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Interview results | PMC10576350 | |||
Reasons for accepting or declining randomisation | ’d | INVASIVE CANCER | Interviews took place a median of 22 days after randomisation. During the interview, the women were given the opportunity to elaborate further on the reasons they had given on the CTQ for accepting or declining randomisation. The three most frequent reasons for accepting randomisation were the same for this subset of 89 women as the 175 who completed a CTQ. Anticipating future benefit for others was selected by 19/89 (21%) as the most important factor, e.g. “I’ve got 9 grandchildren and 6 of them are girls. What if same thing happens when they grow up and the only option was the operation? I hope that anything I do helps, not just for my family, but all women.” (P24). Helping with the doctor’s research was also selected by 19/89 (21%), e.g. “Well it’s like anything else, if we don’t have individuals giving their time and biopsy samples, we’ll never find out if these dormant cells will turn into invasive cancer. It will help future generations, I think this is what you need. I think there should be more research in general and more money should be spent on research. My husband was worried that I’d get monitoring, but I was happy to join either part of the trial.” (P102). And for another 19/89 (21%), the most important reason for accepting randomisation was the belief that the trial offered the best treatment e.g. “I thought getting yearly rather than 3 yearly mammograms was a good idea. Getting checked more often was the main reason.” (P48).The four women who withdrew from their treatment allocation after randomisation had all been allocated to standard treatment but did not want surgery. For example, one woman talked about how surgery did not fit in with her busy lifestyle as a self-employed fitness instructor and that she felt it was currently unnecessary. Nearly all the decliners interviewed (7/8) were sure they wanted surgery, generally for peace of mind or because of family considerations, with just one woman declining randomisation because she did not want surgery. | PMC10576350 |
Information provision | DCIS, SHOCKED | For 83/89 (93%) acceptors who were interviewed, the trial had been discussed with more than one HCP, including research nurses (82/89, 92%), surgeons (75/89, 84%), radiologists (11/89, 12%), and an oncologist (1/89, 1%). Most acceptors (83/89, 93%) did not feel that their decision to take part had been influenced by their discussion with an HCP. Similarly, all but one of the decliners had discussed the trial with more than one HCP. Two out of the nine women in this group felt their decision had been influenced at least to some extent by an HCP: one because the surgeon had made it clear that the patient had to be content with both options on offer before entering the trial and one because the surgeon had mentioned surgery before anything else.All the women who were interviewed remembered receiving and reading at least one of the three written information documents: 89/100 (89%) reported reading the PIL, 91/100 (91%) reported reading PIS-A and 97/100 (97%) reported reading PIS-B. Some women talked about reading everything very carefully, and even going online to find out more about both DCIS and the LORIS study or sharing the information with friends who were HCPs. Others described skimming the leaflets or just reading what they considered to be important. One woman explained how she had been too fearful to read the trial sheets initially but had felt comforted about the whole process after a nurse went through everything verbally. Another individual initially found the information too much but followed a friend’s advice to read each PIS bit by bit.Further interview questions focussed specifically on PIS-B, which explained randomisation. Most of the women (73/100, 73%) shared this leaflet with someone else, usually family members but also friends and colleagues. Some who chose not to share PIS-B talked about it being a private matter or not wanting to worry anyone. Most found PIS-B either very or somewhat useful (97/100, 97%) and either very or somewhat clear (98/100, 98%). Two participants talked about finding the concept of randomisation very difficult to understand. Some wanted more information, e.g. about extra tissue being taken, the risks and side effects of surgery, personal benefits of joining LORIS, whilst two women thought there was too much information or that it was too technical. Despite PIS-B being generally perceived as useful and clear, 39/89 (44%) of acceptors did not think it had helped them make a decision, most commonly because they had already decided to join the trial.Most of those interviewed (70/100, 70%) had watched the patient information film and often shared it with a family member, friend or colleague (45/70, 64%). Many who did not watch the film had already made their decision or did not have a DVD player and/or access to the internet. All film viewers found it either very or somewhat clear and useful. The part of the film which was most commonly cited as being particularly useful (37/70, 53%) was the Q&A section. Very few, 4/70 (6%), identified aspects of the film as being unhelpful. Two were concerned about terminology, one woman noted she already knew some of the information from the PISs and one felt some of the questions in the Q&A session were poor. Despite positive opinions from the film viewers, there was a 50:50 split in terms of whether the film helped them decide whether to join the trial; most who did not feel the film had helped with decision making had already decided what to do before viewing it. Nevertheless, many described feeling reassured that they had made the right decision having watched the film, e.g. “I’d already decided to take part at that point. DVD was really important for me to see the doctors’ faces, who are doing the study, Good that the DVD is very short, but really helpful. Made me feel part of something.” (P88)Three additional questions were included in the final 65 interviews, if relevant. One asked about the timing of the PIL: one woman felt it had been given too early but all the other women who remembered receiving it felt it was about right. Some talked about finding the PIL useful because they had been shocked after receiving their mammogram results but appreciated having written information to take away and digest. The other two questions related to whether the women were aware that their biopsy results could make them ineligible for LORIS and how clear they felt this information was in the PIL. Most of the women who answered these questions knew that their eligibility for LORIS depended on their biopsy results (56/61, 92%) and felt that information explaining this in the PIL was either very or somewhat clear (47/51, 92%). Some highlighted how helpful it had been for an HCP to also explain everything orally. | PMC10576350 | |
Sites | word carcinoma, cancer’ | DCIS, RECRUITMENT | Initially, four communication workshops were held, two in London, one in Birmingham and one in Wycombe, with a total of twenty delegates attending. Two further workshops, both in London, held as part of the Recruitment Recovery Plan, were attended by 17 health care professionals. The delegates were a mixture of trial coordinators, research nurses, radiologists, radiographers, and surgeons. Analysis of the pre- and post- workshop questionnaires resulted in a significant improvement in knowledge (The response rate to the postal survey about which aspects of the LORIS protocol was perceived as challenging was good from PIs, 34/47 (72%), and site leads, 45/53 (85%), but poor from other members of the recruiting team, 12/197 (6%). Most respondents reported they were well aware of the aims of LORIS (88/91, 97%) and comfortable with these (87/91, 96%). However, only about half stated they themselves would participate in LORIS, if relevant, or encourage a friend or relative, (45/87, 52%), many were unsure (35/87, 40%) and a few would not participate (7/87, 8%).Most respondents were clear about the study logistics pathway (78/91, 86%) and thought the process of obtaining histopathology slides for central review was streamlined (64/85, 75%). However, the need for a second biopsy to confirm eligibility was sometimes or often thought to deter team members from recruiting patients by nearly half of respondents (37/83, 45%), and sometimes or often thought to act as a deterrent to potential participants by most respondents (68/83, 82%). Another challenge for sites was changes in their key staff since LORIS opened at their site, reported by 38/89 (43%) of respondents.When asked about the most challenging aspect of recruiting patients (free text item), the most common reason given was the low number of eligible patients (34/81, 42%). Additionally, some respondents (12/81, 15%) noted that many patients were deemed ineligible following central review. The second most common barrier, reported by 18/81 (22%), was that many women had a strong preference for a particular treatment arm. The challenge of trying to explain active surveillance (7/81, 9%), and local logistic issues (6/81, 7%) were also barriers reported by more than one respondent. In the semi-structured phone interviews, held with 20/47 PIs (43%) and 40/53 site leads (75%), the same barriers were identified more frequently. These interviews also provided an opportunity for participants to describe in more detail specific local challenges. Some interviewees suggested that it would be beneficial to educate the general public about DCIS and the LORIS trial in general. There was also an issue noted with the use of the word carcinoma in DCIS and the use of the term ‘cancer’ in the patient information provided by hospitals, in that this could lead to more women having a strong preference for surgery.Based on the information gained from the survey and interview, refresher SIVs were suggested for six sites and attendance at a communication workshop for 14 sites. Online refresher SIVs were held for all six sites but only five sites sent delegates to a communication workshop. | PMC10576350 |
Discussion | cancer | DCIS, CANCER, RECRUITMENT | From the outset of the LORIS study, it was anticipated that recruitment might be difficult because the two arms (conventional treatment and active monitoring with annual mammography) could be perceived as comparing ‘something’ with ‘nothing’ [Since the LORIS trial opened to recruitment, a Cochrane review highlighting factors that impact recruitment to health care RCTs has been published [The Cochrane review also emphasised the importance of tailoring the invitation to participate in a trial to each individual. This was reflected in the findings for LORIS: some women described reading everything very carefully and doing additional research, whilst others skimmed through the written materials; some wanted more detailed information whilst some wanted shorter, less technical information. Strategies for providing trial information in a more flexible way should be considered in the future to try to meet the needs of potential participants who have different preferences and different levels of health literacy. As well as providing information in different modalities, the provision of information with different levels of detail should be considered and this could be facilitated by digital information provision. A recent systematic review of digital tools in the informed consent process found that whilst there was no evidence of negative outcomes, more research was required to confirm benefit [As well as allowing individuals to tailor information provision, digital tools also have the potential to reduce the risk of researcher bias, i.e. the researcher influencing the patient’s decision on participation. This is important for a study like LORIS: about half of site staff reported that, if they were eligible for LORIS, they would either not take part or were unsure. Although the assumption of clinical equipoise underpins RCTs, these findings indicate that many site staff had a preconceived preference for a treatment arm, and this may have impacted recruitment. Although digital tools may benefit the informed consent process, it is important to consider the needs of potential participants with a low level of digital literacy and ensure they have sufficient support to use these tools.Whilst the LORIS patient information materials were well received, many women did not think these had influenced their decision about whether to accept randomisation. Nor did most women feel that their decision had been influenced by discussions with HCPs. Of those who were registered in LORIS and remained eligible following central review, 81% agreed to be randomised, even though randomisation was a concern for nearly half of those women. The major drivers for participation were the belief that the trial offered the best treatment and altruism. The women who withdrew after randomisation did so because they did not want surgery and had been hoping to be randomised to the active monitoring arm. Most of the women who declined randomisation were clear that they wanted surgery, either because of their own concerns or concerns of others. Clear individual patient preference for how DCIS is managed was the reason that the trial design for the LORD study was amended from an RCT to a patient preference design [Communication workshops for site staff improved knowledge about LORIS and confidence to discuss the trial, but it was not possible to explore whether this improved recruitment rates, given other variables, e.g. staffing levels, which affect recruitment. Site staff suggested that low recruitment was due to the stringent inclusion criteria, meaning there were low numbers of eligible patients, and where applicable, the need for a second biopsy, as well as women’s own preferences. Some staff suggested that providing education to the public about DCIS and presenting it outside the cancer context could influence patient decision making. | PMC10576350 |
Limitations of the study | Some women declined to take part in the study when first approached. Data were not collected from these individuals and it may be that their reasons for declining trial entry were different from those women who declined randomisation. The number of women who declined participation when first approached about the study will be reported in the main trial results paper. Less than half of those who declined to be randomised completed a CTQ so some caution is required in generalising from the CTQ and interview results presented here on decliners. Education level was not collected so it is not possible to explore whether this affected the decision to participate in the trial. | PMC10576350 | ||
Conclusions | RECRUITMENT, RECRUITMENT | Recruitment to LORIS was challenging despite employing recommended strategies aimed at patients and site staff which were well received by both groups, and improved staff knowledge and confidence. A more flexible approach to information provision, tailoring to individual needs and preference, would support informed decision making and may improve future recruitment. Crucially, before recruitment opens, all trial staff need to be fully on board with the trial. How can we expect trial staff to recruit others if they would not participate themselves? | PMC10576350 | |
Acknowledgements | Samantha Brace-McDonnell | EVANS, STUART, FRANCIS | We would like to thank all the women who took the time to complete questionnaires and take part in the telephone interviews. The late Professor Adele Francis and the late Maggie Wilcox were responsible for the original concept design and launch of the LORIS trial.LORIS Trial Management Group members: John M. S. Bartlett, Lucinda Billingham, Sarah Bowden, Samantha Brace-McDonnell, Cassandra Brookes, Henry Cain, David Dodwell, Andrew Evans, Patricia Fairbrother, Lesley Fallowfield, Douglas Ferguson, Adele Francis, Claire Gaunt, Andrew Hanby, Fiona Hoar, Simon Holt, Valerie Jenkins, Cliona Kirwan, Lucy Matthews, Stuart McIntosh, Sarah E. Pinder, Sarah Pirrie, Daniel Rea, Malcolm Reed, Tracy Roberts, Jennifer Rusby, Nisha Sharma, Pauline Sibley, Jeremy Thomas, Matthew G Wallis, Maggie Wilcox and Jennie Young. | PMC10576350 |
Authors’ contributions | SW carried out the analyses and produced the first draft. LM performed the patient interviews. VJ and LF led the work described in this paper and made substantial contributions to the conception and design of the trial. SM managed the data. DR, MGW, SP and CG made substantial contributions to the conception and design of the trial. PF provided input from the patient perspective. JY made substantial contributions to the design of the trial and acquisition of the data. All authors read and approved the final manuscript. | PMC10576350 | ||
Funding | The study was funded by the National Institute for Health Research HTA Programme (11/36/16). MGW was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). Department of Health Disclaimer: The views expressed are those of the authors and not necessarily those of the Department of Health and Social Care. | PMC10576350 | ||
Availability of data and materials | The datasets used and analysed during the current study are available from the corresponding author on reasonable request. | PMC10576350 | ||
Declarations | PMC10576350 | |||
Ethics approval and consent to participate | WEST | LORIS was approved by the West Midland Solihull Ethics Committee (Ref: 14/WM/0083) and NHS R&D permissions obtained for each participating centre. The study was sponsored by the University of Birmingham. All participants provided written informed consent. | PMC10576350 | |
Consent for publication | Not applicable. | PMC10576350 | ||
Competing interests | Not applicable. | PMC10576350 | ||
References | PMC10576350 | |||
1. Introduction | Lower extremity arterial occlusive disease, LEAOD | ATHEROSCLEROSIS, ARTERIAL OCCLUSIVE DISEASE | Lower Extremity Arterial Occlusive Disease (LEAOD) is a prevalent condition affecting many patients worldwide, which requires careful management and patient cooperation. This study aimed to evaluate the effectiveness of holistic nursing interventions based on the Fast Track Surgery (FTS) concept in patients with LEAOD. A retrospective analysis of 92 LEAOD patients, randomized into control and experimental groups, was performed. Conventional rehabilitation nursing interventions were applied to the control group, while the experimental group received holistic rehabilitation nursing interventions based on the FTS concept. Patient adherence was assessed before and after the intervention using a hospital survey, and sleep quality was evaluated using the Pittsburgh Sleep Quality Index on days 3, 7, and 15 post-interventions. Post-intervention, the experimental group exhibited significantly improved adherence to balanced diet, regular exercise, timely medication, and regular review visits compared to the control group (Lower extremity arterial occlusive disease (LEAOD) represents a significant health challenge, arising as a consequence of atherosclerosis, which leads to a narrowing or blockage of the arteries in the lower extremities.In view of these postoperative challenges, the emphasis on comprehensive, high-quality nursing care is paramount to optimize patient recovery. The contemporary paradigm of holistic nursing intervention has emerged as a significant focus area in this regard, particularly when combined with the principles of Fast Track Surgery (FTS). FTS, also known as Enhanced Recovery After Surgery, embodies a multi-disciplinary, multi-modal approach that aims to minimize surgical stress, optimize perioperative care, and thereby expedite postoperative recovery.This paper aims to provide a comprehensive review of the current understanding of LEAOD, and the challenges associated with its management. We propose a structured approach for implementing holistic nursing interventions based on the FTS concept in the care of patients with LEAOD. We also discuss the potential barriers to implementation and propose strategies to overcome these. The objective is to contribute to an improved standard of care for patients with LEAOD, ultimately enhancing patient satisfaction, compliance, functional recovery, and quality of life. | PMC10713153 |
2. Methods | PMC10713153 | |||
2.1. Study design and population | necrosis, lower extremity infection, mental illness, liver and kidney dysfunction, septicemia, edema, heart valve disease, LEAOD, sepsis, injury syndrome | ULCERATION, SEPTICEMIA, DISEASE COURSE, EDEMA, DISEASE, HEART VALVE DISEASE, ACUTE CORONARY SYNDROME, NECROSIS, SEPSIS | This research was approved by the Medical Ethics Committee. A retrospective analysis was performed on 92 patients with LEAOD admitted to our vascular surgery department from November 2020 to December 2022. Patients were divided into a control group and an experimental group, each consisting of 46 individuals (Fig. Flow diagram of the study design and population.Inclusion criteria encompassed those who (1) met the diagnostic criteria for LEAOD through angiography, magnetic resonance angiography, color Doppler ultrasound, and serum lipid laboratory examination; (2) had Fontaine stage I to III disease; and (3) had complete clinical data and signed an informed consent form. Exclusion criteria included: (1) a family history of severe mental illness within the last 3 generations; (2) severe lower extremity infection leading to sepsis or septicemia; (3) concomitant severe heart valve disease, acute coronary syndrome, severe liver and kidney dysfunction or frostbite injury syndrome; and (4) severe necrosis, edema, or ulceration of the lower limbs. No statistically significant differences in age, gender, disease course, or Fontaine staging were found between the 2 groups (Comparison of baseline characteristics between control and experimental groups. | PMC10713153 |
2.2. Nursing interventions | PMC10713153 | |||
2.2.1. Control group. | Conventional rehabilitation nursing interventions were implemented. The department’s head nurse supervised these interventions, which were conducted by the responsible nursing staff. Patients were informed about the disease-related knowledge and were guided through preoperative examinations, intraoperative coordination, and postoperative timed and measured rehabilitation training. | PMC10713153 | ||
2.2.2. Experimental group. | lower extremity arterial occlusive disease, voice, knee joints | A holistic rehabilitation nursing intervention based on the FTS concept was implemented. A rehabilitation nursing team was established, including a senior resident physician specialized in vascular surgery, a head nurse, 4 specialist responsible nurses, and a rehabilitation therapist. The nursing staff utilized academic websites like PubMed to retrieve professional literature related to “lower extremity arterial occlusive disease,” “rehabilitation exercise,” and “sleep quality.” Information gathered from the literature was presented in the form of videos and images, and one-on-one explanations were given to newly admitted patients at their bedside. The nursing team also encouraged patients to voice their concerns and anxieties, summarized these problems, and deliberated within the group to formulate improvement measures. During surgery, nursing staff assisted the surgeon to maximize the exposure of the surgical field. They placed soft pads at the bony prominences such as the ankle and knee joints to avoid the great saphenous vein. Nonoperative areas were wrapped in cotton pads or heated electric blankets maintained at 40 to 42 °C. The wound cleansing solution used was warm saline at 38 to 40 °C, with vital signs monitored every 15 minutes. Postoperatively, patients were guided to perform early ankle pump exercises on the bed for 10 to 15 minutes within 6 hours after the surgery. After each exercise session, patients rested for 30 to 35 minutes. This was followed by leg raising, toe dorsiflexion, and leg curl resistance training using a yellow TheraBand elastic band. Each exercise was performed in sets of 15 repetitions, 2 to 3 sets in total. Patients were encouraged to engage in early ambulation in their room or the hallway, starting with 15 minutes and gradually transitioning to 25 to 30 minutes, 2 to 3 times a day for 10 to 15 days. Ice packs were applied to the area around the wound for 1 to 20 minutes, with a 2-hour interval between each application, continuously for 24 hours. Patients were guided to perform mindfulness relaxation techniques and positive association or reminiscence for 20 to 25 minutes twice a day, morning and evening. | PMC10713153 | |
2.3. Outcome measures and evaluation criteria | adherence behavior | Patient adherence was assessed before and after the intervention using a self-made hospital survey that evaluated dimensions such as balanced diet, persistent exercise, regular medication, and regular reviews. Each dimension had a maximum score of 25, with the total score positively correlated with adherence behavior (Cronbach alpha = 0.82). | PMC10713153 | |
2.4. Statistical analysis | ± | Data obtained was analyzed using SPSS 26.0. Measurement data was expressed as mean ± standard deviation (x ± s), and comparisons were made using the | PMC10713153 | |
2.5. Treatment satisfaction assessment | To evaluate the level of patient satisfaction with the implemented nursing interventions, a treatment satisfaction survey was utilized post-intervention. This tool was designed to measure patients’ satisfaction in 3 distinct categories: (1) satisfied: This category captured the patients who felt that the nursing interventions met or exceeded their expectations and that their health outcomes had significantly improved; (2) basic satisfaction: patients in this category believed that the nursing interventions had somewhat met their expectations, providing them with a moderate improvement in health outcomes. (3) Dissatisfied: patients who felt that the nursing interventions did not meet their expectations and had little to no improvement in health outcomes were grouped here.The overall satisfaction rate was derived by summing the patients in the “Satisfied” and “Basic Satisfaction” categories. This measure was used to gain a holistic view of the overall contentment of the patients with the nursing care provided.Given the distribution of our data and to ensure accurate inter-group comparisons, Fisher exact test was chosen. This decision was made especially relevant due to instances of cell counts <5 in the data matrix, where conventional methods like the chi-square test might not render precise results. | PMC10713153 | ||
3. Results | PMC10713153 | |||
3.2. PSQI comparisons at different time points | Overall, there were statistically significant differences in the PSQI scores between the groups, at different time points, and in the interaction effect (Comparative analysis of PSQI scores in experimental and control groups at different time points.Compared to this group’s Post-Intervention 3d, Compared to this group’s post-intervention 7d, Compared to the control group at the same time, | PMC10713153 | ||
4. Discussion | lower extremity arterial occlusive disease, LEAOD | DISEASE | The implementation of holistic nursing interventions, under the guidance of the FTS concept, represents an innovative patient-centered approach to rehabilitation planning and care.Leveraging modern information technologies, healthcare professionals can transform disease-related knowledge into a more engaging and visual format. By promoting an active learning environment, patients can better understand the risks associated with their disease, appreciate the importance of self-care strategies, and become more equipped to independently execute disease-related interventions.Moreover, our repeated measures variance analysis of the post-intervention sleep quality at 3, 7, and 15 days revealed that, as the nursing intervention time continued, the PSQI scores of the experimental group were consistently lower than those of the control group (In conclusion, for patients with LEAOD, holistic nursing interventions guided by the FTS concept can lead to increased adherence, improved sleep status, and contribute significantly to the sustainable development of healthcare institutions. By shifting the paradigm of patient care from a passive to a more active and engaging learning environment, we can empower patients to play a more proactive role in their treatment and recovery process. Furthermore, these interventions can also improve the quality of perioperative care, thereby enhancing postoperative outcomes and accelerating early recovery. Therefore, this study offers important insights into how the principles of FTS can be integrated into nursing practice, with the potential to significantly improve patient outcomes in the context of LEAOD management. The results also underscore the need for further research to explore the application and impacts of such holistic nursing interventions in other contexts and patient populations.Despite the valuable insights provided by our study into the application of holistic nursing interventions based on the FTS concept for patients with lower extremity arterial occlusive disease, it is crucial to acknowledge its limitations. Our study was limited by a relatively small sample size, which may restrict the statistical power and external validity of our results. This was compounded by the fact that the research was carried out in a single medical institution, possibly confining the diversity of patient data and healthcare practices examined. Furthermore, the focus was primarily on the immediate postoperative period up to 15 days, thereby neglecting potential long-term impacts of the interventions. The use of self-reported measures for assessing outcomes such as sleep quality and patient adherence could also be subject to recall bias or social desirability bias. Finally, the absence of randomization or blinding procedures might introduce potential biases. Additionally, the study did not evaluate patients’ psychological well-being or exercise tolerance, which could offer a more comprehensive understanding of the intervention’s impact. Although these limitations should be considered when interpreting our results, they also offer a roadmap for future research to enhance these areas, leading to more robust and universally applicable findings. | PMC10713153 |
5. Conclusions | lower extremity arterial occlusive disease | In conclusion, our study underscores the potential benefits of integrating holistic nursing interventions based on the FTS concept for patients with lower extremity arterial occlusive disease. These interventions significantly improved patient adherence and sleep quality, thereby potentially enhancing postoperative recovery and overall health outcomes. Despite the inherent limitations of our study, the findings provide a solid foundation for future research to explore the full potential of holistic nursing approaches in the context of FTS. | PMC10713153 | |
Acknowledgments | We appreciate the cooperation and informed consent provided by the patients for this study. | PMC10713153 | ||
Abbreviations: | lower extremity arterial occlusive disease | WEST | Fast Track Surgerylower extremity arterial occlusive diseasePittsburgh Sleep Quality IndexWritten informed consent for publication was obtained from all patients and their families included in this retrospective analysis.All methods of this study were carried out in accordance with relevant guidelines and regulations, which were approved by the Ethics Committee of the West China School of Medicine/West China Hospital of Sichuan University, and subject’s written informed consent was obtained.The authors have no conflicts of interest to disclose.The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.How to cite this article: Zhang J, Zeng G, Zhang L, Huang J, Liu X. Implementation of holistic nursing interventions based on fast track surgery concept in patients with lower extremity arterial occlusive disease. Medicine 2023;102:49(e36485). | PMC10713153 |
References | PMC10713153 | |||
INTRODUCTION: | cirrhosis | EVENTS, CIRRHOSIS | The efficacy of targeted albumin therapy in the management of decompensatory events in cirrhosis is unclear, with different reports showing conflicting results. It is possible that only certain subgroups of patients may benefit from targeted albumin administration. However, extensive conventional subgroup analyses have not yet identified these subgroups. Albumin is an important regulator of physiological networks and may interact with homeostatic mechanism differently in patients according to the integrity of their physiological network. In this study, we aimed to assess the value of network mapping in predicting response to targeted albumin therapy in patients with cirrhosis. | PMC10299770 |
METHODS: | cirrhosis | CIRRHOSIS | This is a substudy of the ATTIRE trial, a multicenter randomized trial conducted to assess the effect of targeted albumin therapy in cirrhosis. Baseline serum bilirubin, albumin, sodium, creatinine, CRP, white cell count (WCC), international normalized ratio, heart rate, and blood pressure of 777 patients followed up for 6 months were used for network mapping using parenclitic analysis. Parenclitic network analysis involves measuring the deviation of each patient from the existing network of physiological interactions in a reference population. | PMC10299770 |
RESULTS: | end-stage liver disease | Overall network connectivity and deviations along the WCC-CRP axis predicted 6-month survival independent of age and model for end-stage liver disease in the standard care arm. Patients with lower deviation along the WCC-CRP axis showed lower survival in response to targeted albumin administration over a 6-month follow-up period. Likewise, patients with higher overall physiological connectivity survived significantly less than the standard care group after targeted albumin infusion. | PMC10299770 | |
INTRODUCTION | sepsis, deaths, liver disease | SEPSIS, DISEASES, LIVER DISEASE, SPONTANEOUS BACTERIAL PERITONITIS | There has been an epidemic of liver disease during the past 50 years in the United Kingdom, with a 4-fold increase in liver-related deaths (Other clinical trials of albumin infusion have shown conflicting results. For instance, a meta-analysis of albumin use in patients with spontaneous bacterial peritonitis reported significant benefit (Healthy individuals show a high degree of functional connectivity between physiological organ systems. Disruption of organ system coupling is a hallmark of complex diseases, and recent studies showed that reduced network connectivity was linked with poor survival in patients with sepsis (Targeted albumin infusion has the potential to challenge the physiological network through alteration of oncotic pressure, plasma volume, glomerular filtration rate (GFR), and transportation of various physiological molecules. Therefore, the assessment of physiological interaction as a network may allow for a more precise prediction of patients' response or outcome. The parenclitic network mapping allows network analysis of static, baseline clinical variables on the individual patient level ( | PMC10299770 |
METHODS | PMC10299770 | |||
Study population | DECOMPENSATED CIRRHOSIS | This is a substudy (and extension) of the ATTIRE trial, which was a randomized controlled trial of targeted albumin infusions vs standard care involving 777 patients hospitalized with decompensated cirrhosis from 35 hospitals across England, Wales, and Scotland (2016–2019) ( | PMC10299770 | |
Parenclitic network analysis | REGRESSION | Parenclitic network analysis is a novel static network analytical method (Schematic representation of the network mapping method used in this study for the reference population (top panel) and individual patients (lower panel). Top panel: The correlation between a pair of biomarkers (e.g., A-B, A-C, or B-C) was used for network mapping of the reference population (i.e., survivors in the standard care group). The blue dots represent individual reference data, and the black regression lines represent the expected relationship models (rThe ATTIRE survivors' population at 6 months was used as the reference population for the development of the parenclitic model, and deviations from this model for individual patients (survivors and nonsurvivors) were computed and used to weigh the correlation network map of clinical variables. Furthermore, the parenclitic indexes, including deviations along variable pairs and a global network topology of all patients (treatment and standard care), were computed using an in-house code in MATLAB (MathWorks, CA). For the measurement of global network topology, indexes such as network diameter, mean centrality, and shortest path length were calculated. Please see Supplementary Table S1 (Supplementary Digital Content, To validate the prognostic value of the parenclitic indexes, a split technique was used whereby ∼50% of patients in the standard treatment arm were randomly selected (training sample, n = 194), and the remainder were used as the validation sample (n = 203). Survivors in the training group were used as a model for the calculation of the coefficients that were used for the calculation of parenclitic deviations in the validation group. Statistical analysis was performed to test whether the prognostic values persist following the random split in the validation sample. This is to confirm whether the result generated was independent of the population studied. | PMC10299770 | |
Statistical analysis | REGRESSION, EVENT | Statistical analysis was performed using Stata statistical software (Stata/MP, Version 17.0) and SPSS Statistics 26 (IBM Corp., Armonk, NY), with data presented as median and interquartile range (IQR) or mean ± SD. A 2-tailed Initially, we performed the Mann-Whitney Receiver operating curve (ROC) analyses were performed and the area under the curve (AUC) computed for individual and combinatory indexes to generate cutoffs. The specificity and sensitivity of resulting cutoffs were then used to generate the positive and negative predictive values based on Bayesian priors (% mortality) (To test whether parenclitic indexes may differentiate between survivors and nonsurvivors at 6 months after targeted albumin treatment, we performed a multivariate Cox regression including patients' treatment arm (albumin or standard care) and each of the parenclitic indexes as interacting variables. The cutoff of parenclitic indexes that showed significant interaction with treatment in predicting survival was then used to categorize each patient into “1” if ≥cutoff and “0” if otherwise. The treatment arm of patients was then used to plot ROC curves to assess the 6-month survival grouped by the cutoffs of the significant parenclitic indexes.To assess possible improvement in prognostic performance of MELD due to the addition of parenclitic indexes, Brier scores, integrated discrimination improvement (IDI), and net reclassification indexes (NRIs) were computed on Stata statistical software. The Brier score provides the mean of the squared distance between observed and predicted risks of event (mortality) for the individual patient. Generally, the lower the Brier score, the better the predictive model ( | PMC10299770 | |
RESULTS | PMC10299770 | |||
Patient characteristics at ATTIRE trial entry | NAFLD, end-stage liver disease | NONALCOHOLIC FATTY LIVER DISEASE, VIRUS, HEPATITIS C | A total of 397 of 777 (51%) patients received standard care and were subjected to parenclitic analysis. During the 6-month follow-up period, 119 (30%) of these patients died. Table Demographic and baseline clinical variables in the study populationThe bold entries indicate HCV, hepatitis C virus; IQR, interquartile range; MELD, model for end-stage liver disease; NAFLD, nonalcoholic fatty liver disease. | PMC10299770 |
Parenclitic indexes at ATTIRE trial baseline (prealbumin treatment) predict survivors and nonsurvivors at 6 months | end-stage liver disease | The correlation network maps show that survivors had a significantly higher association between the baseline clinical variables compared with nonsurvivors (Figure Correlation network map of survivors (Differences in parenclitic indexes between survivors and nonsurvivors who received standard care in the studied populationThe bold entries indicate parenclitic indexes that significantly predict survival.δ, deviation along an axis; Alb, serum albumin; Bil, total bilirubin; CRP, C-reactive protein; HR, heart rate; INR, international normalized ratio; MELD, model for end-stage liver disease; Na, serum sodium; WCC, white cell count. | PMC10299770 | |
Prognostic values of baseline parenclitic indexes to predict 6-month outcome | end-stage liver disease | REGRESSION | According to our univariate Cox regression analysis, greater parenclitic deviations along WCC-Na, Bil-WCC, WCC-CRP, HR-Bil, and INR-Bil axes were all associated with an increased risk of 6-month mortality (Table Result of univariate Cox regression analysis for parenclitic indexesThe bold entries indicate parenclitic indexes that significantly predict survival.δ, deviation along an axis; Alb, serum albumin; Bil, total bilirubin; CRP, C-reactive protein; HR, heart rate; INR, international normalized ratio; MELD, model for end-stage liver disease; Na, serum sodium; WCC, white cell count. | PMC10299770 |
Independent prognostic values of baseline parenclitic indexes to predict 6-month outcome | end-stage liver disease | REGRESSION | Multivariate Cox regression was performed to assess whether parenclitic indexes that individually predicted 6-month mortality had a prognostic value independent of age and MELD. Parenclitic deviations along the WCC-CRP axis (hazard ratio, 95% CI = 1.112, 1.053–1.174) and Bil-WCC axis (hazard ratio, 95% CI = 1.062, 1.017–1.108) significantly predicted outcome independent of age and MELD of patients at trial entry (Table Prognostic values of parenclitic indexes independent of age and MELD at admissionThe bold entries indicate parenclitic indexes that significantly predict survival.δ, deviation along an axis; Alb, serum albumin; Bil, total bilirubin; CRP, C-reactive protein; HR, heart rate; INR, international normalized ratio; MELD, model for end-stage liver disease; Na, serum sodium; WCC, white cell count.The results of a parenclitic network analysis of a split sample (randomly selected patients) extracted from the study population showed similar correlation network maps of biomarkers (see Supplementary Figures S1 and S2, Supplementary Digital Content, | PMC10299770 |
Receiver operating characteristic curve values of baseline parenclitic indexes to predict 6-month outcome | end-stage liver disease | The area under the receiver operating characteristic (ROC) curves (AUC), cutoffs, and the sensitivity, specificity, positive and negative predictive values, and Brier scores of these cutoffs are presented in Table Area on the ROC curves, sensitivity, specificity, PPV, NPV, and Brier score of parenclitic indexes in combination with MELD compared with MELD aloneδ, deviation along an axis; Alb, serum albumin; AUC, area under the curve; Bil, total bilirubin; CRP, C-reactive protein; HR, heart rate; INR, international normalized ratio; MELD, model for end-stage liver disease; Na, serum sodium; NPV, negative predictive value; PPV, positive predictive value; WCC, white cell count.Measure of prognostic improvement of MELD due to the addition of parenclitic indexesδ, deviation along an axis; Alb, serum albumin; Bil, total bilirubin; CRP, C-reactive protein; IDI, integrated discrimination improvement; INR, international normalized ratio; MELD, model for end-stage liver disease; Na, serum sodium; NRI, net reclassification indexes; WCC, white cell count. | PMC10299770 | |
Assessment of the prognostic value of baseline parenclitic indexes to differentiate between 6-month outcomes comparing standard care with targeted albumin therapy | REGRESSION | The result of multivariate Cox regression for the interaction of targeted albumin treatment with baseline parenclitic variables to predict 6-month survival showed that measures of global parenclitic network characteristics (i.e., diameter and mean shortest path length), WCC-CRP parenclitic deviation, baseline serum albumin, and white cell count significantly interacted with targeted albumin treatment to predict survival (see Supplementary Table S4, Supplementary Digital Content, Kaplan-Meier graph representing 6-month survival prediction of patients based on network shortest path length cutoff (Kaplan-Meier graph representing 6-month survival prediction of patients based on network diameter cutoff (Kaplan-Meier graph representing 6-month survival prediction of patients based on δ (WCC-CRP) cutoff ( | PMC10299770 | |
DISCUSSION | Leukopenia, decompensation, cirrhosis, decompensated cirrhosis, MELD-plus, acute-on-chronic liver failure, dyscoordination | SYSTEMIC INFLAMMATORY RESPONSE, DECOMPENSATED CIRRHOSIS, LEUKOPENIA, DISEASE, CIRRHOSIS, PATHOPHYSIOLOGY, EVENTS, COMPLICATIONS, INFLAMMATORY RESPONSE | Our parenclitic network analyses using baseline clinical data accurately predict outcome in patients with decompensated cirrhosis hospitalized for acute complications, based on disruption of organ system coupling. These analyses also identified that patients with preserved organ system coupling had significantly poorer outcomes after increased albumin treatment.Reduced organ system correlation was associated with poorer prognosis in hospitalized patients with cirrhosis independent of the severity of disease and age. The dyscoordination in the crosstalk between the key markers of systemic inflammatory response, CRP and WCC, provides a novel pathophysiological insight into the dysregulated inflammatory response in decompensated cirrhosis not captured by the MELD severity scoring system. Specifically, we found that reduced coordination between CRP and WCC predicted poorer 6-month outcomes in patients receiving standard clinical treatment. This was in line with our previous validation study in decompensated cirrhosis (Prognostic modeling in cirrhosis from Child-Pugh to MELD-plus and acute-on-chronic liver failure continues to move toward greater recognition of the impact on survival of the extrahepatic involvements of cirrhosis (Leukopenia is associated with a significantly higher risk of decompensation and mortality in patients with cirrhosis (Unexpectedly, patients with lower parenclitic deviation and by extension higher organ system connectivity showed significantly lower survival after targeted albumin therapy for a maximum of 2 weeks that persisted over the 6-month follow-up. We hypothesize that patients with preserved organ system connectivity may achieve this by the diversion of energies/resources needed for normal physiological functions toward maintaining an effective inflammatory response (The main limitation of this study includes the inherent inability of the parenclitic network to capture the time course of organ system connectivity because of the cross-sectional static feature of the data analyzed. For instance, our analysis is not robust to immediate and temporal changes to the network of organ systems that may follow albumin infusion or result from major clinical events that occur after the baseline data were gathered. Finally, although this study is multicenter in design, it applies to patients with decompensated cirrhosis admitted into hospitals in the United Kingdom where standard care may differ in definition from other countries and regions of the world. Thus, interpretation of our findings should be contextualized. However, the clinical management of patients is still strongly informed by baseline clinical variables, and the ATTIRE study represents one of the largest clinical trials of hospitalized patients with cirrhosis who were prospectively recruited and carefully followed up. The calculation of parenclitic deviation along the WCC-CRP axis is feasible at the bedside. However, further validation of the WCC-CRP axis is required in a larger, globally representative reference group to allow clinical incorporation as a bedside scoring system.In summary, network analysis using routine clinical data collected at baseline provides novel insights into the pathophysiology of cirrhosis independent of the MELD score and significantly improved MELD's prognostic value. Furthermore, we showed that an unsupervised network analysis has potential value and may predict a poor response to targeted albumin therapy, which was not observed in conventional analyses. Future studies should further investigate the value of WCC-CRP and network mapping to predict outcome in decompensated cirrhosis and improving selection of patients for further trials of albumin or other immune-/inflammation-modulating therapies. | PMC10299770 |
REFERENCES | PMC10299770 | |||
Introduction | deaths, prostate tumor, prostate cancer, tumor | TUMOR, RECURRENT PROSTATE CANCER, PROSTATE TUMOR, TUMOR ANGIOGENESIS, PROSTATE CANCER | Approximately 268,000 men are expected to be diagnosed with prostate cancer in USA in 2022 resulting in 34,500 deaths [Men with locally recurrent prostate cancer after definitive radiotherapy have few therapeutic options that can potentially eliminate the tumor with acceptable safety. Other than expectant management and systemic therapy (i.e., androgen suppression therapy, AST), there are few local therapeutic options for locally recurrent prostate cancer such as salvage radical prostatectomy, salvage cryoablation, salvage brachytherapy, and salvage high-intensity focused ultrasound. Although some have demonstrated encouraging 5-year disease-free survival rates in single institution studies, most are associated with some morbidity and there are no prospective randomized studies demonstrating their long-term effectiveness.Several oncolytic adenovirus-based cytotoxic gene therapy vectors are currently being evaluated in clinical trials. Delivery of a conditionally cytotoxic gene, termed a “suicide gene” to the tumor is usually accomplished by direct intratumoral or systemic injection of a viral vector containing the suicide gene. Two suicide genes that have been evaluated in preclinical models and in the clinic are cytosine deaminase (CD) from yeast or Phagocytes and dendritic cells secrete interleukin-12 (IL-12) in response to pathogens. Subsequently, IL-12 activates innate (natural killer, NK, and natural killer T lymphocytes, NKT) and adaptive (CD4+ Th and CD8+ Tc cells) immune system, causes IFN-γ secretion, enhances antigen presentation, and inhibits tumor angiogenesis.IL-12 has demonstrated significant anti-tumor activity in preclinical models including in prostate cancer [Consequently, we conducted an investigator-initiated phase I dose-escalation clinical trial to evaluate the maximum tolerated dose and safety of Ad5-IL-12 in men with recurrent localized prostate cancer. These men were administered Ad5-IL-12 directly into the prostate tumor at one of five escalating doses. Ad5-IL-12 viral replication, shedding and persistence was measured in patient blood (over time) by PCR. We also assessed the effect of the gene therapy on innate and adaptive immune system by quantitating peripheral blood mononuclear cells (PBMCs) before and after treatment with Ad5-IL-12 by flow cytometry. Additionally, IL-12, INFγ, and CXCL10 levels were measured in patient serum. Finally, the efficacy of the Ad5-IL-12 cytotoxic gene therapy in patients with recurrent prostate cancer was accessed by measuring patient survival. | PMC10503775 |
Results | PMC10503775 | |||
Study design and patient baseline characteristics | ADENOVIRUS, RECURRENT PROSTATE CANCER | All patients had recurrent prostate cancer following at least one cycle of radiation therapy. Patients received an intraprostatic injection of the Ad5-IL-12 adenovirus on day 1 at doses ranging from 1 × 10 | PMC10503775 | |
CONSORT flow diagram. | Total of 60 subjects were accessed for eligibility, out of which 44 were excluded and 1 declined to participate. Remaining 15 subjects participated in this phase-1 clinical study. The subjects were recruited in five different cohorts (n = 3) who were administered with increasing doses of the Ad5-yCD/ | PMC10503775 | ||
Treatment schema. | Subjects underwent a series of pretreatment evaluations and met all the eligibility criteria before enrolled in the study. Subjects received a single intraprostatic injection of the Ad5-yCD/ | PMC10503775 | ||
Toxicities | nausea, diarrhea, fatigue, leukopenia, anemia, lymphopenia, chills | ADENOVIRUS, LEUKOPENIA, ADVERSE EVENTS, ANEMIA, LYMPHOPENIA | By the study endpoint (day 30), a total of 115 adverse events (AEs) were documented. Ninety-two percent of the AEs were grade 1 (mild) and grade 2 (moderate). Several of treatment-related AEs could be either attributed to Ad5-IL-12 adenovirus (flu-like symptoms, chills, fatigue, altered liver enzyme AST/ALT ratio) or the prodrugs such as diarrhea, anemia, nausea, lymphopenia, leukopenia; | PMC10503775 |
Adverse events in all cohorts in Ad5-IL-12 gene therapy trial. | toxicity | ADVERSE EVENTS, ADVERSE EVENT | All the Adverse events (AEs) collected through primary toxicity endpoint (day 30) are collected and are arranged by method of collection. No adverse events measured for Patient #3 due to consent withdrawal. | PMC10503775 |
Experimental endpoints | ADENOVIRUS | We evaluated the persistence of the adenoviral DNA in patient’s blood as a measure of the viral replication. Presence of Ad5-IL-12 adenoviral DNA detected in patient blood 7–10 days after adenoviral administration suggests potential viral replication (at the site of injection). The viral load was measured by PCR for a target sequence that is common for all our adenoviral vector constructs. We evaluated Ad5-IL-12 adenoviral DNA in all the patients as described in methods. Genomic DNA extracted from the blood donated by a healthy volunteer and spiked with the adenovirus was used as a positive control for the PCR. Viral DNA was not detected in cohorts where patients were injected with low viral dose (cohorts 1–3, 1x10 | PMC10503775 | |
PCR of Ad5-IL-12 adenoviral DNA in blood. | POSITIVE | Ct, is the positive control. Positive control DNA was isolated blood of a healthy donor spiked with Ad5-yCD/ | PMC10503775 | |
Cytokine response | We measured the levels of IL-12 in patient’s blood after Ad5-IL-12 adenoviral injection. Since IL-12 secretion causes IFN-γ production by NK, NKT, activated CD4+ Th and CD8+ Tc cells and subsequently CXCL10 by monocytes, fibroblasts, and endothelial cells, the expression levels of IFNγ and CXCL10 were also measured. The blood was drawn before viral injection, on the day of the adenoviral injection and on prescribed days up to 42 days and cytokines were quantitated by serum ELISA. Similar to our earlier observations [ | PMC10503775 | ||
Peak cytokine day and concentration. | VIRUS | Mean serum cytokines, IL-12, IFN-γ and CXCL10, from patients grouped by cohort showed a general trend that patients exhibited increased serum cytokine levels with higher virus doses ( | PMC10503775 | |
Changes in serum IL-12, IFNγ, and CXCL10 levels in each cohort. | Cytokines | ADENOVIRUS | Patient blood was drawn within 30 days of the Ad5-IL-12 adenoviral injection or on the day of adenovirus injection prior to the procedure (day 0) and on the days as described in the clinical protocol (up to day 24). Cytokines were measured by ELISA based on cytokine specific standard curves (IL-12 0–500 pg/mL; CXCL10 and IFNγ 0–1,000 pg/mL). The peak cytokine value for each patient was estimated (pg/mL; as presented in | PMC10503775 |
Changes in serum IL-12, IFNγ, and CXCL10 in subjects # 12 and 13. | Cytokines | Cytokines were measured by ELISA based on cytokine specific standard curves (IL-12 0–500 pg/mL; CXCL10 and IFNγ 0–1,000 pg/mL). Panels | PMC10503775 | |
Shift in CD4 | PROLIFERATION, BLOOD | The effect of the Ad5-IL-12 gene therapy on immune system activation was evaluated by analyzing circulating PBMCs by flow cytometry. Patient blood was obtained at least once before the Ad5-IL-12 gene therapy administration (baseline) and on follow-up days as described in the clinical protocol. Blood was processed on the day of draw and collected PBMC’s were frozen at -80C until all the samples were collected from a patient. Subsequently, frozen PBMCs were thawed, processed and quantitated by multi-color flow cytometry as described in Materials and Methods. Antibodies against CD3, CD56, CD4, and CD8 served to measure NK, Th and Tc cells while activation of the immune system was monitored by staining for CD45RO, CD69, and proliferation by Ki67. Antibodies against Tim3 were used to detect suppression of the immune system following treatment [ | PMC10503775 | |
Peripheral blood mononuclear cell (PBMC) counts and markers for patient # 12 and 13. | ADENOVIRUS, BLOOD | Blood was drawn before and after adenovirus injection on indicated days. Blood was processed, PBMCs were harvested, stained and quantitated by flow-cytometry as described in Materials and Methods. All the data are plotted as mean fold-increase over pre-adenoviral injection (baseline). Natural killer cells (NK), T-helper cells (Th), and cytotoxic T cells (Tc) values from patient #12 are shown in panels Similarly, the highest number of Ki67 expressing CD3 | PMC10503775 | |
Change in PSA levels | VIRUS | PSA levels were measured from the patients before and after the virus injection. Eight of 15 (53.3%) subjects exhibited ≥20% reduction in PSA just after the initiation of gene therapy ( | PMC10503775 | |
Change in patient PSA in response to gene therapy. | PSA doubling time (PSADT) for all the patients were estimated before gene therapy (PSADT.PRE) and after adenoviral injections (PSADT.POST). Mean, median, minimum, and maximum PSADT are tabulated ( | PMC10503775 | ||
PSA through primary toxicity endpoint (day 30). | ADENOVIRUS | Ad dose: Adenoviral dose, PSA FU: PSA follow up, T to PreTx: Time (month) before the start of androgen suppression therapy, % PSA decline: PSA decline for each patient within 30 days of oncolytic adenoviral injection; NR: Not reported, NE: Not estimated, AST: Androgen suppression therapy, #: Patient 3 withdrew the consent, although his PSA was still monitored for clinical care it is not reported here.There was no significant effect of adenovirus injection on the PSA doubling time (PSADT) in individual patients ( | PMC10503775 | |
Discussion | toxicities, pancreatic cancer | RECURRENT PROSTATE CANCER, PANCREATIC CANCER, PROSTATE CANCER, PROSTATE ADENOCARCINOMA | The goal of this phase-1 clinical study was to estimate the maximum tolerated dose of oncolytic, cytotoxic Ad5-IL-12 gene therapy in men with recurrent prostate adenocarcinoma. Patients were administered increasing doses of Ad5-IL-12, ranging from 1 × 10Investigators from our institution have successfully carried out five phase-I and a phase I/II clinical study utilizing ‘in-house’ developed replication competent, oncolytic adenoviruses in newly diagnosed and locally recurrent prostate cancer [Akin to the findings in the pancreatic cancer trial that was conducted with the same adenoviral vector [IL-12 is known to mediate the interaction between innate and adaptive immunity [Serum PSA levels and PSA doubling time (PSADT) are key markers of prostate cancer. We followed PSA in patients before and after gene therapy and estimated PSADT. Although, we observed an initial decrease in PSA in 8 out of 14 patients (>20% decrease; Earlier trials failed to deliver on the promise of a potent proinflammatory cytokine due to toxicities associated with its systemic delivery. Localized IL-12 delivery provides enhanced spatiotemporal distribution, generates systemic antitumor immunity from a locally initiated immune response, brings rapid increase in pro-inflammatory cytokines, including IFN-γ, and IL-6, and reduces opposing negative signaling [ | PMC10503775 |
Materials and methods | PMC10503775 | |||
Study design | toxicity, prostate adenocarcinoma | RECURRENT PROSTATE CANCER, SECONDARY, PROSTATE ADENOCARCINOMA | The study was designed as a single site, prospective, non-randomized, phase I, classical 3+3 dose escalation trial of viral particles (vp). This trial was designed to enroll 15–30 men with locally recurrent prostate cancer after definitive radiotherapy under 5 cohorts with increasing doses. Each cohort of three patients with clinically localized recurrent prostate adenocarcinoma were intraprostatically injected with increasing doses (cohort-1 1x10The primary endpoint of this investigator-initiated phase-I study was to determine the dose-dependent toxicity and maximum tolerated dose (MTD) of oncolytic adenovirus-mediated cytotoxic and IL-12 gene therapy in men with locally recurrent prostate cancer after definitive radiotherapy. Secondarily we evaluated PSA response including PSA doubling time (PSADT) before and after administration of the study therapy. The exploratory aim was to determine a possible association between the primary and secondary outcomes and immunological endpoints including serum IL-12 and IFN-γ levels, and NK cell cytolytic activity. The protocol received all required regulatory approvals before initiation and was conducted under BB-IND 16536 (IRB-9829; Clinical Trials # NCT02555397). Good clinical practices were used throughout. | PMC10503775 |
Patient selection and eligibility criteria | ventricular arrhythmia, respiratory illness, malignancy, cancer, non-melanoma skin cancer, impaired immunity, prostate, COPD, viral infections, active co-morbidity, hepatitis, prostate cancer | ACUTE INFECTION, RECURRENCE, METASTASIS, VENTRICULAR ARRHYTHMIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CANCER, DISEASE, VIRAL INFECTION, METASTATIC DISEASE, PROSTATE, COPD, HEPATITIS, CONGESTIVE HEART FAILURE, HEART, DISEASES, PROSTATE CANCER | Patients were required to have biopsy proven local recurrence of prostate cancer at least one year after the completion of definitive radiation therapy. The biopsy must have been performed within 180 days of study registration. Serum PSA < 100 ng/ or evidence of biologically active disease as demonstrated by an unequivocally rising serum PSA level that is ≥ 2 ng/mL above the nadir. Subjects were eligible if at least 18 years old with Karnofsky performance status ≥70. Patients were required to have negative lymph nodes as established by imaging (pelvic CT or pelvic MRI) within 90 days of registration. Men with lymph nodes equivocal or questionable by imaging were eligible if the nodes were ≤ 1.0 cm. Men with positive lymph nodes by capromab pendetide (ProstaScint) scans were eligible provided a corresponding lymph node identified by CT or MR imaging was ≤ 1.0 cm. Patients were required to demonstrate no evidence of metastatic disease, as evaluated by a bone scan and CT scan of the abdomen and pelvis within 90 days prior to registration. Equivocal bone scan findings were allowed if plain films were negative for metastasis. Patients were required to have adequate baseline organ function, as assessed by the following laboratory values, before initiating the protocol, including: (i) adequate renal function with serum creatinine ≤1.5 mg/dl or creatinine clearance ≥50 ml/min/m2; (ii) platelet count >100,000/μL; (iii) absolute neutrophil count >1,000/μL; (iv) hemoglobin >10.0 g/dL; and (v) bilirubin <1.5 mg/dL, and serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase <3 times the upper limit of normal. Patients had to have the ability to give informed consent and express a willingness to meet all of the expected requirements of the protocol for the duration of the study.Patients with any one of the following conditions were excluded from the study: (i) PSA ≥ 100 ng/mL, (ii) prostate volume > 100 cc, (iii) pathologically positive lymph nodes or nodes > 1.0 cm on imaging (nodes > 1.0 cm but biopsy negative were allowed), (iv) evidence of M1 metastatic disease, (v) prior invasive malignancy except for non-melanoma skin cancer within 5 years of enrollment. Subjects were required to be disease-free for > 5 years, (vi) prior radical prostatectomy, cryosurgery for prostate cancer, or bilateral orchiectomy for any reason, (vii) biochemical failure while on AST if the subject had prior AST, (viii) prior systemic chemotherapy for prostate cancer. Prior chemotherapy for a different cancer was allowed given patients were >2 years post-completion of chemotherapy at the time of registration. Subjects on Proscar therapy were required to stop Proscar therapy to be eligible, (ix) severe active co-morbidity such as New York Heart Association Class II or greater congestive heart failure or active ventricular arrhythmia requiring medication, Chronic obstructive pulmonary disease (COPD) exacerbation or other respiratory illness requiring hospitalization within last 3 months or precluding study therapy at the time of registration, (x) acute infection, (xi) previous history of livery diseases including hepatitis, (xii) immunosuppressive therapy including systemic corticosteroids, and (xiii) impaired immunity or susceptibility to serious viral infections. All patients met the eligibility requirements of the protocol and signed the informed consent document. There were no protocol violations. All patients were recruited between October 2015 to March 2019.1. | PMC10503775 |
Design and manufacturing Ad5-yCD/ | The design and construction of the replication-competent Ad5-yCD/ | PMC10503775 | ||
Pretreatment planning and injection of Ad5-yCD/ | cancer, prostate | ADENOVIRUS, CANCER, PROSTATE, BLOOD | Informed consent was obtained from all patients before study-specific procedures were initiated. Pretreatment planning included transrectal ultrasound guided needle biopsy of the prostate and computerized tomography (CT) simulation. Transrectal ultrasound scan (TRUS)-guided biopsy cores (≥ 6 cores) were taken to map the location of the cancer within the prostate. Blood was collected for baseline detection of the Ad5-IL-12 adenovirus by polymerase chain reaction (PCR) and serum cytokines (IL-12, IFNγ and CXCL10) by Enzyme-Linked Immunosorbent Assay (ELISA).Men received a single intraprostatic injection of Ad5-IL-12 adenovirus on day 1. The injection was performed on an outpatient basis as described previously [ | PMC10503775 |
Prodrug administration | Prodrugs were administered on an outpatient basis. 5-Fluorocytosine (Ancobon; Roche Laboratories, Basel, Switzerland) was administered orally beginning on day 3 and continued for 1 week (7 days). A total of 150 mg/kg/day was given in four equally divided doses. Valganciclovir (Valcyte; Roche Laboratories) was administered orally beginning on day 3 and continued for 1 week (7 days). A total of 1,800 mg/day was given in two equally divided doses every 12 h. The research nurse assigned to the trial counted the pills periodically to monitor patient compliance. | PMC10503775 | ||
Patient monitoring | toxicity, Toxicities, Toxicity, Cancer | ADVERSE EVENTS, ADENOVIRUS, CANCER | Toxicity assessments were performed once a week prior to the start of chemotherapy (first 3 weeks) and then at scheduled follow-up visits at 3, 6, 9, 12, 18, and 24 months. Toxicities were graded using the National Cancer Institute’s Common Toxicity Criteria, CTCAE v.4.03. Case report forms (CRFs) specifically designed for this trial were used to document adverse events (AEs). The study was monitored by an internal Data and Safety Monitoring Board (DSMB). The primary end point, treatment toxicity, was monitored up to and including day 30. After treatment, patients received standard urologic care.The following evaluations were conducted once a week following the adenovirus injection through day 30: (i) physical examination, (ii) blood chemistries and complete blood counts including peripheral blood mononuclear cells (PBMC) (iii) serum PSA, (iv) presence of Ad5-IL-12 viral DNA and infectious adenovirus in blood, (v) cytokines including IL-12, CXCL10 and IFNγ, and (vi) performance status. The presence of Ad5-IL-12 viral DNA in blood, serum IL-12, IFNγ, and CXCL10 levels were monitored at every blood draw until not detected in two consecutive measurements. | PMC10503775 |
PCR of Ad5-yCD/ | ADENOVIRUS, BLOOD | Blood was obtained before the adenovirus injection and at least once a week after for semi-quantitative determination of adenoviral DNA in blood. Total genomic DNA was isolated from 2.5–3 mL of blood using Qiagen columns following the protocols recommended by the manufacturer (QIAGEN GmbH, Hilden, Germany). 2–3 μL of eluted DNA was used as a template for the PCR reactions. The PCR primers have been previously described [ | PMC10503775 | |
Serum cytokines | BLOOD | IL-12, IFNγ and CXCL12 were measured in patient serum. Blood was drawn once pretreatment (between days −30 and −1) and then again on days +3, +7, +14, +21 and +28 (±3 days) to isolate serum and collect PBMCs. ELISA was performed following manufacturer’s protocol (BD Biosciences). For measuring CXCL10, serum samples were run after 10-fold and 100-fold dilution. Undiluted serum was used for IL-12 and IFNγ measurement. Log range dilution of purified cytokines were used for generating standard curve. Absorbance was measured at 450 nm from 96-well ELISA plates. The raw data was organized using MS Excel and analyzed on GraphPad Prism version 9. The data was interpolated using a standard curve with a second order polynomial (quadratic) equation and plotted with a 95% confidence interval (CI). The correlation coefficient (R | PMC10503775 | |
Flow cytometry | Flow cytometry was performed as previously described [ | PMC10503775 | ||
Statistical methods | MIN | ADENOVIRUS, ADVERSE EVENT | Adverse events, graded using CTCAE v4.03, were collected through day 30 (day 1 being the day of the adenovirus injection). The effect of oncolytic adenovirus-mediated cytotoxic and IL-12 gene therapy on serum PSA levels was evaluated by estimating PSA doubling time (PSADT). PSADT was estimated for each patient pre-injection and post-injection. A single model of log (PSA) on time was built for each patient, and the PSA doubling time was calculated for each patient for pre-injection PSADT. For post-injection PSADT estimation, PSA doubling time from nadir was estimated using all PSA values. Minimum (MIN), Median and Mean values were estimated for pre- and post- injection PSADT. Additionally, post-injected PSADT for cohorts 1–3 and 4–5 were pooled.PSADT was calculated assuming first-order kinetics using the following equation:
| PMC10503775 |
Supporting information | PMC10503775 | |||
An estimation of peripheral blood mononuclear cells (PBMCs) for all cohorts. | (DOCX)Click here for additional data file. | PMC10503775 | ||
Serum PSA counts in all subjects over time. | (DOCX)Click here for additional data file. | PMC10503775 | ||
Phase 1 trial of oncolytic adenovirus-mediated cytotoxic and interleukin 12 gene therapy for locally recurrent prostate cancer after definitive radiotherapy. | (PDF)Click here for additional data file. | PMC10503775 | ||
Request for planned change(s). | (PDF)Click here for additional data file.The authors thank Yingshu Zhang for technical assistance and Dr. Kevin Bobbitt for running the samples for flow cytometry. | PMC10503775 | ||
References | PMC10503775 | |||
Subject terms | human behaviors | People judge the nature of human behaviors based on underlying intentions and possible outcomes. Recent studies have demonstrated a causal role of the right temporoparietal junction (rTPJ) in modulating both intention and intention-based outcome evaluations during social judgments. However, these studies mainly used hypothetical scenarios with socially undesirable contexts (bad/neutral intentions and bad/neutral outcomes), leaving the role of rTPJ in judging good intentions and good outcomes unclear. In the current study, participants were instructed to make goodness judgments as a third party toward the monetary allocations from one proposer to another responder. Critically, in some cases, the initial allocation by the proposer could be reversed by the computer, yielding combinations of good/bad intentions (of the proposer) with good/bad outcomes (for the responder). Anodal (n = 20), cathodal (n = 21), and sham (n = 21) transcranial direct current stimulation (tDCS) over the rTPJ were randomly assigned to 62 subjects to further examine the effects of stimulation over the rTPJ in modulating intention-based outcome evaluation. Compared to the anodal and sham stimulations, cathodal tDCS over the rTPJ reduced the goodness ratings of good/bad outcomes when the intentions were good, whereas it showed no significant effect on outcome ratings under unknown and bad intentions. Our results provide the first evidence that deactivating the rTPJ modulates outcome evaluation in an intention-dependent fashion, mainly by reducing the goodness rating towards both good/bad outcomes when the intentions are good. Our findings argue for a causal role of the rTPJ in modulating intention-based social judgments and point to nuanced effects of rTPJ modulation. | PMC9870900 | |
Introduction | intention-oriented attribution | People judge the nature of individual behaviors not only relying on the outcomes caused by their behaviors but also on the underlying intentions. Studies have shown a transition from outcomes-oriented to intention-based moral judgment from children to adults in the normal populationTranscranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS), as non-invasive brain stimulation technique, allows it possible to enhance or disrupt cortical excitability artificially and transiently and further examine the causal role of the rTPJ in intention/outcome attribution during social judgmentUsing a low-frequency (1 Hz) TMS, Young et al., demonstrated that inhibiting the activity of rTPJ enhanced the moral permissibility of attempted (Besides the polarity of the tDCS stimulation, another study examined the effects of stimulation intensity on moral judgments, in which 1.5 mA cathodal tDCS over the rTPJ decreased moral appropriateness of accidental harm (Notably, the aforementioned studies only considered socially undesirable scenarios—bad/neutral intentions and bad/neutral outcomesTo approach the above two questions, a combined behavioral and tDCS study was performed among 62 participants, who randomly underwent anodal (n = 20), cathodal (n = 21), and sham (n = 21) tDCS over the rTPJ. Based on our previous work, we hypothesized that a similar pattern of intention-oriented attribution could be observed in a mixed scenario with good and bad intentions/outcomes in a baseline condition. Moreover, the anodal tDCS and cathodal tDCS may show differentially modulatory effects with anodal tDCS may increase intention attribution while the cathodal may decrease it. | PMC9870900 | |
Materials and methods | PMC9870900 | |||
Participants | In a single-blinded, sham-controlled design, sixty-two college students (20.42 ± 1.9 years, 49 females) were recruited and randomly assigned to one of the three stimulation groups with anodal (n = 21), cathodal (n = 20), or sham (n = 21). We set the sample size based on previous studies on the effects of rTPJ stimulation on the intention processing ranging from 4 to 20 participants in each stimulation group | PMC9870900 | ||
Experimental paradigm and procedure | anxiety | A modified dictator game (see also Ref.(All participants underwent two blocks, a pre-stimulation (baseline) block, and a post-stimulation block, with 27 trials (3 intention conditions × 9 offer levels) in each block. The pre-stimulation block was presented without any tDCS stimulation. The post-stimulation block followed immediately after a 20-min tDCS stimulation (anodal, cathodal, or sham). Subjective ratings on anxiety | PMC9870900 | |
tDCS protocol | The stimulation was administered through a battery-driven constant current stimulator developed by Soterix Medical, America. The stimulation was induced through a saline-soaked pair of surface sponge electrodes. Both anodal and cathodal electrodes were 5 cm × 7 cm in size. To stimulate the rTPJ, the anodal or cathodal electrode was placed between CP6 and C6 according to the international 10–20 EEG system( | PMC9870900 | ||
Data analysis | All analyses were performed using SPSS Version 23. The allocation amounts were categorized into three conditions: good (more than 6 ¥), fair (6 ¥) and bad (less than 6 ¥), which was also indicated in another paper | PMC9870900 | ||
Results | anxiety | To make sure that three groups are comparable across conditions, we first checked the demographic information. Overall, no significant differences in terms of the age were observed among the three stimulation groups, Ages and emotion scores for tDCS groups (mean ± SD).tDCS effects across experiments. Cathodal tDCS over the rTPJ diminished outcome evaluation when the intention is good. *Then, a four-way repeated measure ANOVA was performed with intention (good vs. unknown vs. bad), outcome (good vs. bad), and phase (pre-tDCS vs. post-tDCS) as within-subject variables, stimulation group (anodal, cathodal, sham) as a between-subject variable, and the rating scores as a dependent variable. Our results have revealed a significant interaction effect among the four factors (F (4, 118) = 2.543, Further comparison between pre- and post-stimulation for the cathodal group were performed across three intention levels to address how cathodal stimulation modulated intention attribution. Specially, we found that the cathodal stimulation over the rTPJ largely diminished the goodness rating of both good outcome (pre vs. post: M = 4.59 ± 1.09 vs. M = 4.03 ± 1.22, Lastly, statistics on the subjective questionnaires revealed no difference on the subjective ratings towards anxiety, positive/negative affect, and uncomfortableness levels during stimulation (see Table | PMC9870900 | |
Discussion | In our research, we orthogonalized good/bad intention and good/bad outcome. We found that cathodal tDCS over the rTPJ diminished the goodness ratings towards good/bad outcomes when the intentions are good and showed no difference with ratings under bad/unknown intentions. Our results provide the first evidence that deactivation in the rTPJ disrupted intention-oriented attribution mainly by lowering the goodness ratings toward outcomes when the intentions are good, but not when the intentions are bad/unknown. Our findings argue for a causal role of the rTPJ in modulating intention attribution that may rely on the nuanced intention-outcome combinations. | PMC9870900 | ||
Dissociation of intention and outcome | In our study, no main effect of outcome valence was observed. The judgment difference we have observed in a baseline condition are mainly driven by the intention-oriented attribution, suggesting that goodness ratings were mainly driven by intention. It is possible that participants may show strong demanding prosocial characters, thus leading to higher weighting of intention than outcome. The outcomes (good/bad) here indeed didn’t impact their self-interest as a third-party. Meanwhile, the outcome itself didn’t convey moral values or utilities | PMC9870900 | ||
Comparison with previous studies | First and foremost, we have observed a largely reduced role of the intention on social judgments after inhibiting the rTPJ. Similar impairment on intention attribution was also observed in others’ studiesThe second difference from previous studies is that no modulatory effects on the intention attribution were observed after activating the rTPJ via anodal tDCS. The absence of anodal tDCS effects on judgments of either good or bad intention may be due to the ceiling effect | PMC9870900 | ||
Context-based intention modulation | EVENT | Besides the essential role for intention and outcome processing, the rTPJ was also implicated in the deployment of attention (“attention hypothesis”) to an unexpected event as firstly suggested by Buccino et al | PMC9870900 | |
Limitations and future directions | Our study has some limitations. Firstly, it is still unclear whether the effects we observed in the current experiment can be extended to situations in which consequences are not merely monetary and much more serious. Intentions in our study are limited to the financial fairness dimension. Our experimental design does not speak to more evil motives, such as to harm, to sabotage, and to kill. Secondly, it is possible that other brain regions apart from the rTPJ may also be modulated indirectly by tDCS. Future studies may directly measure the neural activity at the whole brain level after tDCS. Lastly, our findings need to be treated with caution and wait for further replications. Future studies may further investigate the dose effect of tDCS and the effects of other tDCS protocol parameters. | PMC9870900 | ||
Acknowledgements | This research was supported by Tohoku University Operating Fund President's Discretionary Expenses (Research) (No. 56045090) and Japan Society for the Promotion of Science Grant-in-Aid for Early-Career Scientists (No. 22K15626) (to S.S.), Scientific Research Foundation for the High-level Talents from Fujian University of Traditional Chinese Medicine (No. X2019002-talents), National Natural Science Foundation of China (No. 81973751), and Science and Technology Planning Project of Fujian Province of China (No. 2021I0018). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | PMC9870900 | ||
Author contributions | J.Z.: Conception, data collection, methodology, writing-original draft preparation, S.S.: Writing-original draft preparation, reviewing and editing. C.Z.: Data collection, methodology. Y.C.: Data collection. H.L.: Data collection. Z.Y.: Supervision. R.Y.: Supervision. | PMC9870900 |
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