in part A (ORR 2.9%; 95% CI, 0.4–10.1), two CRs and one PR in part B (ORR 13.0; 95% CI, 2.8–33.6), and one minor response per Response Assessment in Neuro-Oncology (RANO) criteria in part C (ORR 0.0; 95% CI, 0.0–8.6). The longer follow-up of patients enrolled in part A allowed further characterization of responses in this cohort, with the patient with a CR having sustained response for 19 cycles. A total of five patients in part A remained on treatment for ≥24 cycles, including a patient who received 38 cycles of treatment and a patient who remains on treatment at cycle 53, corresponding to treatment durations of 3 and 4 years, respectively. One patient with high-grade astrocytoma in part C has a minor antitumoral response that is ongoing at cycle 34, and a further seven patients with advanced solid tumors in part C completed ≥1 year of treatment. These data suggest that trotabresib monotherapy may provide long-lasting disease control in some patients, and demonstrate the long-term efficacy and good tolerability of intermittent dosing of trotabresib even in patients with advanced, progressive disease. Importantly, the durable CR in a patient with progressive diffuse astrocytoma and the minor radiographic response in a patient with high-grade astrocytoma, a tumor type with typically poor outcomes and limited effective treatment options, illustrate the ability of trotabresib to penetrate brain tumor tissueEvaluation of the effects of food on trotabresib PK showed generally comparable exposure and plasma concentrations between fed and fasted patients, with a similar tAs this exploratory phase I first-in-human trial was designed to evaluate trotabresib in patients with advanced cancers for whom no standard therapy was available, as well as to guide dose selection for subsequent studies, it is subject to a number of limitations. Thus, its results should be interpreted with care in the absence of an adequately powered randomized controlled trial.In summary, the results from this study demonstrated a tolerable safety profile during long-term treatment, a long tThe results reported here demonstrate the preliminary anticancer properties of trotabresib monotherapy across a range of heavily pretreated advanced solid tumors and in R/R DLBCL, supporting further investigation of its use in combination with other anticancer agents. Based on the responses observed in this study, a clinical trial has been initiated to investigate trotabresib in combination with temozolomide in patients with newly diagnosed glioblastoma (NCT04324840) | PMC10011554 |
Methods | PMC10011554 | |||
Study design | The CC-90010-ST-001 trial comprises three parts (Fig. | PMC10011554 | ||
Patient selection | follicular lymphoma, DLBCL, endometrial carcinoma, bidimensionally measurable disease, midline carcinoma, transformed lymphoma, NHL | DISEASE PROGRESSION, SALIVARY GLAND CARCINOMA, FOLLICULAR LYMPHOMA, DISEASE, SOLID TUMORS, BCC, ENDOMETRIAL CARCINOMA, NHL | Patients were enrolled from July 31, 2017 to January 11, 2021. The study included patients aged ≥18 years with an ECOG PS of 0 or 1. Part A included patients with histologically or cytologically confirmed advanced or unresectable solid tumors or R/R advanced NHL that had progressed on standard anticancer therapy or for which no conventional therapy was available.Part B included patients with histologically or cytologically confirmed R/R DLBCL that had progressed following two or more previous lines of therapy, including autologous stem cell transplant, or that had progressed after at least one previous line of therapy and where the patient was not eligible for or had declined autologous stem cell transplant. Patients with transformed lymphoma following chemotherapy for follicular lymphoma who had received at least two standard treatment regimens for DLBCL were also eligible. Patients must have had a lack of response after chimeric antigen receptor (CAR) T-cell therapy (if available), been ineligible for CAR T-cell therapy, or declined CAR T-cell therapy. Part B also included a cohort of patients with histologically or cytologically confirmed advanced BCC, nuclear protein in testis (NUT) midline carcinoma, advanced salivary gland carcinoma, or advanced endometrial carcinoma and disease progression on, or inability to tolerate, standard therapy, or for whom no standard therapy exists. Patient enrollment in this cohort was subsequently restricted to patients with advanced BCC only in a protocol amendment.Part C included patients with histologically or cytologically confirmed advanced solid tumors and disease progression on, or inability to tolerate standard therapy, or for whom no standard therapy exists.Patients with solid tumors had at least one site of measurable disease; patients with NHL had bidimensionally measurable disease on cross-sectional imaging, with at least one lesion >1.5 cm in diameter. | PMC10011554 |
Endpoints | Tumors, Cancer | TUMORS, ADVERSE EVENT, SECONDARY, CANCER | The primary endpoints of the study were the safety and tolerability of trotabresib, as well as the MTD and/or RP2D of trotabresib. Safety was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03Secondary objectives were the preliminary efficacy of trotabresib in terms of clinical benefit rate (CR + PR + SD of ≥4 months’ duration), ORR (CR + PR), duration of response or SD, PFS, OS, and the PK of trotabresib. In addition, part C assessed the effects of food on the PK and the safety of trotabresib as a secondary objective. The pharmacodynamics of trotabresib were assessed as an exploratory objective.Response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | PMC10011554 |
Pharmacokinetic and pharmacodynamic assays | Serial blood samples for PK and pharmacodynamic analyses were collected for each dosing schedule after the first and last doses in cycle 1. Additional blood samples for assessment of the food effect on trotabresib PK in part C were collected during cycle 2. The food effect–evaluable population comprised all patients with adequate PK data to allow calculation of trotabresib AUC from time 0 (day 1) to day 22 from both the fed and fasted treatment periods and who had completed a 4-h post-dose fast during the fasted cycle or consumed the entire high-fat, high-calorie meal during the fed cycle and had received all trotabresib doses during both treatment periods.Changes in peripheral | PMC10011554 | ||
Statistical analyses | toxicity, PD | REGRESSION | Bayesian logistic regression model based on dose-limiting toxicity was used to provide initial guidance for dose recommendations in the dose-escalation phase. The final decision was reached by considering the totality of safety, PK, and PD data. For binary efficacy endpoints, two-sided 95% Clopper–Pearson exact confidence intervals were provided. For time-to-event endpoints (PFS and OS), the median and 95% CI were estimated using the Kaplan–Meier method. | PMC10011554 |
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