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Conclusion | The challenge for the Australian health system is that interventions to address financial hardship traditionally sit ‘outside’ the sector. This results in substantial health system inefficiencies and increased health burdens and costs. | PMC10668198 |
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Supplementary Material | PMC10668198 |
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Reviewer comments | PMC10668198 |
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Data availability statement | Data are available on reasonable request. Data are available on reasonable request to [email protected] (subject to ethical and legal approvals). | PMC10668198 |
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Ethics statements | PMC10668198 |
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Patient consent for publication | Not applicable. | PMC10668198 |
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Ethics approval | WEST | This study involves human participants and this research was approved by the Human Research Ethics Committees of The Royal Children’s Hospital (HREC/57372/RCHM-2019; sites 1, 2, 4–5), and South West Sydney Local Health District (2019/ETH13455; site 3). Participants gave informed consent to participate in the study before taking part. | PMC10668198 |
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References | PMC10668198 |
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Introduction | enema | STIS, SEXUALLY TRANSMITTED INFECTIONS | The HIV epidemic has affected people across the globe over the past four decades, with sexual and gender minorities (SGM; i.e., populations with same-sex or same-gender attractions or behaviors and who may identify with a non-heterosexual identity such as gay, bisexual, queer, etc.)carrying much of the burden of new diagnoses [Researchers and advocates have proposed expanding modalities of PrEP delivery, including the use of rectal microbicides (RMs); topical biomedical products being developed to reduce the risk of HIV and other sexually transmitted infections (STIs) for use with sexual activity [Most rectal microbicide candidates have been formulated as gels because of their similarities to lubricants, highlighting the potential for the rectal microbicide gel to be readily incorporated into users’ sexual practices [Survey research with SGM populations across various countries has found high hypothetical acceptability to a rectal microbicide formulated as a suppository, insert, or enema [The primary objectives of MTN-035 were to evaluate the acceptability and safety of and adherence to three placebo modalities–an insert, a suppository, and an enema–that could be used prior to RAI in a randomized, cross-over trial. We hypothesized that all three modalities would be acceptable and safe for use prior to RAI, and that SGM participants would report high adherence to these modalities given their behavioral congruence with cleansing practices (e.g., enemas) and their familiar use to deliver medications (e.g., suppositories; fast-dissolving inserts) via the rectum. | PMC10096248 |
Materials and methods | PMC10096248 |
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Sample | HIV-uninfected transgender men, transgender women, and cisgender MSM between the ages of 18 and 35 were recruited into the trial (see | PMC10096248 |
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CONSORT disposition of participants. | Participants were recruited from a variety of sources, including outpatient clinics, universities, community-based locations, online websites, and social networking applications. In addition, participants were also referred to the study from other local research projects, research registries and other health and social service providers. At some sites, prospective participants were pre-screened by phone, using an IRB-approved phone script, to assess presumptive eligibility based on select behavioral and medical eligibility requirements. This includes a review of the prospective participants’ sexual history and engagement in receptive anal sex in their lifetime and within the previous three months. For those deemed presumably eligible when a phone screen was conducted, a screening visit was scheduled. A re- affirmation of all eligibility criteria was obtained and confirmed during a formal screening and enrollment visit, described below.The study was reviewed and approved by Institutional Review Boards (IRB)/Ethics Committees at all participating institutions, including the Health Research Ethics Council, South African Health Products Regulatory Authority, the College of Medicine Research and Ethics Committee, the Johns Hopkins Bloomberg School of Public Health IRB, the Research Institute for Health Sciences Human Experimentation Committee, the Medical Device Control Division/Thai Food and Drug Administration (FDA), the IMPACTA Bioethics Committee, the Peruvian National Institute of Health (Instituto Nacional de Salud), the Peruvian FDA, the Peruvian Ministry of Health, the University of Pittsburgh IRB, the University of California San Francisco IRB, University of Alabama at Birmingham IRB, and the University of Pennsylvania IRB. This study was submitted to clincialtrials.gov on September 14, 2018, assigned number NCT03671239. | PMC10096248 |
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Inclusion criteria | inflammatory bowel disease or anorectal condition | REPRODUCTIVE TRACT INFECTION, URINARY TRACT INFECTION | Inclusion criteria included: 1) men (cis or transgender) and transgender women between 18–35 years old; 2) ability and willingness to provide written informed consent in local language; 3) HIV- 1/2 uninfected at Screening and Enrollment; 4) ability and willingness to provide adequate contact and location information; 5) availability to return for all study visits and willingness to comply with study participation requirements; 6) deemed to be in general good health by a healthcare provider at Screening and Enrollment; 7) a reported history of consensual RAI at least three times in the past three months and expectation to maintain at least that frequency of RAI during study participation; 8) willingness to not take part in other research studies involving drugs, medical devices, genital or rectal products, or vaccines for the duration of study participation; 9) For individuals who could get pregnant (transgender men with a female reproductive system), a negative pregnancy test at Screening and Enrollment; 10) For individuals who could get pregnant, use of an effective method of contraception for at least 30 days (inclusive) prior to Enrollment, and intention to use an effective method for the duration of study participation. Exclusion criteria included history of inflammatory bowel disease or anorectal condition impeding product placement or assessment of tolerability; anticipated use of non-study rectally administered products; any prior participation in research studies involving rectal products; having an active anorectal or reproductive tract infection requiring treatment or symptomatic urinary tract infection (these participants could be retested during screening and could enroll if resolved); and pregnancy or breast-feeding. | PMC10096248 |
Screening, enrollment and retention | genital/reproductive tract infections | SEXUALLY TRANSMITTED INFECTIONS, URINARY TRACT INFECTIONS | Participants were screened for eligibility prior to enrolling in the study. All enrolled participants provided written informed consent. Participants returned to the clinic within the 45-day screening window where they completed administrative, behavioral, clinical, and laboratory procedures. Additionally, clinical results or treatments for urinary tract infections, genital/reproductive tract infections, sexually transmitted infections (UTIs/RTIs/STIs) or other findings were provided as clinically indicated at all visits. At all clinic visits, participants were also dispensed condoms and lubricant. Consented and enrolled participants were then randomized into one of six sequences, each varying the order in which participants used the study placebo products, with a 1-week wash-out period between each 4-week product use period ( | PMC10096248 |
Randomization sequence order. | Participants were randomly assigned in a 1:1:1:1:1:1 ratio to one of six study product application sequences (A-F), with the randomization configuration based on permuted blocks, to keep the allocation balanced. The randomization scheme, including enrollment of replacement participants, was generated and maintained by the MTN Statistical Data Manager Center (SCHARP), and it was configured in the Medidata Balance system prior to site activation. This allowed for participants being assigned to a randomized sequence by the system, only after site staff confirmed them as eligible and willing to enroll in the study.Each participant was followed for approximately 3.5 months and was expected to complete eight visits (including Screening and Enrollment visits). A regular visit was considered missed if the participant did not complete any part of the visit within the visit window. If an interim visit was completed to make up for the missed regular visit, then the missed regular visit was calculated as completed. | PMC10096248 |
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Study procedures | Each participant received placebo inserts, placebo suppositories, and placebo (water) enema bottles for pericoital rectal administration (see | PMC10096248 |
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MTN-035 placebo study products. | The products were administered in order of the assigned sequence and prior to each respective product use period. Participants were instructed to use one dose of the assigned study product between 30 minutes and 3 hours prior to RAI, following their usual pre-RAI practices, and not to use more than one product dose in 24 hours. If a participant did not engage in RAI in a given week, they were asked to insert a dose of the product in the absence of RAI. Participants self-administered the first dose of each product in the clinic to ensure correct administration.The schedule of participants’ study activities is depicted in | PMC10096248 |
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MTN-035 study schema. | VAGINA | After an approximately 7-day washout period following study product use periods, participants returned to the clinic to complete Visits 4 and 6. At these visits, participants completed study procedures, including pharyngeal, urine, blood, pelvic (individuals with a vagina or neovagina), and anorectal tests, if indicated. Additionally, participants self-administered one dose of the product they were dispensed and collected the remaining product in their sequence to use for the next four weeks during periods 2 and 3; they were also given product use instructions.Visit 8 served as the follow-up safety contact and termination visit where participants completed study procedures as well as received clinical results or treatment for UTIs/RTIs/STIs or other findings. Participant reimbursement was based on local guidelines and approved by the local IRBs/ECs prior to study implementation.We undertook several efforts to minimize the impact of the COVID-19 pandemic during our data collection period, including revising when and how products were dispensed during periods of COVID-19 restrictions. Of the 78 enrolled participants when the COVID-19 pandemic began, only four did not receive all three products (see Jacobson et al. [ | PMC10096248 |
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Primary safety endpoint | AIDS | ADVERSE EVENTS, ADVERSE EVENT, AIDS, MAY | Our primary safety endpoint was defined as the presence of a Grade 2 or higher related adverse events (AEs) as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 and Addenda 1, 2 and 3 (Female Genital [Dated November 2007], Male Genital [Dated November 2007] and Rectal [Clarification dated May 2012] Grading Tables for Use in Microbicide Studies [ | PMC10096248 |
Primary acceptability endpoint | Acceptability endpoints were based on participants’ responses to the CASI for each product at their respective product use end visits (Visits 3, 5 and 7). Using a 10-point scale (1 = Very Unlikely; 10 = Very Likely), participants were asked to answer the following question about their most recently used product: “Think about the positive and negative experiences you have had using the [study product] during the past 4-week period. If this [study product] was available and it provided some protection against HIV, how likely would you be to use it before receptive anal sex?”. The endpoint was operationalized as binary, with scores 1 to 6 grouped as “low acceptability” and scores 7 to 10 as “high acceptability”. | PMC10096248 |
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Primary adherence endpoints | enema | Adherence to use of each assigned product, as per-protocol, was based on the number of weeks that a participant missed using an assigned product (0 to 4 weeks), using a given product use end visit CASI assessment: “The following questions refer to your use of the study provided rectal [study product: enema, insert or suppository] over the past 4 weeks. You were asked to insert the study provided rectal [study product] in your rectum at least once a week during the past 4 weeks. However, for different reasons, people might have encountered difficulties using the [study product]. Thinking about your experience during these past four weeks, in how many of the weeks did you miss a rectal [study product] application?”. The adherence per-protocol was operationalized as binary, with participants who reported not having missed any application classified as “adherent”.Additionally, adherence per RAI-act was defined (for participant-periods with at least one RAI act was reported) as the proportion of times that participants reported having used the study-provided enema, insert or suppository before RAI. We determined adherence per RAI act by dividing participants’ responses to their CASI assessments regarding the number of times a participant noted using the study product before RAI by the total number of RAI acts self-reported over the same 4-week period. Participants are classified as fully adherent per RAI-act if they reported using the study product for all reported RAI acts. | PMC10096248 |
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Statistical analysis | There is no control group for comparison in this study. The main goal was not to compare between the three different placebo modalities, but to obtain overall rates of acceptability, adherence, and safety of each modality. The selected sample size provides at least 90% power to rule out rates of acceptability or adherence below 70%.Baseline characteristics are described for all enrolled participants. The study’s safety endpoint was evaluated among participants who received at least one of the study products (excluding any study periods when participants did not receive a product). The acceptability and adherence primary endpoints were evaluated among participants who received all three study products and completed the scheduled product use (which we refer to as the “per-protocol” subset), thus providing relevant data from all three periods of study. To support the generalizability of acceptability and adherence results, we compared baseline characteristics between participants in the per-protocol subset and those who were lost to follow-up.For the safety endpoint, the proportion of participants with Grade 2 or higher related AEs is reported, along with a 95% confidence interval (CI) (Clopper-Pearson method). For adherence and acceptability endpoints, the proportion of participants classified as adherent, or who reported a high acceptability score, are also provided, along with 95% CIs.To test for potential effects of the assigned sequence and/or sites in the overall acceptability and adherence, generalized linear mixed models with a logistic link function were used. The participant’s assigned sequence, site, and the modality used in the study period were included as fixed effects, with a random effect at the participant level to account for the cross-over design. To test if overall differences exist between sites or assigned sequences, omnibus likelihood ratio tests were used. No adjustment of p-values was performed. | PMC10096248 |
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Results | PMC10096248 |
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Demographics of enrolled participants | We screened 257 individuals across the seven study sites and enrolled 217 participants in five countries; 40 were not enrolled: 29 were not eligible, five were eligible but did not enroll, and six did not complete their screening (see The mean age was 24.9 years (SD = 4.7), ranging from 18 to 35 years old. Most of the sample reported having a male sex indicator assigned at birth (n = 214; 99%). Twenty percent of the sample identified as a gender minority. Overall, 13 (14%) participants in the U.S sites identified as Hispanic/Latinx. The racial, ethnic, and tribal affiliation of participants across the study sites is noted in | PMC10096248 |
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Participants’ sociodemographic characteristics, overall and by site. | USA: United States of AmericaParticipants reported having had an average of 3 male partners (SD = 6.35; range: 0–70) in the prior 30 days. Participants’ average total number of RAI occasions during that 30-day period was 4.76 (SD = 8.50; range: 0–100), with an average of 2.57 (SD = 7.74; range: 0–100) condomless RAI occasions self-reported during the same period. Two thirds of participants (n = 142; 65.4%) reported prior use of an enema, with fewer participants self-reporting that they had used a suppository (n = 8; 3.7%) or insert (n = 10; 4.6%) prior to RAI. | PMC10096248 |
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Study product use period completion | enema | HIV INFECTION | A study product use period was considered completed if the participant received the study product and completed the scheduled study product use period. Study product use period completion rates were 94% for the insert, 95% for the suppository, and 95% for the enema. Among enrolled participants, 92% exited the study at their scheduled end of study visit. Reasons for early study terminations included “Participant refused further participation” [n = 2 (1%)], “Participant is unwilling/unable to comply with required procedures” [n = 6 (3%)], “Lost to follow-up” [n = 4 (2%)], “Investigator decision” [n = 1 (<1%)], “Unable to contact participant” [n = 3 (1%)], “HIV infection” [n = 1 (<1%)], and “Other, specify” [n = 1 (<1%), participant relocating].The per-protocol subset of participants (those who completed all three study product use periods) included 202 (93%) out of the 217 participants enrolled (see | PMC10096248 |
Primary safety endpoint | There were 204 AEs in the study reported by 98 participants (45% of the total sample; see | PMC10096248 |
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Number of adverse events (AEs) reported. | Notes. 98 out of the 217 participants reported one or more AEs. | PMC10096248 |
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Primary acceptability endpoint | The proportion of participants reporting “high acceptability” was for inserts: 72% (95%CI: 65% - 78%), suppositories: 66% (95%CI: 59% - 73%), and enemas: 73% (95%CI: 66% - 79%) (see | PMC10096248 |
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Acceptability and adherence by study product. | Notes. Estimates exclude missing data for acceptability (Rectal insert (n = 3); Suppository (n = 2); Enema (n = 5)) and adherence (Rectal insert (n = 3); Suppository (n = 3); Enema (n = 2)).From the logistic mixed model (see | PMC10096248 |
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Primary adherence endpoint | The adherence primary endpoint was evaluated on the per-protocol subset of 202 participants (see As noted in | PMC10096248 |
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Adherence per-sex-act | enema | Participants in the per-protocol subset reported an average of about 7 sex acts in the 4-week period of product use: insert (M = 7.2; SE = 0.7), suppository (M = 7.7; SE = 0.7), and enema (M = 7.8; SE = 0.8). Among participants who reported at least one sex act during the product use period, the percentages of participants fully adherent per RAI-act were similar among the three study products: insert (n = 99/168; 58.9%), suppository (n = 101/174; 58.0%) and enema (n = 107/182; 58.8%). | PMC10096248 |
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Discussion | enema, flatulence, diarrhea | EVENTS | RMs are needed for individuals with an increased chance of acquiring HIV through RAI, particularly young SGM across the globe [All three administration modalities with placebo products were found to be safe for use, with less than 20% of AEs deemed related to the study products/modalities and only two related events being graded as having moderate clinical severity or higher. These findings align with our study hypothesis. The safety profile of all three administration modalities with placebo products is promising and underscores the potential of all three modalities as viable for rectal drug delivery. The low incidence of distinct product-related AEs (e.g., diarrhea, flatulence) across study products is also noteworthy, as it mirrors common AEs reported when using over-the-counter rectal products (e.g., enemas) and prior rectal microbicide candidates in clinical trials (e.g., gels). while we should continue to reduce the occurrence of any AEs during product development, the promising safety profiles for the three modalities using placebo products employed in this trial offer a threshold whereby future clinical trials examining these same modalities with active drug ingredients can benchmark their safety endpoints.Consistent with our hypotheses for our acceptability and adherence endpoints, SGM participants reported high overall acceptability for all three products and high overall adherence per protocol and per RAI act. While survey research literature has noted high hypothetical acceptability to RMs as an HIV prevention strategy prior to RAI [While overall acceptability and adherence were high for each product, we observed differences in acceptability and adherence after SGM participants had used all three modalities. While the products were rated similarly in their acceptability and there were no differences based on participants’ assigned product sequence, adherence to the enema was higher when compared to the fast-dissolving insert or the suppository. Given the high prevalence of rectal douching prior to RAI among SGM globally [We also observed differences for both acceptability and adherence between participants living in the different communities across the five countries participating in the trial. Compared to San Francisco, participants in the other regions reported greater acceptability of the three rectal modalities under study. Consistent with prior research with hypothetical and real-world studies with rectal candidates [ | PMC10096248 |
Strengths & limitations | This study had several strengths. First, this is the first study to examine the safety and acceptability of and adherence to these three promising modalities for rectal drug delivery prior to RAI. Examining each product’s use in real life contexts strengthens the social validity of our findings and the potential use for these three modes of delivery in the future. Second, the crossover randomized design of our trial allowed us to assess SGM participants’ acceptability of and adherence to these three modalities within the same trial, offering a unique opportunity to compare their acceptability, safety, and adherence within individuals who used all three products prior to RAI. Third, given the variability in both legal protections and social acceptance of SGM people between and within these countries, our ability to recruit and retain a large sample of young SGM living in geographically and socio-politically diverse countries is noteworthy and strengthens the generalizability of our findings to diverse contexts. Finally, our efforts to minimize the impact of the COVID-19 pandemic during our data collection period minimized interruptions to our trial and ensured that rigor was preserved [Nonetheless, our trial also had several limitations. First, self-reported responses tend to be favorable due to social desirability; however, we tried to minimize bias by having participants complete their questionnaires in a private location during their clinical visits. Second, there is a possibility of recall bias when participants completed their surveys. Third, we recruited a convenience sample of participants willing to use each of the study products at least once per week, as required by the protocol. We acknowledge that the generalizability of our clinical trial findings may not be representative of all individuals practicing RAI. Fourth, given the placebo nature of the three products used in our trial, we were unable to employ a biological confirmation method regarding participants’ product use and adherence, or examine the extent and duration of rectal coverage afforded by each product during and after sex. These data will be crucial in the future, particularly as drug candidates are embedded into these modalities and tested for safety and adherence. Fifth, we were unable to recruit the sexual partners of our study participants. Given existing data regarding partners’ roles in young SGMs’ decision-making when selecting HIV prevention strategies prior to sex, future research examining these dyadic dynamics may be warranted. Finally, while we designed our clinical trial to resemble participants’ product use to as close as ‘real-world’ settings possible while maintaining rigor, we acknowledge that the trial protocols may hinder the social validity of the findings. Future research examining these products in real-world situations may further clarify their potential for use as rectal microbicide modalities. | PMC10096248 |
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Conclusions | HIV infections | HIV INFECTIONS | Advances in biomedical strategies for HIV prevention continue to emerge. Efforts to diversify HIV prevention options will strengthen our ability to reduce new HIV infections among SGM, whether some SGM desire systemic modalities (e.g., daily oral PrEP; PrEP injectables) or prefer topical protection (e.g., RMs). Regardless of the mode of administration, the effectiveness of these HIV prevention strategies will require that users have access to safe and acceptable products which are easy to use consistently. Our trial addresses the limited data available regarding the safety and acceptability of and adherence to enemas, inserts, and suppositories as potential modalities through which to deliver a rectal microbicide. findings from this trial demonstrate high safety profiles, alongside high levels of acceptability and adherence, among all three modalities. future research examining the acceptability, adherence, safety, and efficacy of promising prep candidates using these three rectal microbicide modalities is encouraged. | PMC10096248 |
Supporting information | PMC10096248 |
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CONSORT checklist for MTN-035 trial. | (DOC)Click here for additional data file. | PMC10096248 |
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MTN-035 protocol. | MITCHELL, BROWN | (PDF)Click here for additional data file.The study team gratefully acknowledges the study participants of MTN-035. We are grateful to the local research teams for their work. We also recognize the contributions of staff across the study sites. In Malawi, we recognize the work of Abigail Mnemba, Alinafe Kamanga, Annie Munthali, Daniel Gondwe, Linly Seyama, Yamikani Mbilizi, Noel Kayange, Mary Chadza, and Josiah Mayani. In South Africa, the MTN-035 team included Helen Rees, Kerushini Moodley, Krishnaveni (Krina) Reddy, Thesla Palanee-Phillips, Andile Twala, Ashleigh Jacques, Tsitsi Nyamuzihwa, Nazneen Cassim. In Peru, we recognize the work of Ana Miranda, Diana Morales, Helen Chapa, Javier Valencia, Milagros Sabaduche, Pedro Gonzales, Karina Pareja, Katherine Milagros, and Charri Macassi. We also recognize the Thailand MTN-035 team, including the work by Suwat Chariyalertsak, Pongpun Saokhieo, Veruree Manoyos, Nataporn Kosachunhanan, and Piyathida Sroysuwan. In the United States, we recognize the work of Allison Matthews, Amy Player, Andrea Thurman, Carol Mitchell, Christine O’Neill, Christy Pappalardo, Christopher Quan, Cindy Jacobson, Clifford Yip, Craig Hendrix, Craig Hoesley, Danielle Camp, Deon Powell, Devika Singh, Diana Ng, Edward Livant, Elizabeth Brown, Emily Helms, Emily Schaeffer, Faye Heard, Gina Brown, Gustavo Doncel, Holly Gundacker, Hyman Scott, Jackie Fitzpatrick, James Gavel, Jeanna Piper, Jenna Weber, Jennifer Schille, Jessica Webster, Jessica Maitz, Jillian Zemanek, Jim Pickett, Jonathan Lucas, Julie Nowak, Kathleen Dietz, Ken Ho, Krissa Welch, Kristine Heath, Lisa Rohan, Lizardo Lacanlale, Lynn Mitterer, Lorna Richards, Marcus Bolton, Mei Song, Naana Cleland, Nicholas Ng, Nicole Macagna, Nnennaya Okey-Igwe, Onkar Singh, Patricia Peters, Rebecca Giguere, Renee Weinman, Roberta Black, Scott Fields, Sharon Riddler, Sharon Hillier, Sherri Karas, Sherri Johnson, Stacey Edick, Sufia Dadabhai, Susan Buchbinder, Taha Taha, Tarana Billups, Teri Senn, Theresa Wagner, Tim McCormick, and Yuqing Jiao. The rectal placebo inserts used in this study were provided by CONRAD as part of a project entitled Development of Novel On-Demand and Longer-Acting Microbicide Product Leads funded by a cooperative agreement between the US Agency for International Development (USAID) and Eastern Virginia Medical School (AID-OAA-A-14-00010). | PMC10096248 |
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Introduction | posttraumatic stress disorder, non-affective, traumatic, affective and non-affective paradigms, PTSD | Trauma-focused psychotherapy (TF-psychotherapy) is the frontline treatment of choice for posttraumatic stress disorder, and is recommended in most treatment guidelines for PTSD [One of important lines of enquiry to study mechanisms of change in TF-psychotherapy is understand how neural functioning is associated with symptom improvement. Numerous studies of adults with PTSD have used functional magnetic resonance imaging (fMRI) during a range of tasks to map how treatment response is associated with neural changes when performing different tasks. Most studies have employed affective tasks that include fear conditioning [There are no previous studies that have employed both affective and non-affective paradigms in the same treatment study to investigate how treatment response is associated with changes in neural functioning following TF-psychotherapy in PTSD. The goal of the present study was to examine the relationship between response to TF-psychotherapy in adults with PTSD with changes in neural activity and connectivity across affective and non-affective tasks. In this sense, this study attempted to extend on most previous studies by utilizing diverse paradigms to provide a more comprehensive investigation of neural functions that may be affected by TF-psychotherapy. This study focused on passive viewing of affective stimuli, reappraisal of traumatic stimuli, and response inhibition of neutral stimuli to provide indices of distinct neural functions in the context of treatment response. We hypothesized that improvement following TF-psychotherapy will be associated with an increase in activation of the prefrontal cortical regions for both the passive viewing and reappraisal affective paradigms and this activation to be at levels expected in healthy individuals post treatment. Due to only one previous treatment study in non-affective paradigms, we tested whether the prefrontal cortical activation for response inhibition also significantly increases following TF-psychotherapy. Due to mixed previous results for the amygdala, we did not have a particular hypothesis for changes in amygdala activation for the two affective paradigms. | PMC9998447 |
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Materials and methods | PMC9998447 |
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Participants | abuse, motor vehicle accidents, PTSD, Administered PTSD | RECRUITMENT | Participant recruitment for the study commenced from August 2009 and ended June 2014. Participants were 51 treatment-seeking patients, 36 of whom had viable imaging data at baseline and 27 of these with follow-up MRI data. For this manuscript we include data from the 27 PTSD patients (13 females; age = 40.9 ± 11.8 years) who completed MRIs at both visits (see CONSORT diagram in Supplementary Fig. SThe PTSD sample had developed PTSD after experiencing assault, childhood abuse, motor vehicle accidents, or during police duties. PTSD was diagnosed according to DSM-IV criteria by masters or doctoral level clinical psychologists using the Clinician Administered PTSD Scale (CAPS; [All participants underwent clinical and imaging assessments at baseline and again 12 weeks later. This study was approved by the Western Sydney Area Health Service Human Research Ethics Committee and informed consent was obtained from participants. | PMC9998447 |
Treatment protocol | PTSD, trauma | Approximately two weeks after baseline clinical and fMRI testing, participants in the PTSD group began a 9-week TF-psychotherapy treatment protocol administered by a doctoral or masters-level clinical psychologist. Treatment occurred in weekly 60–90 min sessions and was consistent with TF- psychotherapy protocols. Therapy comprised one session of psychoeducation about psychological responses to trauma, followed by six sessions of 40 min imaginal exposure to the trauma memory, together with instructions regarding in vivo exposure to avoided situations. In these sessions cognitive reframing of catastrophic thoughts about the trauma and oneself were addressed, as well as an additional session that reinforced cognitive reframing exercises. A final session instructed participants on relapse prevention strategies [ | PMC9998447 |
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Imaging acquisition and data analyses | Functional brain images were collected with a 3.0 T GE Signa HDx scanner (GE Healthcare, Milwaukee, Wisconsin) using an echo planar imaging protocol and an eight-channel head coil and were analyzed using SPM12 (Statistical Parametric Mapping) software on MATLAB2018. Details of MRI acquisition, tasks and pre-processing steps of all fMRI data has been described in detail previously [Participants completed the following fMRI tasks (Fig. | PMC9998447 |
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Summary of tasks performed by participants. | PTSD | Each participant performed every task. There was a conscious and nonconscious version of the emotional faces task.First level general linear models were performed for each task and contrast images generated for each task for every participant. We then employed a region of interest (ROI) analysis approach for second level analyses. For the emotional face processing task, we selected ROIs based on networks involved in positive and negative emotion processing [As done in our previous work using the 3 tasks, contrast images reflecting response inhibition in the Go/No-Go task were created by comparing No-Go trials to Go trials and to the implicit baseline. Contrast images for the emotional faces processing tasks (conscious and nonconscious) were derived by comparing each affective expression (angry, fearful, happy, sad, disgust) to the neutral condition or to the implicit baseline and were entered as a within-subjects factor in a repeated-measures design. For the reappraisal task, the contrast image for cognitive reappraisal was created by comparing Think vs Watch trials, and the contrast image for emotional reactivity was created by comparing Watch trials to Neutral trials.To evaluate activation changes over the course of therapy, each participant’s baseline contrast image was subtracted from their post-treatment contrast image. This produced a ‘delta’ contrast image which reflected the degree of change in activation between the two scans which was then used to evaluate voxel-wise correlations with each participant’s CAPS-change score to identify brain regions associated with treatment response (at For functional connectivity analyses, a generalized psychophysiological interaction (gPPI; [To compare the treatment related neural changes observed in the PTSD group with controls, we performed a voxelwise linear mixed model analysis using a MATLAB based toolbox called | PMC9998447 |
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Results | PMC9998447 |
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Go/No-go task | There were no significant correlations between change in activation for either of the cognitive control ROIs and CAPS-change scores for both response inhibition contrasts (NoGo-vs-Go and NoGo-vs-baseline). | PMC9998447 |
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Changes in fMRI activation during the emotional face processing task and cognitive reappraisal task. | PTSD | Columns depict brain regions in which the change in activation during the task from pre-treatment (T1) to post-treatment (T2) significantly correlated with changes in PTSD symptoms. Scatter plots on the second row depict change in signal intensity in the identified region and percentage reduction in PTSD symptoms. Bar plots in the third row depict mean activation in these regions at T1 and T2 for the PTSD and control groups.ROIs displaying significant correlations with CAPS change scores were selected as seed regions for the connectivity (gPPI) analysis. The insula regions were split into anterior and posterior subregions (see supplementary section) because each pole correlated in opposite directions with CAPS change scores in the activation analyses. Using the left hippocampus as seed, significant negative correlations with CAPS change scores were found for the left amygdala ( | PMC9998447 |
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fMRI connectivity changes during the emotional face processing task. | PTSD | Changes in connectivity of the left hippocampus to the left amygdala, pgACC and sgACC, and of the right insula to the left dlPFC, significantly correlated with changes in PTSD symptoms.For the above significant effects, there were no significant differences in changes in activation or connectivity over time between the PTSD and control groups (no group-time interaction). | PMC9998447 |
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Cognitive reappraisal Task | PTSD | For the contrast reflecting cognitive reappraisal (Think vs Watch), there was a significant negative correlation between activity change in the left dlPFC and CAPS change scores (As for the emotion processing task, there were no differential effects for changes in left dlPFC activation over time between the PTSD and control groups. | PMC9998447 |
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Discussion | extinction and cognitive models, PTSD, non-affective | REMISSION, RECRUITMENT, CORTEX | It is notable that across the paradigms employed in this study, the two affective paradigms involved associations between improvement of PTSD symptoms after treatment and changes in neural activity. In contrast, the non-affective paradigm involving response inhibition was not implicated in any associations between symptom and neural changes. This latter finding accords with one previous study that also found no association between PTSD remission and neural activation during a Go-NoGo paradigm [The finding that improvement after treatment was associated with decreased left hippocampal activation and connectivity when viewing affective faces accords with the role that the hippocampus plays in context processing. PTSD models have emphasized that the hippocampus is implicated in extinction memory because it enables differentiation between contexts and in this way can influence fear generalization [The association between response and increased activation in the anterior insula as well as reduced activation in the posterior right insula during emotional processing can be understood in the context of the functional role of this region. The posterior insula encodes somatosensory information, which is integrated with affective information in the middle insula which projects to the anterior insula, in which limbic and sensory information is used for other cognitive processes [The observation that response was associated with decreased recruitment of the left dlPFC during reappraisal was contrary to our hypothesis and previous meta-analytical finding that prefrontal cortex activation is increased following treatment [We note several limitations in this study. First, the sample size available in our analysis was modest and further study is required with larger samples. Although we commenced with 37 PTSD participants, a significant number would not participate in a second scanning session, and future studies need to initially oversample in recruitment to ensure adequate sample size is maintained at the subsequent scanning session. Second, although we included a comparison healthy control group, our design lacked a wait-listed PTSD group that did not receive TF-psychotherapy. Even with our control group we did not observe differences in change in neural measures with treatment in PTSD. This could possibly be due to the limited sample size available. We conducted exploratory analyses after splitting PTSD responders and non-responders relative to controls at each time and observe differences in hippocampal and posterior insula activation at pre and post-treatment (supplementary section: Supplementary Figs. SIn summary, this study demonstrates differential associations between affective and non-affective neural processing with level of remission of PTSD symptoms after TF-psychotherapy. This pattern of findings converges with the goals of TF-psychotherapy that enhances more effective and efficient mastery of affective states, which converges with extinction and cognitive models of PTSD that emotional processing as a central change mechanism of successful treatment. | PMC9998447 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41398-023-02375-9. | PMC9998447 |
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Acknowledgements | Anxiety | This research was supported by a NHMRC Program Grant (1073041) and a NHMRC Centre for Clinical Research Excellence in Anxiety (1023043). | PMC9998447 |
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Author contributions | MSK, THW | RAB conceptualized the study. MSK and THW performed data analysis. MSK, THW, and RAB wrote the first draft of the manuscript. MSK, KLF, LMW, and RAB contributed to data collection and data management. RAB, KLF, GSM, and LMW contributed to funding acquisition. All authors contributed to interpreting the results and revising the manuscript. | PMC9998447 |
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Competing interests | The authors declare no competing interests. | PMC9998447 |
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References | PMC9998447 |
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Introduction | CLI | CRITICAL LIMB ISCHEMIA | With the advent of newer techniques and growing evidence, endovascular intervention is a frontline treatment strategy for treating below-the-knee (BTK) lesions with critical limb ischemia (CLI) [ | PMC10642822 |
Methods | angioplasty | This randomized clinical trial was conducted in 18 well-experienced tertiary endovascular intervention centers in South Korea to compare the efficacy of SENS implantation to balloon angioplasty alone for BTK lesions following successful balloon angioplasty (SENS-BTK trial). The study was conducted in accordance with the ethical guidelines of the 2004 Declaration of Helsinki. Institutional Review Board (IRB) of a Korea University Guro Hospital (KUGH) approved all of the consenting procedures. All patients or their legal guardians were given a thorough written and verbal explanation of the study procedure before obtaining written consent for the participation in this study. The authors of this manuscript have certified that the information contained herein is true and correct as reflected in the records of the IRB (#KUGH MD120008). Angiographic images and data management were analyzed by the Cardiovascular Intervention Research Institution, a core laboratory independent of the sponsor (Abbott Vascular, Redwood City, Santa Clara, California, USA). | PMC10642822 |
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Patient selection and study design | stenotic lesions, peripheral arterial disease, CLI, ischemic rest pain, gangrene | PERIPHERAL ARTERIAL DISEASE, LIMB ISCHEMIA, ULCERS, GANGRENE, COAGULOPATHY | This trial compared the clinical outcomes of primary stenting and POBA for the treatment of patients with CLI and BTK lesions. Between December 2012 and September 2016, patients with CLI and BTK lesions were enrolled in this prospective, multicenter, randomized trial. Patients were eligible if they had peripheral arterial disease with ischemic rest pain, wounds, such as ulcers or gangrene, that manifested as BTK lesions. More than half of included patients had wounds with a Rutherford classification (RC) of 4–6. If the wound site was related to a vascular origin according to the angiosome concept, patients were included regardless of the RC of their wound. Patients with acute limb ischemia, those with a life expectancy < 1 year, systemic coagulopathy, or intolerance to antiplatelet agents were excluded. Angiographic eligibility criteria included the presence of de novo stenotic lesions involving 50% of the lumen or occlusion of BTK arteries, and patients meeting these criteria were considered acceptable for endovascular therapy (2.0–4.5 mm in diameter, lesion length < 80 mm owing to the stent length). | PMC10642822 |
Randomization | Eligibility was assessed, and informed consent was obtained by the physicians. Randomization was performed in a 1:1 ratio using a computer-generated randomization sequence so that all patients enrolled in this study were randomized to undergo either SENS implantation (stenting group) or POBA alone (POBA group). For a fair comparison, patients who achieved satisfactory results with balloon angioplasty were randomly assigned to either the POBA group or the stenting group. The POBA group ended the procedure after randomization and the stenting group received SENS implantation. To compare groups in which the lesions had a homogeneous character, only a single target lesion < 80 mm in length in each leg of each patient was selected and treated with an individual stent or POBA alone. Between December 2012 and September 2016, 119 patients were included in this study. In total, 61 patients were randomly assigned to undergo POBA alone, and 58 patients were randomly assigned to undergo SENS implantation ( | PMC10642822 |
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Flow chart. | PMC10642822 |
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Intervention and antiplatelet regimen | restenosis | RESTENOSIS | All patients were administered loading doses of clopidogrel (300–600 mg) and aspirin (200–300 mg) before the procedure. After sheath insertion at the arterial access site, a bolus dose of unfractionated heparin (70–100 units/kg) was administered. All patients received aspirin (100 mg daily) and clopidogrel (75 mg daily) as a dual antiplatelet (DAPT) maintenance regimen for at least 1 month. Cilostazol (100 mg bid or 200 mg dp daily) was prescribed based on the physician’s discretion as a triple antiplatelet on top of clopidogrel-based DAPT. Some physicians used cilostazol-based DAPT 3–6 months after the index procedure to reduce restenosis.PTA was performed using the standard technique. After successfully crossing the target lesion with a 0.014-inch guidewire, either intraluminally or subintimally, prolonged balloon dilatation with an adequately sized balloon (1–1.1:1 balloon-to-artery ratio) was performed for 2–3 min. Some patients were recanalized via the retrograde or transcollateral approach following unsuccessful reentry into the distal true lumen using an antegrade approach. To minimize crossover from PTA to stent implantation, prolonged balloon dilatation was performed in patients with unsatisfactory results for balloon dilatation. Once the POBA results were acceptable and the procedure was completed, randomization was performed to leave it alone or with additional stenting. In the stenting group, Xpert (Abbott Vascular, Abbott Park, IL, USA) SENSs were used for routine primary stenting. | PMC10642822 |
Study endpoints | stroke, Death, CLI | MYOCARDIAL INFARCTION (MI), RECURRENCE, STROKE, CARDIAC DEATH, SECONDARY | The main study end-point was the target extremity amputation rate of the patient groups at 1 year. Imaging follow-up was intended to be an additional study endpoint. However, patient characteristics and limitations of insurance coverage in South Korea with CLI made routine follow-up with imaging studies difficult. In addition, limb salvage is considered the most important target of revascularization in patients with CLI. Hence, to assess more clinically relevant information, target extremity amputation was set as the primary endpoint, revascularization including TLR at 1 year, was set as the secondary endpoint.Death, including cardiac death, myocardial infarction (MI), stroke, and wound recurrence were also assessed during follow-up. Follow-up visits were planned at 1, 6, and 12 months after the index procedure; clinical examinations, laboratory investigations, and imaging studies were performed according to the physician’s advice. One year after the index procedure, follow-up data were collected via face-to-face interviews at the outpatient clinic, review of medical records, and/or telephone conversations with the patients. | PMC10642822 |
Statistical analyses | SECONDARY | Data for all endpoints were evaluated using intention-to-treat analysis. All data are expressed as mean ± standard deviation. The unpaired Student’s t-test and Mann–Whitney rank test were used to compare continuous variables. Categorical variables were compared using the chi-squared and Fisher’s exact tests. The Kaplan-Meier method with a log-rank test was used to compare the cumulative incidence of primary and secondary endpoints. A p value < 0.05 was considered statistically significant. All statistical analyses were performed using the SPSS software (version 20.0, SPSS Inc., Chicago, IL, USA). | PMC10642822 |
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Results | PMC10642822 |
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Baseline clinical and angiographic characteristics of patients, limbs, and lesions | The baseline clinical and laboratory characteristics are presented in | PMC10642822 |
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Baseline clinical and laboratory characteristics. | TIA | TIA, TRANSIENT ISCHEMIC ATTACK | POBA, plain old balloon angioplasty; TIA, transient ischemic attack; HbA1c, hemoglobin A1c; HDL, high density lipoprotein; LDL, low density lipoprotein; hs-CRP, high sensitivity c-reactive protein; RAS, renin-angiotensin system. | PMC10642822 |
Baseline clinical characteristics of the patients’ limbs. | POBA, plain old balloon angioplasty; TcPO2, transcutaneous oxygen pressure. | PMC10642822 |
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Baseline angiographic and clinical characteristics of the patients’ lesions and limbs during procedures. | POBA, plain old balloon angioplasty; PTA, percutaneous transluminal angioplasty; BTK, below-the-knee. | PMC10642822 |
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One-year clinical outcomes | A clinical investigation was performed on all patients at the 1-year follow-up visit. The 1-year clinical outcomes are presented in | PMC10642822 |
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The cumulative incidence of target extremity amputation and revascularization up to 1-year by Kaplan-Meier analysis. | PMC10642822 |
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One-year clinical outcomes. | angioplasty | MYOCARDIAL INFARCTION | POBA, plain old balloon angioplasty; MI, myocardial infarction; TLR, target lesion revascularization; TVR, target vessel revascularization. | PMC10642822 |
Discussion | CLI, iliac artery, amputation, femoral artery lesions, claudication, arterial disease, restenosis, ulcer, diabetes | RECURRENCE, EVENT, ARTERIAL DISEASE, RESTENOSIS, ULCER, DIABETES | The main findings of this study were as follows. In patients with CLI with a BTK lesion undergoing an intervention, (1) clinical outcomes, including amputation and cardiovascular event rates, were similar between the primary stenting and POBA groups; (2) amputation and revascularization rates were relatively low in both groups; and (3) reasonable results could be derived only from short-term clinical follow-up, and imaging follow-up was not compulsory.With the rapid improvement in device technology along with increasing operator experience, interventional treatment is a well-accepted procedure in patients with a BTK lesion and CLI [The most critical limitations of previous studies on patients with CLI were the format of the study and the heterogeneous strategies, including primary and bail-out stenting in patients undergoing stenting with BTK lesions [CLI with a BTK lesion is usually an extensive and multilevel arterial disease that results in adverse clinical outcomes [In this study, the primary stenting (0.0%) and POBA (1.6%) groups showed a low major amputation rate. Even with the use of advanced techniques, the development of an interventional method alone is insufficient to explain the significantly low limb recovery rates demonstrated in both groups. The development of wounds and CLI are related to diabetes [This study also elucidated the importance of setting an appropriate endpoint for the treatment of BTK lesions with CLI. In the coronary era, clinical practices have shifted toward minimizing the use of routine imaging tests and focusing on clinical symptoms, and this has resulted in good patient outcomes [This study had some limitations. First, it addressed only BMS and POBA alone. However, there are several newer devices, such as drug-coated balloons, DES, and polymer-free stents, and a study comparing these devices should be conducted. Second, the relatively small sample size and short duration of the study period did not provide strong evidence of the actual clinical efficacy and safety of the procedures. Third, although this was a multicenter study and the general goal of CLI treatment was early-phase ulcer healing, large-scale and long-term clinical investigations are required. Fourth, this study was designed to focus on a “patient-centric” concept; hence, follow-up imaging modalities, such as computed tomography angiography and conventional angiography, were not routinely performed. These investigations were only performed in the event of wound recurrence or at the physician’s discretion, regardless of ischemic symptoms. Even if restenosis occurred, follow-up imaging tests may not have been performed if the wound did not recur or patients did not complain of definite claudication during the follow-up period after the index procedure. Thus, the actual restenosis rate may not have been reflected. Finally, due to the characteristics of the lesions in the patients with CLI, there were patients with iliac artery or femoral artery lesions [ | PMC10642822 |
Conclusions | CLI | ADVERSE EVENTS | In this prospective randomized multicenter study, during the 1-year follow-up, primary stenting with SENS and POBA alone demonstrated a significantly low rate of clinical adverse events in treating patients with CLI and BTK lesions. These results indicate that POBA may be an acceptable option in treating CLI with BTK lesions avoiding stent implantation. Also, based on the non-inferior results of the stenting group, SENS implantation could remain the preferred treatment option in special circumstances such as persistent recoil and flow-limiting dissection despite prolonged balloon dilatation in the treatment of CLI with BTK lesions. Long-term follow-up studies with larger study populations and routine imaging follow-up tests are necessary to elucidate the final conclusions. | PMC10642822 |
Supporting information | PMC10642822 |
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Reporting checklist for randomised trial. | (DOCX)Click here for additional data file. | PMC10642822 |
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SENS-BTK prospective clinical study protocol. | (DOC)Click here for additional data file.The authors are grateful for the contributions of all the investigators. | PMC10642822 |
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References | PMC10642822 |
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Background | toxicity, ESCC | OESOPHAGEAL SQUAMOUS CELL CARCINOMA | Two cycles of neoadjuvant PD-1 blockade plus chemotherapy induced favorable pathological response and tolerant toxicity in patients with locally advanced esophageal squamous cell carcinoma (ESCC). However, approximately 25% of patients relapsed within 1 year after surgery, indicating that a short course of treatment may not be sufficient. Therefore, exploring the effects of intensive treatment is needed for optimal clinical outcomes. | PMC10290378 |
Methods | ESCC | Locally advanced ESCC patients were administered three cycles of camrelizumab plus nab-paclitaxel and capecitabine, followed by thoracoscopic esophagectomy. The primary endpoint was pathologic response. Secondary endpoints included safety, feasibility, radiologic response, survival outcomes, and immunologic/genomic correlates of efficacy. | PMC10290378 |
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Results | Forty-seven patients were enrolled in the study. Forty-two patients received surgery, and R0 resection was achieved in all cases. The complete and major pathological response rates were 33.3% and 64.3%, respectively, and the objective response rate was 80.0%. Three cycles of treatment significantly improved T down-staging compared to two cycles ( | PMC10290378 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12967-023-04273-6. | PMC10290378 |
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Keywords | PMC10290378 |
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Background | death, toxicity, cancer, ESCC, Esophageal cancer | ESOPHAGEAL CANCER, MALIGNANT TUMOR, CANCER | Esophageal cancer (EC) is the seventh most common malignant tumor and the sixth leading cause of cancer-related mortality worldwide [Neoadjuvant therapy could increase the rate of R0 resection and improve survival compared with surgery alone [As a newcomer to cancer treatment, programmed cell death 1 (PD-1) blockade-based immunotherapy exploits a strategy based on immune evasion mechanisms to restore antitumor immunity. Camrelizumab is a humanized high-affinity IgG4-kappa anti-PD-1 monoclonal antibody that has demonstrated efficacy and safety in patients with advanced ESCC [To date, a few clinical trials have reported that neoadjuvant immunochemotherapy of PD-(L)1 blockade induced a favorable pathological response and tolerant toxicity in patients with locally advanced ESCC [In our previous retrospective study [ | PMC10290378 |
Methods | PMC10290378 |
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Participants | ESCC | PRIMARY TUMORS, LYMPH NODE METASTASES, SECONDARY, ONCOLOGY, METASTASES | In this single-center, single-arm, phase II trial, camrelizumab was combined with chemotherapy followed by surgery for locally advanced ESCC. Inclusion criteria were (1) stage II or III locally advanced resectable ESCC diagnosed before enrollment (2) no distant organ metastases or cervical lymph node metastases prior to enrollment (3) no secondary primary tumors (4) an Eastern Cooperative Oncology Group (ECOG) performance status score 0 or 1 (5) no prior exposure to anticancer therapy, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. | PMC10290378 |
Procedure | Tumors, tumor, death, cardia | TUMOR, RECURRENCE, DISEASE, TUMORS, REGRESSION | Participants were administered three cycles of chemotherapy and PD-1 blockade. For each cycle of treatment, patients were intravenously administered a flat dose of camrelizumab (200 mg) along with a single dose of nab-paclitaxel (260 mg/mIn approximately four to six weeks after the last course of neoadjuvant therapy, a thoracoscopy esophagectomy was performed with cervical esophagogastric anastomosis and total dissection of two-field lymph nodes (LNs). The removal of lymph nodes included recurrent laryngeal nerve nodes, subcarinal nodes, paraesophageal nodes, pulmonary ligament nodes, cardia nodes, left gastric artery nodes, and lesser curvature nodes. Surgical sections were stained with hematoxylin and eosin (H&E), and pathological regression was assessed by two independent pathologists. Complete pathological response (pCR) was defined as the absence of residual invasion disease. Tumors with ≤ 10% residual viable tumor cells were considered as obtaining an MPR.After surgery, follow-up was conducted every 3 months in the first year, every 6 months for the second and third years, and every 12 months thereafter. Overall survival (OS) was defined as the time between the surgery and the end of follow-up or death. Disease-free survival (DFS) was calculated from the surgery date to the end of follow-up or the date of the first recurrence. | PMC10290378 |
Outcome | SECONDARY | The primary endpoint of the study was pCR. The secondary endpoints included safety, feasibility, MPR, radiologic response, DFS, and OS. | PMC10290378 |
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Exploratory analysis | tumor, PD-L1-positive tumor | CPS, TUMOR | Pretreatment tumor biopsy was obtained using EUS for biomarker analysis, including programmed cell death-ligand 1 (PD-L1) expression, tumor mutational burden (TMB), and tumor immune microenvironment (TIME). PD-L1 expression was assessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies). The combined positive score (CPS) was used to define PD-L1 expression, which was determined by dividing the number of PD-L1-positive tumor and immune cells by the total number of viable tumor cells and multiplying by 100. Next-generation sequencing (NGS) was performed using whole-exome sequencing or a 733-gene panel (3D Medicines Inc.). As defined, the TMB was the number of somatic single nucleotide variations (SNVs) and insertions/deletions (indels) per megabase of coding genome sequenced. Synonymous and non-synonymous mutations, stop gains/losses, and splicing variants were all considered SNVs. Indels included both frameshift and non-frameshift insertions and deletions. Non-coding alterations were excluded from the calculation of TMB. TIME was evaluated using multiplex immunofluorescence (mIF) staining. The quantities of CD8 | PMC10290378 |
Statistical analyses | This study applied superiority designs with the primary endpoint of pCR. According to previous studies, the pCR rate of chemotherapy is hypothesized to be 15% [ | PMC10290378 |
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Results | PMC10290378 |
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Treatment exposure | myocarditis | MYOCARDITIS | Of the 47 patients, 45 (95.7%) received three cycles of immunotherapy combined with chemotherapy, and two patients (4.3%) discontinued treatment after the second cycle for immune-related myocarditis (n = 1) and informed consent withdrawal (n = 1). Forty-two patients (89.4%) completed surgery as planned. The reasons for not undergoing surgery included patient refusal (n = 4) and immune-related myocarditis (n = 1). | PMC10290378 |
Safety | Cancer | ADVERSE EVENTS, ADVERSE EVENT, CANCER | Neoadjuvant camrelizumab plus nab-paclitaxel and capecitabine did not cause any previously unreported TRAEs (Table Summary of treatment-related adverse eventsAll adverse events were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 | PMC10290378 |
Surgery | death, anastomotic leakage, intraoperative bleeding, chylothorax | ADVERSE EVENTS, CHYLOTHORAX, INTRAOPERATIVE BLEEDING | Among 42 patients who underwent surgery, the mean time from the last dose of neoadjuvant therapy to surgery was 4.3 ± 1.0 weeks. R0 resection was completed in all cases, which took 255.3 ± 8.69 min on average. The intraoperative bleeding volume was 145.4 ± 52.8 ml. The mean number of lymph node dissections was 47.7 ± 2.9, and positive lymph nodes were observed in 11 (26.2%) patients. Eight (19.0%) and 1 (2.4%) patients experienced anastomotic leakage and chylothorax, respectively. The median ICU stay was one day (range, 1–7), and the median postoperative hospital stay was 15 days (range, 9–95). No postoperative immune-related adverse events or death occurred within 90 days after surgery (Additional file | PMC10290378 |
Radiography and pathological responses | PD, tumor, SD, fibrosis | TUMOR, PRIMARY TUMOR, RESIDUAL TUMOR, DISEASE, FIBROSIS, REGRESSION, INFILTRATED | After three cycles of neoadjuvant treatment, three patients achieved complete response (CR), 33 had a partial response (PR), and nine had stable disease (SD), according to RECIST 1.1. No patients developed progressive disease (PD). The objective response rate (ORR) was 80.0% (95% confidence interval [CI], 65.4–90.4%) (Fig. Clinical and pathological responses to neoadjuvant camrelizumab combined with chemotherapy. Among the 42 patients who underwent surgery, postoperative pathological results showed median tumor regression of 90% (range, 10–100%). A total of 27 (64.3%; 95% CI, 48–78.4%) patients had an MPR in the primary tumor. pCR was achieved in 14 (33.3%; 95% CI 19.6–49.5%) cases, of whom 13 (92.2%) had no residual tumor in either primary tissue or lymph node (Fig. Clinical response to neoadjuvant immunochemotherapy. Surgical tissues obtained from pCR or MPR patients were infiltrated by a large number of neutrophils and macrophages, fibrosis, and cholesterol clefts. Besides, we also observed classical TLSs, which have been reported to be associated with a favorable prognosis after immunotherapy [ | PMC10290378 |
Efficacy and safety of two and three cycles of neoadjuvant treatment | CT and safety assessments were conducted before the initiation of treatment and after the second and third courses of neoadjuvant immunochemotherapy to compare the efficacy and safety of two and three treatment cycles. Of the 45 patients who had received three cycles of neoadjuvant treatment, two and three courses of treatment led to CR in 2.2% (1/45) versus 6.7% (3/45) ( | PMC10290378 |
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Survival | MAY | The median follow-up was 24.3 months (range, 6.1–34.3 months) (database cutoff: May 12, 2023). The 1-year DFS and OS rates of the patients who received surgery were both 97.6%, and the 2-year DFS and OS rates were 92.3% and 97.6%, respectively. (Fig. Survival of the patients who received surgery. | PMC10290378 |
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Biomarker analyses | tumor | CPS, TUMOR, TUMOR STROMAL, SOLID TUMORS | PD-L1 expression in pretreatment biopsies was measured in 34 patients. Four of 11 pCR and four of 23 non-pCR patients had a CPS of ≥ 1. No significant difference in PD-L1 expression was found between the pCR and non-pCR cases (TMB is a biomarker for immunotherapy efficacy in multiple solid tumors. A total of 30 cases had adequate pretreatment specimens for NGS. We observed an average of 4.136 ± 1.431 mutations per patient. The most frequent driver mutations were Annotated tissue specimens collected from 40 patients before neoadjuvant treatment and during surgery were subjected to multiplex immunofluorescence to get a glimpse of their TIME. Depending on sample quality, the TIME of tumor center and tumor stromal area in the pretreatment was analyzed in 35 and 40 patients, respectively. The densities of CD8 | PMC10290378 |
Discussion | toxicity, cancers, ESCC, tumor | METASTASIS, CANCERS, RECURRENCE, TUMOR | In this phase II trial conducted in 47 patients with locally advanced ESCC, the pCR and MPR were 33.3% and 64.3%, respectively, and the ORR was 80.0%. Forty-two patients received surgery, and R0 resection was achieved in 100% of patients having undergone surgery. Three treatment cycles elicited a significantly higher rate of T down-staging than two (84.4% vs. 62.2%) without a significant increase in TRAEs. The most common TRAEs were grade 1–2, and no surgical delay was reported. With a median follow-up of 24.3 months, the 1-year DFS and OS rates were both 97.6%, and the 2-year DFS and OS rates were 92.3% and 97.6%, respectively. The density of CD56Neoadjuvant therapy is recommended in many cancers to achieve tumor downstaging and improve the curative rate. However, different cycles of neoadjuvant treatment could influence the prognosis and the quality of perioperative life. In a randomized phase II study [The toxicity of intensive cycles of camrelizumab plus chemotherapy was tolerated. Most of the TRAEs were grade 1–2, which was similar to previous data of two treatment cycles [For surgery completion, R0 resection was achieved in 100% of patients who underwent surgery, which was consistent with that of other two-cycle regimens (96.3–100%) [In this study, the pCR rate was 33.3%, similar to the results from other immunochemotherapy trials of ESCC. Taking an intensive-cycle regimen does not seem to impact the pCR (data from two-cycle immunochemotherapy studies: 25–35.3%) [Furthermore, our study found that 2.4% (1/42) of patients developed local recurrence and 4.8% (2/42) experienced distant metastasis at a median follow-up time of 24.3 months after surgery, which were numerically lower than the respective rates of 20% (4/20) and 10% (2/20) observed in patients who received two cycles of neoadjuvant PD-1 blockade plus chemotherapy at a median follow-up time of 13.5 months [The pathological response was significantly predictive of prognosis [Molecular genetic analyses demonstrated multiple genetic abnormalities in ESCC. Our study found some specific driver mutations, including To summarize, intensive cycles of neoadjuvant chemotherapy combined with camrelizumab demonstrated favorable efficacy and acceptable toxicity, particularly an encouraging 1-year DFS and OS. The abundance of CD56 | PMC10290378 |
Acknowledgements | The authors would like to acknowledge all patients participating in the study. We would also like to thank 3D Medicines, Inc. for conducting NGS and mIF analysis. | PMC10290378 |
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Author contributions | TB, MH | GY: Conceptualization, data curation, formal analysis, investigation, methodology, software, visualization, writing—original draft, writing—review and editing. XS, GL: Conceptualization, Data curation, formal analysis, investigation, methodology, software, visualization, writing—review and editing. ZW: Investigation, methodology, writing—review and editing. PC: Conceptualization, investigation, methodology, writing—review and editing. YZ: Data curation, formal analysis, investigation, methodology, software, visualization, writing—review and editing. TB: Visualization, writing—original draft, writing—review and editing. MH: Investigation, methodology, writing—review and editing. YB, HH, MC, JZ, YH, QG: Investigation, methodology. JX: Conceptualization, investigation, methodology. XZ: Conceptualization, funding acquisition, investigation, methodology, Project administration, resources, supervision, writing—original draft, writing—review and editing. | PMC10290378 |
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