Trial Cohort Research Articles

Racial and gender disparities in traumatic brain injury clinical trial enrollment

OBJECTIVE Despite the increasing number of women and racial/ethnic minorities sustaining traumatic brain injuries (TBIs), they are underrepresented in TBI clinical trials. This study aimed to evaluate gender and racial diversity in enrolled cohorts of TBI clinical trials to identify trends and predictors of increased disparity over time. METHODS The authors reviewed TBI clinical trials with reported results registered on the website ClinicalTrials.gov between 2008 and 2022. The studies were assessed for the proportion of women and racial/ethnic minorities enrolled as well as their reporting of race- and gender-specific characteristics such as gender ratio (GR) and Racial Diversity Index (RDI). Further study parameters, including year and duration, phase, trial design, type of funding, and trial completion, were also included. RESULTS One hundred thirty-five clinical trials met inclusion criteria, of which 65 and 134 reported race and gender, respectively. Twenty-five trials were found to have existing racial disparity (RDI < 1). Comparatively, industry-funded trials had a 26% greater likelihood of racial disparities (p = 0.026), whereas federally funded trials were 30% less likely to demonstrate racial disparities (p = 0.031). Sixty-six trials had gender disparities (GR < 0.4) present, with federally funded trials showing 37.1% greater rates of gender disparity (p < 0.001, adjusted OR 5.47, 95% CI 2.26–14.25). The impact of funding source on race and gender remained significant despite adjusting for other covariates in the multivariate analyses. Racial disparity was negatively correlated with trial completion rate (p < 0.001). Disparities were not found to improve over the 14-year time span. CONCLUSIONS Racial and gender disparities in TBI clinical trial enrollment persist, and the lack of diversity may lead to biased evidence-based medicine. Efforts should be made to increase the representation of women and racial/ethnic minorities in TBI clinical trials to ensure equitable access to effective treatments for all populations.

Reflecting real-world patients with mesothelioma in research: an interim report of baseline characteristics from the ASSESS-meso cohort.

Mesothelioma varies in clinical phenotype and survival. Clinical trials are unavoidably affected by selection bias, reducing generalisability. ASSESS-meso is a UK, multicentre, prospective, mesothelioma cohort study (ISRCTN61861764). This pre-specified interim analysis, conducted when recruitment reached 25% of target, summarised participant characteristics and evaluated external validity through comparison with real-world and clinical trial cohorts. The study took place at 14 hospitals across the UK. People diagnosed with mesothelioma, at any anatomical site, were eligible. Clinical, radiological and biochemical data were collected at enrolment. In this interim report, the external validity of the cohort was investigated through comparison of baseline demographic data with populations included in the 2020 UK National Mesothelioma Audit (real-world cohort), and CHECKMATE-743 and MAPS trials (clinical trial cohorts). 244 patients were enrolled between 7 April 2017 and 1 March 2022. The cohort was predominantly male (195 out of 244; 80%) with a median age of 74 years. Pleural disease and epithelioid subtypes were most prevalent. ASSESS-meso participants were more similar to the real-world population with regard to age, performance status, disease site and stage than the clinical trial population. ASSESS-meso participants were more likely to be formally staged and less likely to have undifferentiated histology compared with the real-world cohort, possibly reflecting high rates of discussion of ASSESS-meso participants at regional mesothelioma multidisciplinary team meetings. As expected, poorer performance status, non-epithelioid histology and neutrophil-lymphocyte ratio were associated with shorter survival in the adjusted analysis. ASSESS-meso is representative of the UK mesothelioma population. Future outputs from the cohort will help characterise different mesothelioma phenotypes with high external validity.

Comprehensive analyses of immune tumor microenvironment in papillary renal cell carcinoma

BackgroundPapillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC, and associated with poor outcomes in the metastatic setting. In this study, we aimed to comprehensively evaluate the...

Overall Survival After Treatment Failure Among Patients With Rectal Cancer

Oncologic outcomes among patients with rectal cancer after developing local recurrence and/or distant metastases remain poorly studied. To analyze the trend of overall survival after treatment failure for patients with rectal cancer within three consecutive phase 2 or 3 trials of the German Rectal Cancer Study Group. This cohort study is a post hoc analysis of 3 randomized phase 2 or 3 trials (CAO/ARO/AIO-94, -04, and -12 trials, conducted in Germany) that included 1948 patients with locally advanced rectal adenocarcinoma. The CAO/ARO/AIO-94 trial recruited patients between February 1995 and September 2002, the CAO/ARO/AIO-04 trial recruited patients between July 2006 and February 2010, and the CAO/ARO/AIO-12 trial recruited patients between June 2015 and January 2018. Statistical analysis was conducted between September 2022 and March 2023. A total of 119 of 391 patients in the CAO/ARO/AIO-94 trial group A, 295 of 1236 patients in the CAO/ARO/AIO-04 trial, and 69 of 306 in the CAO/ARO/AIO-12 trial experienced treatment failure (R2 resection or local recurrence or distant metastases) and were included in further analyses. Characteristics of treatment failure and overall survival were assessed in all 3 trial cohorts. Of the 1948 patients treated in the 3 trials, 15 were excluded because of missing data. Of the remaining 1933 patients (median age, 62.5 years [range, 19-84 years]; 1363 men [71%] and 570 women [29%]) with locally advanced rectal adenocarcinoma (cT3 or 4 or cN+) treated within 3 consecutive clinical trials, 483 experienced treatment failure and were analyzed. After a median follow-up of 36 months (IQR, 24-51 months) for all patients, overall survival after treatment failure was significantly improved in the CAO/ARO/AIO-04 trial (at 3 years, 44% [IQR, 37%-51%]; hazard ratio [HR], 0.61 [95% CI, 0.47-0.79]) and further improved in the CAO/ARO/AIO-12 trial (at 3 years, 73% [IQR, 60%-87%]; HR, 0.32 [95% CI, 0.18-0.54]) compared with the CAO/ARO/AIO-94 trial (at 3 years, 30% [IQR, 22%-39%]) (both P < .001). Distant metastasis was the main reason for treatment failure throughout a 5-year follow-up (range, 67%-87%), and the relative risk for treatment failure was highest in the first 18 months in all 3 trials. ypTNM stage was significantly associated with the risk and time interval to treatment failure. Improvement in overall survival after treatment failure was independent of sex. This cohort study suggests that advancements in salvage strategies during the past decades have likely improved overall survival among patients with rectal cancer who experienced treatment failure.

An intronic genetic variant of ZHX2 predicts response to pegylated interferon α therapy in HBeAg-positive chronic hepatitis B patients

ZHX2 plays a crucial role in host immunity and modulates hepatitis B virus (HBV) replication. However, its correlation with immunomodulator-related treatment, i.g., pegylated interferon α(PegIFNα), for HBV remains uncertain. To explore the link between single nucleotide polymorphisms (SNPs) in ZHX2 and response to PegIFNα therapy for chronic hepatitis B (CHB) patients, we conducted a retrospective study in 945 hepatitis B e antigen (HBeAg)-positive CHB patients with at least 48 weeks of PegIFNα treatment and 24 weeks of follow-up from two phase-IV, multicenter trials (Cohort 1, n = 238; Cohort 2, n = 707). Thirty-eight tag SNPs were selected across the whole ZHX2 gene region. A polygenic score (PGS) was constructed by integrating multiple SNPs. The associations of ZHX2 SNPs and PGS with treatment response were assessed in both cohorts and their combination. Among the 38 tag SNPs, ZHX2_rs17289471 (T>C) was significantly associated with combined response (CR, i.e., HBeAg seroconversion and HBV DNA level <3.3log10IU/mL) at week 72 in both cohorts. The CR rate at week 72 increased steadily from rs17289471 TT to CT and CC genotype carriers in both Cohort 1 (P = 0.002) and Cohort 2 (P = 0.025) as well as Cohort 1 + 2 (P = 3.50 × 10−4). Moreover, a PGS integrating ZHX2_rs17289471 and five other previously identified SNPs was further significantly associated with CR rate at week 72 in Cohort 1 (P = 2.38 × 10−6), Cohort 2 (P = 1.04 × 10−7) and Cohort 1 + 2 (P = 9.37 × 10−13). Overall, ZHX2_rs17289471 and PGS have the potential to predict response to PegIFNα treatment of HBeAg-positive CHB patients.

Short-term outcomes associated with the use of a new powered circular stapler for rectal reconstructions: a retrospective study comparing it to manual circular staplers using inverse probability of treatment weight analysis

BackgroundThe most common postoperative complication in malignant rectal surgery is anastomotic leakage (AL). AL after anterior or low anterior resection in rectal tumors is a fatal postoperative complication. Recently, the first automated suture circular stapler, which is expected to reduce the incidence of AL, (J&J).Materials and methodsThis study included a total of 248 rectal tumor patients who underwent double stapler technique (DST) anastomotic procedures in the department of gastroenterological surgery /pediatric surgery at Gifu University School of Medicine from January 2017 to December 2021. The experience of a single institution utilizing the The Echelon circular™ stapler (ECP stapler:Manual VS Automatic) in rectal surgery cases was evaluated retrospectively from maintained database.ResultOne hundred thirty-nine patients (58.4%) were performed by manual circular stapling, 99 patients (41.6%) by powerd circular stapling. Diverting stoma was performed in 45 cases (32.4%) by manual circular stapling, 42 patients (42.4%) by powerd circular stapling Postoperative complications were occurred clavien-dindo grade II or higher in 57 cases (23.9%) and grade III or higher in 20 cases (8.4%). Anastomotic leakage occurred in 14 patients (5.9%) within all grades. After IPTW, the variables of patient characteristics was SMD ≤ 0.2 (Table.3), and there was a significant difference in anastomotic leakage (Odds Ratio (OR), 0.57; 95% Confidence Interval(CI), 0.34–0.98 and there was a significant difference in anastomotic leakage (Odds Ratio (OR), 0.58; 95% Confidence Interval(CI), 0.34–0.98; p = 0.044). In addition, there was no significant difference in postoperative complications in grade II or higher (OR, 0.88; 95%CI, 0.65–1.18; p = 0.394) and grade III or higher (OR, 0.45; 95%CI, 0.28–0.73; p = 0.001) were significantly remarkable lower in powered circular stapling group.ConclusionIn this IPTW comparison of patients undergoing rectal reconstructions, the ECP trial cohort had lower risks of several surgical complications AL and statistically signifcant lower rates of ileus/bowel obstruction, infection, and bleeding as Clavien-Dindo ≥ grade II and III as compared with for whom manual circular staplers were used.

Gender Disparities in Nephrology Trials: A Meta-Analysis of Enrollment Trends between 2000 and 2021.

Gender disparities in the incidence and complications of kidney diseases are well described. However, analysis to elucidate gender disparities in enrollment in nephrology randomized clinical trials (RCTs) has not been performed. We performed a systematic review and meta-analysis of high impact nephrology RCTs published between 2000-2021. We. included RCTs enrolling participants age ≥18 in the following categories: 1) chronic kidney disease (CKD); 2) acute kidney injury (AKI); 3) glomerulonephritis (GN); 4) maintenance dialysis; and 5) kidney transplantation. We summarized trial characteristics according to reporting and enrollment of participants, enrollment site, publication year, trial category, and intervention type. Outcomes of interest include the proportion of enrolled male and female participants overall and according to trial category. Additionally, we compared enrollment trends in the United States and globally to estimates of kidney disease prevalence. The majority of qualifying trials (373/380, 98%) reported the distribution of male and female participants. Enrollment was imbalanced overall with male participants accounting for 62% (n=215,850) of the enrolled participants and female participants for just 38% (n=133,082). Male participants formed the majority of trial cohorts in AKI (65%), CKD (62%), Dialysis (55%) and transplant trials (65%), whereas women were majority enrollees in glomerulonephritis trials (61%). CKD trials under-represented women in both US trials and worldwide. Women are under-represented in high impact nephrology trials with the exception of GN trials. This imbalance may contribute to disparities in outcomes and gaps in the care of women with kidney disease.

Evaluating ethnically diverse patients' perspectives of considering participation in renal clinical research.

Clinical trial cohorts do not often reflect target patient populations because minority ethnic groups are underrepresented in clinical trials. To increase minority ethnic groups' opportunities to participate in clinical trials, by evaluating ethnically diverse patients' perspectives of considering participation in renal clinical research. The authors gave patients participating in at least one research study the opportunity to take part in a structured survey. The survey explored preferences, barriers and opportunities that patients considered when deciding whether to take part in a clinical trial. The authors included participants from multiple ethnic groups so they could compare data for different ethnicities. Participation was a positive experience for most patients, mostly because of the research team's flexibility and professionalism. Researchers' gender and ethnicity did not affect the participants' decision to participate. Cultural preferences were not obvious from the data as 80% of the participants were white. Patients preferred a face-to-face approach and the expertise of the research team affected participation more than any other characteristics did. However, respondents were already research-engaged and conducting a similar study with those who have declined to participate in research may show different results.

Predictive Factors Associated with Delayed Graft Function Following Renal Transplantation: A Retrospective Cohort Study

Kidney transplantation has become a routine procedure for end-stage renal disease. Although improvement in short term graft patency has been achieved, delayed graft function (DGF) is one of the important complications following kidney transplantation. DGF results from ischemia-reperfusion injury and involves a multitude of contributing elements including donor characteristics and etiology of the end-stage renal disease. The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are easily applicable methods for evaluation of systemic inflammation. We hypothesized that these parameters could refine the detection of the patients with DGF in post- renal transplantation and guide management. To test our hypothesis, we investigated whether the NLR, PLR, and creatinine reduction ratio CRR could serve as prognostic indicators for identifying patient cohorts at an elevated risk of negative treatment outcomes following renal transplantation. We also assessed demographic and clinical factors as an independent predictor to detect negative early graft function outcomes in patients after renal transplantation. This single center retrospective cohort trial comprising 55 patients who received a kidney graft from deceased or living donors was performed in Northern Cyprus Ministry of Health’s Dr. Burhan Nalbantoglu State Hospital, over a 6 year period. The demographic and clinical variables included age, gender, body mass index, the etiology of end-stage renal disease, kidney graft from living or deceased donors, NLR, PLR and CRR. DGF was defined as GFR&lt;60 on the 21th day following renal transplantation. Of the patients included in this study, 26 (47.3%) and 29 (52.7%) received deceased and living donor kidney transplantation, respectively. On the 21st day following transplantation, 27 patients (49%) had an eGFR&lt;60, whereas 28 patients (51%) had an GFR≥60. None of the patients had undergone dialysis within the first week after transplantation. There were no significant differences in demographic and clinical characteristics between the patients with eGFR 60 and eGFR 60. In logistic regression analysis, none of the predictors including etiology of the end-stage renal disease, source of donor, or demographic baseline characteristic were associated with DGF. We suggest that the NLR and PLR parameters are not associated with the presence of DGF after renal transplantation. Keywords: Renal transplantation, Delayed graft function, Renal failure, Glomerular filtration rate, End-stage renal disease.

Ultra-low-dose CT vs. chest X-ray in non-traumatic emergency department patients – a prospective randomised crossover cohort trial

Ultra-low-dose CT (ULDCT) examinations of the chest at only twice the radiation dose of a chest X-ray (CXR) now offer a valuable imaging alternative to CXR. This trial prospectively compares ULDCT and CXR for the detection rate of diagnoses and their clinical relevance in a low-prevalence cohort of non-traumatic emergency department patients. In this prospective crossover cohort trial, 294 non-traumatic emergency department patients with a clinically indicated CXR were included between May 2nd and November 26th of 2019 (www.clinicaltrials.gov: NCT03922516). All participants received both CXR and ULDCT, and were randomized into two arms with inverse reporting order. The detection rate of CXR was calculated from 'arm CXR' (n=147; CXR first), and of ULDCT from 'arm ULDCT' (n=147; ULDCT first). Additional information reported by the second exam in each arm was documented. From all available clinical and imaging data, expert radiologists and emergency physicians built a compound reference standard, including radiologically undetectable diagnoses, and assigned each finding to one of five clinical relevance categories for the respective patient. Detection rates for main diagnoses by CXR and ULDCT (mean effective dose: 0.22mSv) were 9.1% (CI [5.2, 15.5]; 11/121) and 20.1% (CI [14.2, 27.7]; 27/134; P=0.016), respectively. As an additional imaging modality, ULDCT added 9.1% (CI [5.2, 15.5]; 11/121) of main diagnoses to prior CXRs, whereas CXRs did not add a single main diagnosis (0/134; P<0.001). Notably, ULDCT also offered higher detection rates than CXR for all other clinical relevance categories, including findings clinically irrelevant for the respective emergency department visit with 78.5% (CI [74.0, 82.5]; 278/354) vs. 16.2% (CI [12.7, 20.3]; 58/359) as a primary modality and 68.2% (CI [63.3, 72.8]; 245/359) vs. 2.5% (CI [1.3, 4.7]; 9/354) as an additional imaging modality. In non-traumatic emergency department patients, ULDCT of the chest offered more than twice the detection rate for main diagnoses compared to CXR. The Department of Biomedical Imaging and Image-guided Therapy of Medical University of Vienna received funding from Siemens Healthineers (Erlangen, Germany) to employ two research assistants for one year.

Dehydroepiandrosterone sulfate to cortisol ratio as a prognostic factor in cirrhotic patients with spontaneous bacterial peritonitis

BackgroundChronic liver disease and decompensated cirrhosis are associated with serious complications; spontaneous bacterial peritonitis is considered one of them that may lead to sepsis and adrenal insufficiency. This trial aimed to study the role of dehydroepiandrosterone sulfate (DHEAS) and DHEAS/cortisol ratio for assessing cirrhotic patients’ adrenal function and as a possible prognostic factor in cirrhotic cases with spontaneous bacterial peritonitis (SBP).Patients and methodsIt was a prospective cohort trial carried out on 100 patients in the Internal Medicine Department, Tanta University Hospital, from June 2021 to July 2022 divided into 2 studied patient groups: group I, 50 cases with liver cirrhosis and sterile ascites; and group II, 50 cases with liver cirrhosis and SBP. Adrenal function was evaluated using serum cortisol levels (9 A.M, 9 P.M, and post synacthen stimulation test), DHEAS level, and DHEAS/cortisol ratio.ResultsThe cirrhotic patients with SBP have significantly decreased DHEAS, decreased DHEAS/cortisol ratio, and high cortisol level post stimulation compared with patients with sterile ascites, cirrhotic cases with decreased DHEAS/cortisol ratio (< 0.65) had elevated C-reactive protein (CRP) levels, a higher model for end-stage liver disease (MELD) score and Child–Pugh score had higher hospital mortality. Both DHEAS and the DHEAS/cortisol ratio were significant predictors of hospital mortality (area under the receiver operating characteristic curve 0.267 and 0.298, respectively). The cirrhotic patients with SBP had decreased DHEAS and DHEAS/cortisol ratio but higher hospital mortality, compared to the cirrhotic patients with sterile ascites.ConclusionsIt was found that a significant increase in cortisol level was after synacthen stimulation, decreased DHEAS, and low DHEAS to cortisol ratio in the cirrhotic patients with spontaneous bacterial peritonitis and was associated with high mortality compared to cirrhotic patients without spontaneous bacterial peritonitis.

Comparative effectiveness between mosunetuzumab monotherapy clinical trial and real-world data in relapsed/refractory follicular lymphoma in third or subsequent lines of systemic therapy

A comparison of clinical outcomes in the third or subsequent line (3 L+) of systemic therapy between a real-world data (RWD) external control cohort and a mosunetuzumab single-arm clinical trial cohort is presented. Data for 3 L + patients with relapsed/refractory follicular lymphoma (FL) were obtained from the mosunetuzumab single-arm trial (n = 90) and a US electronic health records database (n = 158), with patients meeting key eligibility criteria from the trial, balanced on pre-specified prognostic factors. Overall response and complete response rates were 80% and 60% in the mosunetuzumab cohort and 75% and 33% in the RWD cohort, odds ratios of 1.23 (95% CI, 0.52–2.93) and 3.18 (95% CI, 1.41–7.17), respectively. Hazard ratios for progression-free survival and overall survival were 0.82 (95% CI, 0.53–1.27) and 0.43 (95% CI, 0.19–0.94). These findings support a clinically meaningful benefit of mosunetuzumab monotherapy as a chemotherapy-free option for the 3 L + FL population.

Rewind for Posttraumatic Stress Disorder: A Randomised Controlled Trial

Background. The Rewind Technique (Rewind) is a psychological therapy for people with posttraumatic stress disorder (PTSD), which is already used regularly in the National Health Service (NHS), the third sector and private practice across the UK. This study set out to explore the potential efficacy and feasibility of remotely delivered Rewind for the treatment of PTSD. Methods. This study was a two-armed, exploratory RCT to assess the preliminary efficacy, adherence, feasibility, and factors affecting outcome of Rewind versus a waitlist control group. Results. The entire trial was delivered remotely using video calls for treatment sessions and outcome assessments. A total of 40 participants were randomised with 80% retention at the primary endpoint of 8-week postrandomisation. The difference in Clinician-Administered PTSD Scale for DSM-5 scores between the immediate and delayed Rewind arms was 12.64 (95% CI, 2.29 to 22.99, F = 6.38 , df = 1 , p = 0.02 ) at 8 weeks. The Cohen’s d was 1.05 indicating a large effect size at 8 weeks with maintenance in symptom improvement at 16 weeks. Conclusion. Rewind, delivered remotely, demonstrated a large effect size in treating symptoms of PTSD within this trial cohort. This trial demonstrates a preliminary signal of efficacy supporting the clinical use of Rewind in the treatment of people with PTSD.

Presence of the partner in the operating room during a category 1 cesarean section: a prospective explorative study

BackgroundLittle information exists regarding attitudes related to the presence of the partner in the operation room (OR) during category 1 emergency cesarean section (cat. 1 CS). We investigated how cat. 1 CS under general anesthesia is experienced, both by partners present in the OR and those not. MethodsAn explorative prospective cohort trial, with qualitative elements, involving all cat. 1 CS in 2022 in two hospitals. At site 1 the partner was present in the OR during cat. 1 CS, whereas at site 2 the partner was not. Parents and staff answered questionnaires following each cat. 1 CS and semi-structured interviews with partners were held three months after surgery. Qualitative data were analyzed using content analysis. The primary outcome was the partner’s answer to the question: “Would you have preferred not being present/being present in the OR?” respectively. ResultsSeventeen and eight cat. 1 CS occurred at each site respectively. All parents agreed to participate. No partners in site 1 would have preferred to wait outside, and all evaluated the experience very positively. Partners at site 2 also evaluated not being present positively. Overarching themes from the qualitative analysis were “Being the family witness” and “Experience of being the partner”. Mothers and staff from site 1 were very positive about their partners’ presence. ConclusionPartners present in the OR during cat. 1 CS under general anesthesia evaluated this very positively. Most partners, who had not been present in the OR, also evaluated this positively. No partners had post-traumatic stress.

Effect of the addition of a mental health specialist for evaluation of undiagnosed patients in centres for rare diseases (ZSE-DUO): a prospective, controlled trial with a two-phase cohort design

People with complex symptomatology but unclear diagnosis presenting to a centre for rare diseases (CRD) may present with mental (co-)morbidity. We hypothesised that combining an expert in somatic medicine with a mental health specialist working in tandem will improve the diagnostic outcome. Patients aged 12 years and older who presented to one of the 11 participating German CRDs with an unknown diagnosis were recruited into this prospective cohort trial with a two-phase cohort design. From October 1, 2018 to September 30, 2019, participants were allocated to standard care (SC, N=684), and from October 1, 2019 to January 31, 2021 to innovative care (IC, N=695). The cohorts consisted mainly of adult participants with only a minority of children included (N=67). IC included the involvement of a mental health specialist in all aspects of care (e.g., assessing medical records, clinic visits, telehealth care, and case conferences). Clinicaltrials.gov identifier: NCT03563677. The proportion of patients with diagnoses established within 12 months after the first visit to the CRD explaining the entire symptomatology (primary outcome) was 19% (N=131 of 672) in the SC and 42% (N=286 of 686) in the IC cohort (OR adjusted for centre effects 3.45 [95% CrI: 1.99-5.65]). The difference was mainly due to a higher prevalence of mental disorders and non-rare somatic diseases in the IC cohort. The median time to explaining diagnoses was one month shorter with IC (95% CrI: 1-2), and significantly more patients could be referred to local regular care in the IC (27.5%; N=181 of 659) compared to the SC (12.3%; N=81 of 658) cohort (OR adjusted for centre effects 2.70 [95% CrI: 2.02-3.60]). At 12-month follow-up, patient satisfaction with care was significantly higher in the IC compared to the SC cohort, while quality of life was not different between cohorts. Our findings suggested that including a mental health specialist in the entire evaluation process of CRDs for undiagnosed adolescents and adults should become an integral part of the assessment of individuals with a suspected rare disease. The study was funded by the Global Innovation Fund from the Joint Federal Committee in Germany (Innovationsfonds des Gemeinsamen Bundesausschusses), grant number 01NVF17031.

Foley catheter for induction of labor after cesarean section

Induction of labor may be necessary in around twenty-five to thirty percent of a woman's subsequent pregnancies when she has already given birth through cesarean section. During our research, the objective had been to ascertain the rate of spontaneous vaginal birth, rate of cesarean section, and rate of complications that followed the induction of labor with transcervical foley catheter in females who had previously had 1 cesarean section. This retrospective cohort trial was performed in the largest city in Palestine at a tertiary teaching hospital. In subsequent pregnancy, pregnant cases with a history of a prior CS delivery (n = 306) underwent labor induction at term with a Foley catheter. Women who underwent labor induction with transcervical foley catheter at Al-Ahli Hospital in Hebron, Palestine. From April 2017 until March 2020. Our research revealed that 46.7 percent of women had spontaneous vaginal births, 14.4 percent had assisted vaginal births, and one woman experienced uterine rupture. The frequency of postpartum hemorrhage is 30 percent, the most prevalent complication. 10 percent and 5 percent of mothers experienced intrapartum and postpartum infections, correspondingly. 5% of newborns had a confirmed infection, and there was one perinatal fatality related to uterine rupture.

171P Combined expression of MKI67, FOXC1 and PDL1 is a pan-tumor tissue-agnostic predictor of PD1/PDL1 inhibitor efficacy in metastatic renal cell cancer: Validation in checkmate 009, 010 and 025 clinical trial cohorts

171P Combined expression of MKI67, FOXC1 and PDL1 is a pan-tumor tissue-agnostic predictor of PD1/PDL1 inhibitor efficacy in metastatic renal cell cancer: Validation in checkmate 009, 010 and 025 clinical trial cohorts

Validation of a Genomic Classifier in the NRG Oncology/RTOG 0521 Phase III Trial of Docetaxel with Androgen Suppression and Radiotherapy for Localized High-Risk Prostate Cancer

Decipher is a prognostic genomic classifier (GC) validated in several prospective NRG Oncology Phase III trials. Herein, we validate the GC in pre-treatment biopsy samples for risk stratification in a cohort of high-risk men treated with definitive radiotherapy and androgen suppression with or without docetaxel chemotherapy. As per a pre-specified and approved NCI analysis plan (Navigator #1061), we obtained available formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled on the NRG/RTOG 0521 randomized phase III trial. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays (Veracyte, San Diego, CA) and GC scores were obtained. Pre-specified categorical GC scores, adjusted for archival tissue analysis, were used to define higher (>0.46) and lower (≤0.46) risk groups. The primary objective was to validate the independent prognostic ability of GC for metastasis-free survival (MFS) with Cox multivariable analyses (MVA). Samples were obtained from 283 consented, evaluable patients with tissue (50% of trial) yielding 183 (65%) GC scores that passed quality metrics, 91 from control and 92 from the interventional arm. Median age was 66 years, median PSA was 19.3 ng/uL (IQR: 8.1-41.4), 81% had clinical stage ≥T2 and 80% had Gleason score ≥8 (47% ≥9). Median GC score was 0.55 (IQR: 0.38-0.78) and overall the arms were balanced for key covariates. With a median follow-up of 9.9 years (IQR: 9.3, 10.7), 67 MFS events including 34 distant metastases (DM) were observed. On MVA, only the GC (per 0.1 unit) was independently associated with MFS (HR 1.12, 95% CI 1.01-1.25) as well as DM (sHR 1.22, 95% CI 1.06-1.41), whereas the 4 pre-defined trial risk groups used for stratification (based on Gleason score, T-stage and PSA), randomization and patient age were not. For categorical GC, on MVA, higher-risk GC patients (65%) had worse DM (sHR 2.82, 95% CI 1.1-7.3) compared to those with lower GC. Cumulative incidence of DM at 10-years was 27% for higher GC vs 9% (95% CI 7-18%) for lower GC. No biomarker-by-treatment interaction with GC and the addition of docetaxel was detected. In pre-treatment biopsy samples from a randomized Phase 3 trial cohort, GC demonstrated its ability to further risk stratify clinically high-risk men demonstrating an independent association of GC score with DM and MFS. High-risk prostate cancer is a heterogeneous disease state and GC can improve risk stratification to help personalize shared decision-making. NRG-GU009/PREDICT-RT (NCT04513717) aims to determine the optimal therapy based on GC score for high-risk prostate cancer.

TROG 15.03/ANZUP International Multicenter Phase II Trial of Focal Ablative STereotactic RAdiotherapy for Cancers of the Kidney (FASTRACK II)

Stereotactic body radiotherapy (SBRT) is an emerging non-invasive alternative for primary renal cell cancer (RCC) in patients unsuitable for surgery. The objective of the FASTRACK II clinical trial was to investigate the efficacy of SBRT for primary RCC. This non-randomized, intergroup multi-institutional phase II study was activated in 7 Australian centers and 1 Dutch center, through the Trans Tasman Radiation Oncology Group (TROG) and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). Eligible patients had biopsy confirmed diagnosis of primary RCC with a single lesion within a kidney, ECOG performance ≤2 and were medically inoperable, high risk or declined surgery. For tumors ≤4 cm a single fraction of 26 Gy was prescribed, for tumors > 4 cm, 42 Gy in three fractions was prescribed. The primary outcome of the study was to estimate the efficacy of SBRT for primary RCC, defined as local control based on RECIST criteria. The study was powered assuming that 1-year local control would be 90%, with the null hypothesis of ≤80% considered undesirable and not worthy of proceeding to a future randomized controlled trial. Between July 2016 and February 2020, 70 patients were enrolled with a median follow-up of 42 months. Median age was 77 years. Forty-nine patients were male (70%), median BMI was 32 and median Charlson comorbidity score was 7. The median [IQR] RENAL complexity score was 8 [7-10]. Biopsy confirmation was 100%. Twenty-three patients (33%) had T1a disease. The median (interquartile range [IQR]) tumor size was 4.6cm [3.7-5.5]; it was 3.3cm [3.0-3.6] in those receiving single fraction (n = 23), and 5.3cm [4.6-6.0] in those receiving 3-fraction SBRT (n = 47). During real-time pre-treatment quality assurance review, 10 cases (14.3%) required resubmission for protocol deviation, 2119 variables were assessed at final review, and final protocol compliance was 99.3%. Seven (10%) patients experienced grade 3 treatment-related adverse events, with no grade 4 or 5 events observed. Eleven (16%) patients reported no adverse events. Local control was 100% throughout the lifetime of the trial (p<0.001). Cancer-specific survival was also 100% throughout the lifetime of the trial. Freedom from distant failure (95% CIs) at 1 and 3 years was 99% (90-100%). Overall survival (95% CIs) at 1 and 3 years was 99% (90-100%) and 82% (70-89%), respectively. Baseline mean eGFR (95% CI) was 61.1 mLs/min (56.6; 65.6) and reduced by -10.8 mLs/min (-13.0; -8.6) by 1-year, by -14.6 mLs/min (-17.0; -12.2) by 2-years and plateaued thereafter. In the first multicenter prospective trial of a non-surgical primary RCC cohort, enrolling mostly T1b+ disease, SBRT was an effective treatment strategy with no observed local failures. We observed an acceptable side effect profile and renal function after SBRT. These outcomes support the design of a future randomized clinical trial of SBRT versus surgery for primary RCC. The trial was registered with ID: NCT02613819.

Modeling Acute Chemoradiotherapy (CRT) Diarrhea Severity Using Automatically Contoured Small Bowel

Acute severe diarrhea is a common toxicity in rectal cancer patients receiving CRT. A better understanding of the radiation tolerance of the small bowel is needed especially for novel radiation drug combinations. We investigate the dose impact by providing auto-contoured small bowel, using data from the ARISTOTLE phase III trial ISRCTN: 09351447. A subset of participants (n = 93/564) with locally advanced rectal cancer in the ARISTOTLE trial testing the addition of concurrent irinotecan (n = 48) to neoadjuvant capecitabine (n = 45) CRT (45/25 Gy/fx), in an MRI defined high risk of loco-regional failure. CRT was delivered with conformal techniques. Diarrhea was measured using CTCAE v4.0 weekly. We applied an AI-based auto-contouring model to segment the small bowel on planning CT. The small-bowel DVH parameters were combined with the treatment arm, age, sex and MRI-defined tumor stage in a linear regression (LR) model to predict acute diarrhea severity. Explainable Shapley values (conditional marginalized expectation of a machine learning model per feature) were used to quantify the independent and normalized impact of radiation dose vs Irinotecan on the likelihood of severe diarrhea. The auto-contouring model accuracy was consistent with clinical practice (mean dice coefficient = 0.739) and clinically acceptable when reviewed by clinicians. The treatment arm, MRI-defined T stage and small-bowel mean dose were found to be independently correlated to the diarrhea severity (p<0.001). V30Gy showed the strongest correlation to diarrhea severity in all the DVH parameters. The LR using the three variables yielded mean AUC scores of 0.898 (95% CI: [0.831,0.958]) on predicting Grade 2 and higher diarrhea, and 0.774 (95% CI: [0.678,0.869]) on predicting Grade 3 diarrhea based on 10-fold cross-validation. Shapley values showed that V30Gy>30.56 cm3 increases the likelihood of more severe diarrhea against the average (grade = 1.03) in the cohort. The impact of irradiation will be larger than the usage of Irinotecan within the patients with V30Gy >160.93 cm3. We accurately modelled acute diarrhea (AUC = 0.90) for rectal cancer patients receiving CRT using AI-contoured small-bowel structures. The treatment arm and small-bowel dose were independently correlated to the diarrhea severity. The explainable model allowed us to quantify the impact of radiation dose, usage of irinotecan, and its combination, with a threshold of V30Gy = 160.93 cm3 yielding an equivalent impact. We will be extending the analysis to the whole trial cohort to improve the statistical power.