Current Standard Research Articles

P615 Clinical efficacy of accelerated 4-weekly vs. Conventional 8-weekly ustekinumab dosing in Inflammatory Bowel Disease: A single centre experience

Abstract Background 8-weekly dosing regimen of ustekinumab in the treatment of moderate-to-severe Inflammatory Bowel Disease (IBD) is the current standard of care. Accelerated 4-weekly dosing has been suggested to be efficacious, however not licensed, in ‘non-responders’. The aim of this study is to determine how 4-weekly accelerated dosing regimen in ustekinumab drug levels correlate with response to treatment in patients with IBD. Methods Patients for inclusion were identified retrospectively utilising online prescription records at Mercy University Hospital, Cork. Inclusion criteria consisted of IBD patients commenced on ustekinumab with a treatment duration of at least 6 months. Participants were separated into 4-weekly and 8-weekly treatment groups. Faecal calprotectin (FCP) levels/ustekinumab drug levels were recorded from the 12-week check in post initiation and at the 2nd assessment. Symptoms were scored at these visits and further quantified using the Harvey Bradshaw index for Crohn’s Disease and the partial mayo score for Ulcerative Colitis. Results 101 patients at the Mercy University Hospital Cork were identified utilising a database of prescriptions and physical charts (4-weekly: 27; 8-weekly: 74). A statistically significant decrease in FCP levels at 2nd assessment was noted in patients with 4-weekly dosing (p=0.028). There was no statistically significant relationship between dosing interval and symptoms (p=0.735). Individual patient factors including age, gender, type of IBD, and concurrent IBD medications did not have a statistically significant effect on faecal calprotectin levels or symptoms. Conclusion The greater percentage decrease in faecal calprotectin provides objective evidence supporting the escalated dosing interval at the Mercy University Hospital IBD centre. However, further study is necessary to justify increasing the dosing interval for all patients treated with ustekinumab for IBD.

Preserving vascular integrity during totally robotic sigmoidectomy: unleashing the power of vessel-sparing precision.

This study assesses the feasibility, safety, and clinical utility of vessel-sparing approach in totally robotic sigmoidectomy for adenocarcinoma. A comprehensive protocol for completely vessel-sparing robotic sigmoidectomy (VsRS) was established at the authors' institution from January 2019 through December 2020. Surgical and pathological outcomes were indagated and compared with results of current literature. The study population consisted of 34 patients. The median number of examined lymph nodes (ELN) was 21 (range 15-28); the median number of positive lymph nodes (PLN) was 0 (range 0-8). Mean operative time was 240 min (sd 43.56, range 180-360 min), and conversion to open rate was 0%. Anastomotic leak rate was 0%. The median follow-up period was 28 months CONCLUSION: This pilot series represents a significant step forward in the development of completely vessel-sparing sigmoidectomy for adenocarcinoma. The study demonstrates the safety and feasibility of this innovative approach, which aims to achieve oncological radicality while preserving vital vascular structures. Notably, the postoperative outcomes observed in this study were comparable to those reported in the existing literature for the current standard of care at high-volume centers. Nevertheless, further validation through prospective and controlled investigations is essential before this technique can be fully incorporated into clinical practice.

P433 Short-term outcomes of surgical treatment in primary ileocecal Crohn’s disease patients. Results of Crohn’s(urg) study, multicenter, retrospective, comparative analysis between indications for luminal and complicated phenotype

Abstract Background Recent evidence challenges the current standard of offering surgery to patients with ileocecal Crohn’s disease only when they present complications of the disease. Methods A retrospective, multicenter comparative analysis was performed including patients operated for primary ileocecal CD at 12 referral centers. Patients were divided in 2 groups, according to indication of surgery for inflammatory (ICD) or complicated (CCD) phenotype. Short-term results were compared. Patients operated on for primary isolated ileocaecal CD (last 50 cm of the terminal ileum and cecum), either for predominantly inflammatory phenotype or for complications of the disease (stricturing or fistulizing pattern), between January 2012 - December 2021 were considered eligible to participate in this study. Patients with previous abdominal procedures for CD, and patients who had activity of the disease in other intestinal segments other than the ileocaecal region at the time of surgery, were excluded from the study. Results 2013 patients were included, 291 (14.5%) in the ICD group. No differences were found between groups in time from diagnosis to surgery or in the levels of exposure to biologic drugs before indication of surgery. CCD patients had higher rates of low BMI, anemia (40.9 vs. 27%, p: < 0.001), and low albumin (11.3 vs. 2.6%, p: < 0.001). CCD patients had longer operations, lower rates of laparoscopic approach (84.3 vs. 93.1%, p: 0.001), and higher conversion rates (9.3 vs. 1.9%, p: < 0.001). CCD had longer hospital stay and higher postoperative complication rates (26.1 vs. 21.3%, p: 0.083). Anastomotic leakage and reoperations were also more frequent in this group. More patients in the CCD group required an extended bowel resection (14.1 vs. 8.3%, p: 0.017). In multivariate analysis, CCD was associated with prolonged surgeries (OR: 3.44, p: 0.001) and requirements of multiple intraoperative procedures (OR: 8.39, p: 0.030). Conclusion Indication of surgery in patients who present an inflammatory phenotype of CD was associated with better outcomes when compared to patients operated on for complications of the disease, without a difference between groups in time from diagnosis to surgery.

PARP Inhibitors in Prostate Cancer – Understanding the Current Landscape

Poly (ADP [adenosine diphosphate]-ribose) polymerase inhibitors (PARPi) are a current standard of care treatment option for patients with metastatic castration resistant prostate cancer (mCRPC), defined as prostate cancers that continue to progress despite treatment with the usual first-line androgen-deprivation therapies. PARPi’s function by targeting faulty homologous recombination repair pathways that result in cytotoxic double strand DNA break (DSB) accumulation in prostate cancer cells. While the efficacy of PARPi’s as a monotherapy option in mCRCP has been demonstrated clinically, the added utility of PARPi’s in combination with other anti-cancer agents is still being explored. This article will review the scientific rationale behind PARP-inhibitors, discuss the germline and somatic mutation testing critical to identifying predictive biomarkers for PARPi efficacy, and present the currently approved PARPi combination therapies and their indications. This review will also examine the incidence and management of PARPi toxicity, summarize ongoing trials, and propose areas of future study.

LASSO regression shows histidine and sphingosine 1 phosphate are linked to both sepsis mortality and endothelial damage

Sepsis is a major cause of death worldwide, with a mortality rate that has remained stubbornly high. The current gold standard of risk stratifying sepsis patients provides limited mechanistic insight for therapeutic targeting. An improved ability to predict sepsis mortality and to understand the risk factors would allow better treatment targeting. Sepsis causes metabolic dysregulation in patients; therefore, metabolomics offers a promising tool to study sepsis. It is also known that that in sepsis endothelial cells affecting their function regarding blood clotting and vascular permeability. We integrated metabolomics data from patients admitted to an intensive care unit for sepsis, with commonly collected clinical features of their cases and two measures of endothelial function relevant to blood vessel function, platelet endothelial cell adhesion molecule and soluble thrombomodulin concentrations in plasma. We used least absolute shrinkage and selection operator penalized regression, and pathway enrichment analysis to identify features most able to predict 30-day survival. The features important to sepsis survival include carnitines, and amino acids. Endothelial proteins in plasma also predict 30-day mortality and the levels of these proteins also correlate with a somewhat overlapping set of metabolites. Overall metabolic dysregulation, particularly in endothelial cells, may be a contributory factor to sepsis response. By exploring sepsis metabolomics data in conjunction with clinical features and endothelial proteins we have gained a better understanding of sepsis risk factors.

Pancreatic biopsy evaluation with nsCanary: A “smart ROSE” device for feedback on sample adequacy and cancer presence in endoscopic biopsies—Initial human clinical trial results.

618 Background: Pancreatic cancer (PC) accounts for 0.5 million new cases and 4.7% of the world's cancer-related deaths in 2020. Endoscopic ultrasound (EUS) guided fine needle biopsies (FNB) are the current standard of care for confirming suspicious lesions, however the diagnostic accuracy is reported below 70%. Rapid on-site evaluation (ROSE) improves the diagnostic performances of biopsies to reduce the number of needle passes, complication rates, and the need for additional procedures. However, availability of an on-site pathologist is often not feasible. NovaScan has pioneered the use of an impedance spectroscopy biomarker for cancer detection in different tissues based on the Cole Relaxation Frequency (CRF). NovaScan has developed the nsCanary, a ”smart ROSE” device that assesses PC presence in FNBs obtained during endoscopic procedures ex vivo, in real-time and on-site, without altering the tissue sample or affecting the workflow. Methods: Data were collected in a double-blind, IRB approved study from a cohort of 53 patients (28 males, 25 females) undergoing EUS procedures for suspected pancreatic lesions at the Texas International Endoscopy Center. FNBs were performed with a 22 gauge biopsy from a transduodenal approach. Each biopsy sample was transferred onto a disposable strainer allowing for any excess fluid to drain. An electrode for scanning was placed onto the core samples for data collection with the nsCanary a low cost, portable device used in the operating room. CRF is measured in the 1 kHz - 10 MHz frequency range via custom-designed hardware and assessment of the sample is completed in a few seconds. Subsequently, the sample is flushed into a pathology jar to undergo the standard workflow for cytology. The algorithm for extracting the CRF from the measurement was developed based on our previous preclinical study with transgenic KPC mice Samples with a CRF below 1 MHz were considered noncancerous, while CRF values above 1MHz or the absence of a CRF reading were considered cancerous. Results: PC assessment provided by nsCanary was validated against pathology outcomes for each biopsy sample. Findings showing a sensitivity of 86.7% and a specificity of 84.2% are reported in the table. Conclusions: We believe the nsCanary device will provide immediate feedback to the endoscopist on cancer presence and on the adequacy of the sample. This device is intended to support the decision-making process, by enabling clinicians to overcome the challenge of proving cancer presence during the first biopsy procedure, ultimately avoiding revisits and unnecessary trauma.[Table: see text]

Evaluating the safety and efficacy of the addition of liver radiation (RT) to atezolizumab and bevacizumab (A/B) in advanced hepatocellular carcinoma (HCC): A retrospective cohort analysis.

481 Background: Recently, the addition of stereotactic body RT to sorafenib in patients (pts) with advanced HCC demonstrated improved overall survival. However, A/B is the current standard of care for pts with advanced HCC based on IMBrave150. For these pts, RT may potentiate the antitumor immune response of A/B but carries the risk of bowel toxicity and impaired liver function. To date, there are limited data regarding safety and outcomes with the addition of liver RT to A/B in pts with advanced HCC. Here, we describe our single-center experience of adding RT to A/B for pts with advanced HCC. Methods: This single-center retrospective cohort study was conducted at the University of Pennsylvania. We identified all pts with HCC naïve to systemic therapy who received infusions of A/B and those who received RT to the liver within 30 days of starting A/B until discontinuation from 1/1/2020 until 2/2/2023. We assessed the real-world response rate (rwRR) determined from clinician impression after initiating A/B, safety outcomes, overall survival (OS), and time-to-progression (TTP) from initiation of A/B. Time-to-event outcomes were analyzed by the Kaplan-Meier method with log-rank test and Cox proportional hazards modeling. Results: We identified 49 pts (n=34 control, n=15 RT) with advanced HCC receiving first-line A/B. Those who received RT were more likely to have alcoholic liver disease (p=0.013) and were less likely to have ascites (p=0.04) but were otherwise balanced regarding demographics, prior locoregional therapies, presence of macrovascular invasion and extrahepatic spread, and baseline laboratories. The median RT dose was 63 Gy. The rwRR in the RT group was 73.3% (11/15) compared to 17.6% (6/34) in the control group (Risk Ratio (RR) 3.9, 95% CI 1.7-8.6, p<0.001). Two pts in the control group (5.8%) and one patient in the RT group (6.7%) experienced clinically significant bleeding (RR=1.1 95% CI 0.1-11.6). In the RT group, three pts (20%) developed worsening liver dysfunction after completing RT, concerning for possible radiation-induced liver disease. Six pts in the control group and one patient in the RT group developed immune-related adverse events leading to discontinuation of A/B. The median OS in the RT group was 14.4 mos and 10.8 mos in the control group (Hazard Ratio (HR) death 0.49 (95% CI 0.20-1.22, p=0.12)). Median TTP was 6.4 months (mos) with RT compared to 5.8 mos in the control group (HR progression 0.72 (95%CI 0.35-1.46, p=0.36. Conclusions: In our retrospective cohort, the addition of liver RT to standard A/B resulted in increased responses and a non-significant improvement in outcomes without an increased risk of bleeding. An assessment of changes in liver dysfunction by Child-Pugh and ALBI score is ongoing. Overall, these data support prospective trials to evaluate the addition of RT to A/B.

Combining low-dose regorafenib with pembrolizumab for patients with MSI-H colorectal cancer: REGPEM-CRC-01.

TPS238 Background: Treatment for microsatellite instability-high (MSI-H)/mismatch repair deficient (MMR-D) colorectal cancer (CRC) has rapidly evolved in the last decade. The KEYNOTE 177 trial recently established pembrolizumab as a frontline therapy for patients with MSI-H CRC. However, in this study, approximately 40% of patients were noted to have disease progression within 6 months of treatment. Furthermore, an additional 10% of patients experienced acquired resistance to therapy. Therefore, there is an unmet need to improve outcomes for patients with MSI-H CRC. Preclinical studies have shown vascular endothelial growth factor (VEGF) signaling to be overactive in MSI-H compared to MSS CRC (Hansen et al. Colorectal Dis. 2011). Moreover, exploratory analysis of CALBG-80405 and PARADIGM trials showed that patients with MSI-H CRC were more likely to benefit from anti-VEGF therapy than those with MSS disease. Regorafenib, an FDA-approved agent for patients with mCRC, is a potent VEGF inhibitor with immune modulatory effects on the tumor microenvironment. We hypothesize that adding low-dose regorafenib to pembrolizumab as frontline therapy may create synergistic activity in addition to the known clinical activity of each agent in MSI-H CRC. Methods: In the lead-in arm of this prospective study, 22 patients will be enrolled. Patients will receive regorafenib 60 mg daily on days 1–14 (2 weeks on) followed by 7 days off (1 week off) in combination with pembrolizumab 200 mg in the cycle 1. In the following cycles, patients will receive regorafenib 90 mg daily for 2 weeks on 1 week off in combination with pembrolizumab 200 mg every 3 weeks. The primary outcome for the lead-in arm is overall response rate (ORR) within 12 months of treatment by RECIST 1.1. criteria. A formal one-sided hypothesis test will be conducted for futility, assuming that we will reject the null hypothesis of a target ORR only if we have strong evidence. In this study, we assume a null hypothesis that ORR is 0.60, which would reflect significant clinical improvement over the current standard of ORR = 0.43 from KEYNOTE 177. The alternative hypothesis is that ORR is less than 0.60. For the lead-in phase of the study, the emphasis is on controlling Type I error to be small, approximately 0.05. In the randomized phase of the study, patients will receive pembrolizumab monotherapy or pembrolizumab in combination with regorafenib 90 mg. The sample size for the randomized phase of trial was determined based on an assumed median of PFS of 28 months with pembrolizumab and regorafenib combination (investigational arm). The standard of care pembrolizumab monotherapy results in a median PFS of 16 months when given as a first-line therapy. We hypothesize the proposed treatment will increase median PFS to 28 months from 16 months (N=132; H0: 16 months vs., H1: 28 months; Type I error: 0.05, power 80%). Clinical trial information: NCT06006923 .

A multi-centre review of the efficacy of re-challenge with platinum doublet in patients with oesophagogastric cancer treated with first-line trastuzumab and chemotherapy.

367 Background: HER2 amplification or overexpression is seen in 15-20% of metastatic oesophagogastric cancers. The ToGA trial showed an OS benefit for the use trastuzumab with platinum and fluoropyrimidine combination therapy (T-FP) in the first line setting. Second line trials of targeted agents have been disappointing with poor response rates and the current standard of care is paclitaxel and ramucirumab in combination. A recent phase 2 trial showed no OS benefit to continuing trastuzumab with second line chemotherapy but data regarding the efficacy of treatment beyond progression with re-introduction of first line chemotherapy (platinum and fluoropyrimidine) is limited and conflicting. Methods: We conducted a multi-centre retrospective review of patients treated with T-FP in the first-line setting between October 2014 and October 2022 at two large tertiary referral oncology centres in the United Kingdom. Baseline demographic factors and clinical data were collected and compared between responders and non-responders to re-challenge. PFS and OS were estimated using the Kaplan-Meier method. Results: Data was collected for 225 patients in total treated with first-line trastuzumab. We identified 20 patients who had received a re-challenge with FP-T. Best response to first-line treatment was partial response (PR) for 19/20 patients with 1/20 patients with stable disease (SD). There were no differences between baseline demographic factors or tumour pathological features between patients receiving a re-challenge and those treated with chemotherapy alone. The median platinum free interval was 17.8 months. For the re-challenge disease control rate was 75% with an overall response rate of 35% (7 PR, 0 CR). The median number of subsequent trastuzumab cycles was 7, with a median PFS of 6.1 months and median OS of 10 month. Multivariate Cox-regression analysis identified no factors predictive of response in the re-challenge setting. Conclusions: Re-challenge with trastuzumab plus FP chemotherapy is a possible option for patients with relapse. Larger studies will be required to identify predictive biomarkers to identify those patients most likely to benefit. The role of re-assessment of HER2 status at relapse in those receiving re-challenges requires prospective analysis.

MFOLFIRINOX versus mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancer (FROST trial): Study protocol for an open label, multicenter, randomized, phase II study.

TPS230 Background: Patients with high-risk stage III colon cancer have a significantly poorer prognosis than those with stage II or low-risk stage III colon cancer. Despite this distinction, most guidelines recommend similar adjuvant treatment approaches for all stages, and there is a dearth of research focusing on high-risk stage III colon cancer and the potential for improved prognosis through more intensive adjuvant treatment. Given the proven efficacy of triplet chemotherapy in metastatic colorectal cancer, this study aims to assess the effectiveness and toxicity of modified 5-fluoropyrimidine (5-FU)/leucovorin plus irinotecan and oxaliplatin (mFOLFIRINOX) in comparison with the current standard of care—modified oxaliplatin and 5-FU (mFOLFOX-6)—as an adjuvant treatment for patients diagnosed with high-risk stage III colon cancer. Methods: This multicenter, randomized (1:1), open-label, phase II trial aims to compare the adjuvant treatment efficacy of mFOLFIRINOX and mFOLFOX-6 in patients with high-risk stage III colon cancer. The trial aimed to enroll 312 eligible patients aged between 20 and 70 years with an Eastern Cooperative Oncology Group performance status of 0-2, or between 70 and 75 years with an Eastern Cooperative Oncology Group performance status of 0. All patients underwent radical resection and were randomized into two arms: Arm A experimental arm, received 12 cycles of mFOLFIRINOX every 2 weeks, while arm B, the reference arm, received 12 cycles of mFOLFOX 6 every 2 weeks. The primary endpoint of this study was the 3-year disease-free survival, whereas the secondary endpoints included assessing the 3-year overall survival and treatment toxicity. Discussion: The Frost trial is expected to elucidate the safety and oncologic efficacy of mFOLFIRINOX compared to mFOLFOX 6 as adjuvant treatment for high-risk stage III colon cancers, and provide evidence about this treatment, and contribute to improve the prognoses ultimately. Clinical trial information: NCT05179889 .

High-resolution transcriptional signature to predict survival benefit in colorectal cancer (CRC) treated with EGFR inhibitors (EGFRi) independent of RAS/BRAF mutation status or tumor sidedness.

203 Background: Cetuximab (CTX) and Panitumumab (PMB) therapies directed at EGFR have been restricted to left-sided CRC harboring wild-type KRAS ( KRASWT), limiting their utility. Approximately 50% of mCRC fail to respond to EGFRi, thus identification of predictive biomarkers is an unmet need. Here we evaluate a CTX sensitivity score (CTX-S) that we previously reported (Yang M. et al., 2019), in a large, real-world population of RAS/BRAF mutant vs wild-type and in right- vs left-sided tumors. Methods: CTX/PMB-treated CRC specimens (n=1124) with clinical outcomes, NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). 1097 specimens were MSS as determined by IHC of MMR proteins and/or NGS. Association of CTX-S with RAS/BRAF mutation and tumor sidedness was performed in MSS tumors. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RASMUT /BRAFMUT, or RASWT /BRAFWT if no mutation was detected for each gene. Samples were stratified based on CTX-S quintiles. Survival on EGFRi was calculated from the initiation of EGFRi to last contact using Kaplan-Meir method. Results: Higher CTX-S quintiles were significantly associated with longer survival on EGFRi in RAS/BRAF wild-type as well as -mutant subpopulations. Similar results were seen in left- vs. right-sided tumors (Table). Higher CTX-S quintiles were associated with a survival benefit in all CMS classes but CMS2; however, the vast majority of CMS2 tumors (460/467) were among the top 3 CTX-S quintiles. As the median survival among the top 3 quintiles was ~2-fold higher than the bottom 2 quintiles, we used stratification by the 40th percentile for the genomic analysis. CTX-S >40th percentile was associated with an increased prevalence in APC (91 vs 47%) and TP53 (93 vs 76%) mutations and decreased prevalence in BRAF (6 vs 32%), SMAD4 (8 vs 19%), RNF43 (1 vs 12%) and ATM (2 vs 5%) mutations (all q<0.05). Conclusions: Our data suggest that CTX-S may predict longer survival on EGFRi, surprisingly independent of RAS/BRAF mutation status as well as tumor sidedness. Patients with high CTX-S had increased prevalence of CMS2 and harbored more APC and TP53 mutations. A strong EGFRi biomarker would likely expand the utility of EGFRi to right-sided tumors and possibly to RASMUT tumors. Further validation of these biomarkers in a prospective clinical trial is warranted and could change our current standard of care for CRC.[Table: see text]

Developing a comprehensive cell-free DNA (cfDNA) epigenetic signature (ep-Sig) with diagnostic and prognostic value in hepatocellular carcinoma (HCC).

553 Background: HCC is one of the deadliest tumors with poor outcomes often diagnosed in late stages. Current surveillance strategies (alfa-fetoprotein (AFP) plus ultrasound (USG)) for high-risk population (HRP) have poor sensitivity (SN) and reasonable specificity (SP) of 61% and 92%, respectively. Triple phase computed tomography (CT) imaging has good sensitivity and specificity (≈ 90% for both) but the evidence does not support its use for routine surveillance. All these modalities do not have prognostic (survival) value. We attempted to develop a non-invasive, cfDNA-based tests to improve the diagnostic value of the current standard of care modalities (AFP and USG) and help in predicting the outcomes at diagnosis. We hypothesized that RNA and gene expression in HCC tissues is a surrogate for epigenome (DNA-methylation changes). Methods: We curated a 21-gene cfDNA ep-Sig from the literature with a proven prognostic value. Evidence suggests epigenetic changes in every gene of this panel affect HCC outcomes influencing clinicopathological characteristics (large tumor size, vascular invasion, advanced staging) or early post-operative recurrence, and survival. We compared RNA and gene expression of the genes in the ep-Sig between normal (NT) and HCC tissues using a web-based tool, TNMplot.com that uses the data from the Gene Expression Omnibus of the National Center for Biotechnology Information (NCBI-GEO) or Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories was used create this tool. It uses Mann-Whitney or Kruskal-Wallis tests to compute statistical significance. Results: RNA expression of all the genes from the ep-Sig was significantly higher in HCC than NT (1.133, p=5.84e-15). Gene expression was 19/21 genes was higher in HCC tissues (1.15, p=1.3e-08). The other 2 genes were not detected in the tested samples. Conclusions: Our ep-Sig which has a proven prognostic value and reliable prevalence in HCC patients. This study is the first step in developing clinically useful blood-based test that can revamp the current diagnostic and screening practices when used alongside AFP and USG.

Diagnostic and Prognostic Potential of Multiparametric Renal MRI in Kidney Transplant Patients.

Multiparametric MRI provides assessment of functional and structural parameters in kidney allografts. It offers a non-invasive alternative to the current reference standard of kidney biopsy. To evaluate the diagnostic and prognostic utility of MRI parameters in the assessment of allograft function in the first 3-months post-transplantation. Prospective. 32 transplant recipients (54 ± 17 years, 20 females), divided into two groups according to estimated glomerular filtration rate (eGFR) at 3-months post-transplantation: inferior graft function (IGF; eGFR<45 mL/min/1.73 m2 , n = 10) and superior graft function (SGF; eGFR ≥ 45 mL/min/1.73 m2 , n = 22). Further categorization was based on the need for hemodialysis (C1) and decrease in s-creatinine (C2) at 1-week post-transplantation: delayed-graft-function (DGF: n = 4 C1, n = 10 C2) and early graft-function (EGF: n = 28 C1, n = 22 C2). 3-T, pseudo-continuous arterial spin labeling, T1-mapping, and diffusion-weighted imaging. Multiparametric MRI was evaluated at 1-week in all patients and 3-months after transplantation in 28 patients. Renal blood flow (RBF), diffusion coefficients (ADC, ΔADC, D, D, D*, flowing fraction f), T1 and T1 were calculated in cortex and medulla. The diagnostic and prognostic value of these parameters, obtained at 3-months and 1-week post-transplantation, respectively, was evaluated in the cortex to discriminate between DGF and EGF, and between SGF and IGF. Logistic regression, receiver-operating-characteristics, area-under-the-curve (AUC), confidence intervals (CIs), analysis-of-variance, t-test, Wilcoxon-Mann-Whitney test, Fisher's exact test, Pearson's correlation. P-value<0.05 was considered significant. DGF patients exhibited significantly lower cortical RBF and f and higher D*. The diagnostic value of MRI for detecting DGF was excellent (AUC = 100%). Significant differences between patients with IGF and SGF were found in RBF, ∆T1 , and ∆D. Multiparametric MRI showed higher diagnostic (AUC = 95.32%; CI: 88%-100%) and prognostic (AUC = 97.47%, CI: 92%-100%) values for detecting IGF than eGFR (AUC = 89.50%, CI: 79%-100%). Multiparametric MRI may show high diagnostic and prognostic value in transplanted patients, yielding better results compared to eGFR measurements. 2 TECHNICAL EFFICACY: Stage 1.

Inhibition of Bromodomain Proteins Enhances Oncolytic HAdVC5 Replication and Efficacy in Pancreatic Ductal Adenocarcinoma (PDAC) Models.

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive type of pancreatic cancer, which rapidly develops resistance to the current standard of care. Several oncolytic Human AdenoViruses (HAdVs) have been reported to re-sensitize drug-resistant cancer cells and in combination with chemotherapeutics attenuate solid tumour growth. Obstacles preventing greater clinical success are rapid hepatic elimination and limited viral replication and spread within the tumour microenvironment. We hypothesised that higher intratumoural levels of the virus could be achieved by altering cellular epigenetic regulation. Here we report on the screening of an enriched epigenetics small molecule library and validation of six compounds that increased viral gene expression and replication. The greatest effects were observed with three epigenetic inhibitors targeting bromodomain (BRD)-containing proteins. Specifically, BRD4 inhibitors enhanced the efficacy of Ad5 wild type, Ad∆∆, and Ad-3∆-A20T in 3-dimensional co-culture models of PDAC and in vivo xenografts. RNAseq analysis demonstrated that the inhibitors increased viral E1A expression, altered expression of cell cycle regulators and inflammatory factors, and attenuated expression levels of tumour cell oncogenes such as c-Myc and Myb. The data suggest that the tumour-selective Ad∆∆ and Ad-3∆-A20T combined with epigenetic inhibitors is a novel strategy for the treatment of PDAC by eliminating both cancer and associated stromal cells to pave the way for immune cell access even after systemic delivery of the virus.

Is trans-laryngeal ultrasound (TLUS) an accurate and acceptable tool in the assessment of inducible laryngeal obstruction? A protocol for the ILOTUS: A cross-sectional, two-stage feasibility study

BACKGROUND: Inducible laryngeal obstruction (ILO) describes an inappropriate narrowing of the larynx during breathing in. ILO can lead to several respiratory symptoms and be misidentified and treated as asthma, with associated patient morbidity and healthcare cost. ILO is also known as vocal cord dysfunction, or paradoxical vocal fold movement. The current reference assessment tool for diagnosing ILO is a video-laryngoscopy. However, timely access to specialist diagnostic laryngoscopy services may be challenging, and laryngoscopy may be poorly tolerated. AIMS: The aim of this cross-sectional, two-stage feasibility study is to determine whether abnormal vocal fold movements associated with ILO can be adequately visualised using trans-laryngeal ultrasound (TLUS) namely, the ILOTUS study: (ILO assessment via trans- laryngeal ultrasound). The second aim is to compare TLUS with a reference standard diagnostic tool to ascertain whether it may serve as a less invasive screening tool to assess ILO. Participants’ opinions about the acceptability of TLUS will also be gathered and compared with responses to a validated symptom score questionnaire. METHODS: In stage one, healthy volunteers (n = 30) will undergo TLUS to assess whether the vocal folds can be visualised,and whether narrowing of the vocal folds can be seen when they mimic ILO. Stage 2 will be conducted with a patient population(n = 30) referred to a tertiary airways service for breathlessness assessment. Participants in stage 2 will undergo the reference standard laryngoscopy as well as simultaneous TLUS. The level of agreement between TLUS and laryngoscopy will be evaluated, as well as comparison of symptom scores. DISCUSSION: This study will help inform future studies of the utility of TLUS in the assessment of ILO. This will be valuable for understanding whether TLUS could be offered as a non-invasive option for patients in the assessment of ILO if they are not able to tolerate or access laryngoscopy diagnostic services. It is not intended that TLUS will replace the current reference standard of video-laryngoscopy but may have potential as an early screening tool if found to be non-inferior.

SPiRIT study protocol (Shoulder Pain: Randomised trial of Injectable Treatments): a randomised feasibility and pilot study of autologous protein solution (APS) vs corticosteroids for treating subacromial shoulder pain

BackgroundThe management of subacromial shoulder pain represents a significant challenge and is typically managed through either physiotherapy, joint injection or surgical intervention. Recent surgical trials have questioned the efficacy and there is a need to improve the evidence base for the non-surgical management of this condition.The study aims to provide evidence of the feasibility of conducting a randomised controlled trial to compare the efficacy of autologous protein solution (APS) against the current standard of care, corticosteroid injection (CSI) for subacromial shoulder pain. Autologous protein solution (APS) is a blood-derived biological injection which has been shown to have anti-inflammatory effects.MethodsA parallel-group two-arm randomised control trial will be conducted, comparing APS and CSI for shoulder pain. Fifty patients will be recruited. Feasibility will be assessed by examination of the conversion rate of eligible participants to the total number of participants recruited, whether it is possible to collect the appropriate outcome measures and the levels of retention/data compliance at follow-up dates.DiscussionCSI is the mainstay of conservative management of subacromial shoulder pain. Trials and systematic reviews have reported differing conclusions, but the consensus view is that any benefits seen from CSI use are most likely to be short-term and there remains a significant number of patients who go on to have surgical intervention despite CSI.Biological injections, such as APS are being increasingly used, in the anticipation they may offer improved longer lasting outcomes for shoulder pain. However, the evidence to demonstrate the comparative efficacy of CSI versus APS does not currently exist. If feasible, a fully powered study will offer clarity to the treatment pathway of thousands of patients each year with subacromial pain.Trial registrationThe study is funded by the National Institute for Health Research–Research for Patient Benefit, NIHR 201473, Trial Registration Number (ISRCTN12536844: SPiRIT. Shoulder pain: randomised trial of injectable treatments–date of Registration 15/9/2021). Protocol Version V1.0_30Jul2021. IRAS Project ID: 294,982.

Neoadjuvant trastuzumab deruxtecan (T-DXd) with response-directed definitive therapy in early stage HER2-positive breast cancer: a phase II study protocol (SHAMROCK study)

BackgroundThe current standard of care in the neoadjuvant setting for high-risk HER2-positive (HER2 +) breast cancer is to combine systemic chemotherapy with dual HER2 blockade, trastuzumab and pertuzumab. Targeted therapies have significantly improved outcomes for patients with HER2-positive breast cancer. To improve treatment-associated toxicity, chemotherapy-sparing approaches are currently being investigated. Trastuzumab deruxtecan (T-DXd) is an HER2-directed antibody–drug-conjugate (ADC) with promising results in the metastatic setting for HER2-positive breast cancer. The SHAMROCK study investigates neoadjuvant T-DXd in early stage HER2-positive breast cancer, using pathological complete response (pCR) rate as the primary endpoint.MethodsThis is a phase II open-label, single arm, adaptive multi-centre trial of T-DXd in the neoadjuvant setting in stage 2–3 HER2-positive breast cancer. Eligible patients will receive 5.4 mg/kg of T-DXd intravenously every 3 weeks for up to 6 cycles. A repeat biopsy will performed after 2 cycles for the RNA disruption index (RDI) score assessment. According to their likelihood of pCR, as determined by the RDI score, patients will either undergo 4 or 6 cycles of T-DXd prior to imaging. Patients with imaging complete response (iCR) after either 4 or 6 cycles will proceed to surgery. Patients who do not achieve iCR will either undergo further systemic therapy or proceed to surgery.DiscussionThe SHAMROCK study is a chemotherapy-sparing approach to curative intent treatment, investigating neoadjuvant T-DXd. We hypothesise that neoadjuvant T-DXd will have a high pCR rate and be associated low toxicity in early stage HER2-positive breast cancer.Trial registrationEudraCT Number: 2022–002485-32; ClinicalTrials.gov identifier: NCT05710666; Cancer Trials Ireland study number: CTRIAL-IE 22–01.

Methodology of the SORENTO clinical trial: a prospective, randomised, active-controlled phase 3 trial assessing the efficacy and safety of high exposure octreotide subcutaneous depot (CAM2029) in patients with GEP-NET

BackgroundThe current standard of care (SoC) for the initial treatment of unresectable or metastatic well-differentiated gastroenteropancreatic neuroendocrine tumours (GEP-NET) requires initiation of first-generation somatostatin receptor ligand (SRL) therapy, octreotide and lanreotide, which provide safe and efficacious tumour/symptom control in most patients. However, disease progression can occur with SoC SRL treatment and the optimal dose response of SRL remains unknown. Octreotide subcutaneous depot (CAM2029) is a novel, long-acting, high-exposure formulation that has shown greater bioavailability and improved administration than octreotide long-acting release (LAR) with a well-tolerated safety profile. Retrospective data have highlighted a potential benefit of high-exposure SRL for improved disease control in patients who did not adequately respond to the current SoC SRL treatment. This trial will investigate the efficacy and tolerability of CAM2029 compared to the current SoC, including octreotide LAR and lanreotide autogel (ATG).MethodsSORENTO is a prospective, multicentre, randomised, active-controlled, open-label phase 3 trial aiming to demonstrate superiority of treatment with 20 mg octreotide subcutaneous depot (CAM2029) every 2 weeks (Q2W) compared to treatment with the Investigator’s choice of SRL therapy at standard doses for tumour control (octreotide LAR 30 mg or lanreotide ATG 120 mg every 4 weeks [Q4W]) as assessed by progression-free survival (PFS) in approximately 300 patients with unresectable/metastatic and well-differentiated GEP-NET. Upon confirmation of disease progression (determined by a Blinded Independent Review Committee [BIRC] and defined as per RECIST 1.1), patients may enter an open-label extension treatment period with once weekly dosing, to investigate the effects of higher frequency dosing. Overall survival follow-up will end a maximum of 2 years after primary analysis. The primary endpoint will be analysed after 194 confirmed PFS events.DiscussionThis is the first trial investigating the efficacy of CAM2029 versus SoC SRL therapy using a head-to-head, superiority trial design. It is expected to be the first trial to investigate the efficacy of increased dosing frequency of a high-exposure SRL. A BIRC will limit bias and measurement variability and ensure high-quality efficacy data. Additionally, inclusion of patients with well-differentiated Grade 3 NET may elucidate treatment strategies for this rarely investigated patient population.Trial registrationClinicalTrials.gov NCT05050942. Registered on 21st September 2021.

Abstract A002: A phase II study of peri-operative modified FOLFIRINOX in localized pancreatic ductal adenocarcinoma (PDAC)

Abstract Introduction: Advances in adjuvant chemotherapy with 5-fluorouracil, irinotecan, and oxaliplatin (FFX) have improved survival for patients (pts) with resectable PDAC yet few are cured by the current standard of care. Neoadjuvant FFX may lead to early control of micrometastasis and enhance cure rates for this aggressive malignancy. Methods: We performed a single-arm phase-2 clinical trial for resectable PDAC evaluating 6 months of perioperative modified (m) FFX (NCT02047474). Patients underwent baseline pancreatic protocol CT and were reviewed for resectability by a multidisciplinary panel. Enrolled pts received 6 cycles of neoadjuvant mFFX followed by surgery and 6 cycles of adjuvant mFFX. The primary endpoint was a ≥ 66% 12-month progression-free survival (PFS). Additional endpoints included overall survival (OS), circulating tumor DNA (ctDNA), tumor molecular features and tumor Keratin 17 levels. Whole blood was prospectively collected and processed to stored plasma (median volume 5.4 mL, range: 2.6 – 10.2) for retrospective ctDNA analysis using a personalized, tumor-informed ctDNA assay (SignateraTM). Survival rates were estimated by Kaplan-Meier. Results: Forty-six pts enrolled with 63 months median follow up, median age of 65 [R 46–80], 36 (78%) were ECOG 0, 30 (65%) had an endobiliary stent and no pts had staging laparoscopy. All pts started mFFX, and 37 pts (80%) completed all 6 preop cycles. Thirty-three pts (72%) underwent surgery with 3 pts developing investigator-assessed progression during neoadjuvant mFFX. Six pts were unresectable intraoperatively, and 27 pts (59%) underwent resection per protocol (25 R0, 2 R1). Ten additional pts underwent surgery off protocol. The 12-month PFS was 78% (95% CI: 64.2–94.4), median PFS and OS were 36.5 months (95% CI: 16.6–74.5) and 37.2 months (95% CI 17.5–not reached), respectively. Two-year OS was 59% (95% CI: 45.8–74.7). Baseline ctDNA was detected in 16/22 (73%) pts, and after 6 cycles of mFFX ctDNA was detected in 3/17 (18%) of pts. Patients with a positive ctDNA test 4 weeks post-resection had worsened PFS (HR 34.0, 95% CI: 2.6-4758.6; P = 0.006) and OS (HR: 11.7, 95% CI: 1.5–129.9; P = 0.021) compared to ctDNA negative. Mutational signature analysis revealed predominant signatures to be COSMIC signatures SBS1 and SBS5 (age related), and SBS15 (mismatch repair deficiency associated) which was associated with improved OS. Using Keratin 17 as a biomarker of the basal molecular subtype, either in diagnostic needle aspirates or surgical specimens, we found that high K17 expression was associated with worse survival. Conclusion: The perioperative mFFX clinical trial for resectable PDAC met its primary endpoint with a promising survival rate, and R0 resection rate of 93%. These findings warrant further evaluation in a randomized clinical trial. Most pts with detectable ctDNA at baseline experience ctDNA clearance after 6 cycles of neoadjuvant mFFX. In the post-operative setting, ctDNA positivity was strongly associated with recurrence. Signature SBS15 and low K17 were associated with improved OS. Citation Format: Michael Cecchini, Ronald Salem, Marie Robert, Suzanne Czerniak, Moein Rajaei, Jeffrey Townsend, Ondrej Blaha, Daniel Zelterman, Jaykumar Thumar, Jeremy Kortmansky, Wajih Zaheer, Neal Fischbach, Justin Persico, Stacey Stein, Sajid Khan, Charles Cha, Kevin Billingsley, John Kunstman, Sumedha Chowdhury, Robert Tseng, Carlos Mauricio, Deanne Yugawa, Luisa Escobar-Hoyos, Kimberly Johung, Christina Wiess, Erik Spickard, Vasily N. Aushev, George Laliotis, Adham Jurdi, Minetta C. Liu, Jill Lacy. A phase II study of peri-operative modified FOLFIRINOX in localized pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A002.

Abstract A022: Novel nanoparticle delivery of toll like receptor agonists alters the tumor immune landscape and improves response to standard of care therapy in preclinical PDAC models

Abstract The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is becoming an increasingly complex system, driven by the interactions between multiple different cell types. These drivers of cancer progression can suppress local immune responses, promote resistance to therapies, and reinforce a pro-tumorigenic TME. Despite advances in other tumor types with immune checkpoint blockade, minimal progress has been made in the treatment of PDAC with immunotherapies targeted at adaptive responses. As such, with a majority of the TME being made up of innate immune cells being skewed towards immunosuppressive phenotypes, there remains an underutilized immunologic target. Of the potential subset of targets, toll like receptors (TLR) have garnered significant interest given the key role they have in controlling the innate immune response in a number of different immune cells. On their own, agonists of these family of receptors lack efficacy, either through poor tumor penetration, lack of target specificity or toxicity. To address this unmet need, we have developed a nano-delivery approach for TLR agonists for target immune cell uptake. Thus far, we have established two conjugates, a protein-based nanoparticle termed FN-TLR7 for the delivery of a CL307-based conjugate and a DNA nanoparticle termed CAGE-TLR9 for the delivery of a CpG-based agonist. We have found that these conjugates can activate target immune cells within the TME via an advantageous pharmacokinetic profile which significantly reduces nonspecific toxicities compared to free agonists. When paired with the current standard of care options in PDAC, we see significant improvements in tumor control. The implications of nano-delivery of TLR agonists for treating PDAC tumors will be discussed. Citation Format: Nathan Beals, Anthony Sorrentino, Dafna Bar-Sagi. Novel nanoparticle delivery of toll like receptor agonists alters the tumor immune landscape and improves response to standard of care therapy in preclinical PDAC models [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A022.