Investigator-initiated Trial Research Articles

Phase II study of organ preservation (OP) in node-negative (NN) low rectal cancer (RC): Updated clinical and patient reported outcomes (PROs).

148 Background: Total mesorectal excision (TME) is a highly effective treatment for rectal cancer (RC) but is associated with significant morbidity and mortality. Organ preservation (OP) approaches for locally advanced RC have been successful but not well studied for node-negative (NN) low RC. The objective of this investigator-initiated trial (IIT) is to determine the feasibility of performing successful local excision (LE) after neoadjuvant chemotherapy (CTX) in NN low RC. Methods: With IRB approval, patients (pts) with clinical stage T1-3, N0 low rectal adenocarcinomas (<6 cm from anal verge) were included in this single arm phase II IIT. Pts received 6 cycles of FOLFOX (5-FU bolus 400 mg/m2 and infusion 2400 mg/m2, Leucovorin 400 mg/m2, Oxaliplatin 85 mg/m2). Those with evidence of a response underwent LE (transanal excision) 6-12 weeks later. To target occult nodal metastases and reduce in-bowel recurrences, LE was followed by chemoradiotherapy ([CXRT] capecitabine 825 mg/m2 and long course RT to 54 Gy). The primary endpoint was the proportion of pts with successful LE after neoadjuvant CTX (NCT03548961). Results: Nineteen pts with low RC were enrolled; nine were female, and the mean age at diagnosis was 65 years. T stage was as follows: T1- 1(5%), T2 - 11(58%), T3 - 7(36%). Eighteen (95%) pts completed at least 5 cycles of neoadjuvant Ctx and 16/19 (84%) underwent LE. Negative margins were achieved in 79% (15/19), meeting our primary endpoint (p < 0.001). Ten (53%) were downstaged, and complete pathological response was achieved in 5/16 (31%) of pts who underwent LE. Four (21%) pts (all T2 stage) did not meet the primary endpoint (3 with inadequate response to CTX and 1 with LE and positive margins). Of these, three were salvaged (2 with CXRT; 1 with TME), and one died of infection (unrelated complication). All 16 who underwent LE completed CXRT. Of the 15 pts with successful OP at a median follow-up of 25.5 months, no local recurrences have been reported and 1 pt with lung nodules below the threshold for metastases at study entry ultimately developed clear lung metastases. Median DFS was not reached. Patient reported outcomes (PRO) assessment revealed a slight decline in physical health scores after neoadjuvant CTX but improved to baseline at follow-up. No decline was seen in mental health scores. Symptom specific QOL (sexual and bowel function) and long-term survival data will be presented. Conclusions: Neoadjuvant CTX and LE allows for OP in NN low RC and results in a margin negative LE in over three fourths of pts with durable long term local control and preserved QOL. Ongoing trials are investigating an OP approach in NN RC (NCT03259035). Our approach adds to the mounting evidence and will provide early data of the benefit of adjuvant chemoradiation to target occult nodes in this setting. Clinical trial information: NCT03548961 .

Evaluating novel therapies and circulating tumor DNA (ctDNA) as a marker of response in curatively treated gastrointestinal cancers with microscopic residual disease.

TPS850 Background: ctDNA can identify the earliest sign of relapse (MRD) after curative therapies with specificities of 93-100%, positive predictive values over 95%, and median lead times of 8-9 months before radiographic relapse. ctDNA has identified a "new stage" of high-risk patients (pts) with no evidence of disease radiographically (rNED) and MRD who lack treatment (tx) strategies as, traditionally, they wait for radiographic progression of disease (POD) before starting therapies. Treating MRD is a promising strategy supported by observational studies where ctDNA clearance is linked with improved survival and on-tx kinetics predict drug efficacy . We designed a pilot investigator-initiated trial to 1) determine the feasibility of using ctDNA as a rapid signal for positive therapeutic activity and 2) obtain pilot data on the efficacy of a novel combination therapy (atezolizumab [A] + bevacizumab [B]) in eradicating MRD in previously curatively treated pts with GI cancers. Methods: We will enroll 20 pts with any-stage cancers divided over 4 cohorts (n=5 colorectal [CRC], n=5 hepatocellular/biliary tract carcinoma, n=5 upper GI, n=5 pancreatic adenocarcinoma) who have a positive Signatera ctDNA test and rNED any time after completing standard curative therapies. Pts are treated with A 1200 mg IV + B 15 mg/kg IV on day 1 of a 21-day cycle for up to 1 year with imaging every 12 weeks and serial ctDNA testing every 3 weeks. Co-primary endpoints are rates of pt enrollment in 12 months and rates of ctDNA responses at a 12-week landmark after tx initiation. Pts with ctDNA POD (ctDNA doubling on each of 2 sequential tests, any rate of rise in 3 sequential tests, or radiographic relapse) will stop while those with ctDNA complete response (CR; clearance on 2 sequential tests + ongoing rNED) or ctDNA partial/stable response (PR; not ctDNA CR or POD + ongoing rNED) will continue tx. Each cohort's Bayesian predictive probability of positive therapeutic activity will be calculated. If at least 60% of a cohort experiences ctDNA CR, it will be expanded by 5 pts. This scenario is equivalent to Simon's 2-stage Minimax design testing a null hypothesis of 20% CR vs. an alternative hypothesis of at least 60% CR at 5% alpha with 80% power. If at least 5/10 pts in an expanded cohort experience ctDNA CR, this will generate interest in developing a larger confirmatory trial to evaluate pt survival outcomes with A+B and ctDNA as a surrogate for survival. Secondary endpoints are toxicity and enrollment barriers. Exploratory endpoints are associations between ctDNA conversion and disease-free survival, tumor whole exome sequencing data, and peripheral blood immune profiles collected at baseline and on tx. Enrollment began in Q1 2023, paused in 7/2023 due to funding changes, and re-opened 8/2024 with 5 patients enrolled currently (n=4 CRC, n=1 biliary). Clinical trial information: NCT05482516 .

Neoadjuvant chemoradiotherapy with ipilimumab and nivolumab in rectal cancer (CHINOREC): A prospective randomized, open-label, multicenter, phase II clinical trial.

139 Background: Immune checkpoint inhibitors (ICIs) seem only effective in a primed tumor immune microenvironment (TIME). Neoadjuvant radiotherapy (RT) has been shown to induce an immunogenic cell death (ICD) and thereby restores the susceptibility to ICI. This study evaluates the safety of neoadjuvant chemoradiotherapy (CRT) with concomitant ipilimumab (IPI) and nivolumab (NIVO) in curative rectal cancer (RC) patients. Methods: The CHINOREC study (ClinicalTrials.gov identifier NCT04124601) is a prospective, randomized (ratio 50:30), open-label, multicenter, phase II investigator-initiated trial (IIT). Patients with RC received neoadjuvant CRT (50 Gy in 2 Gy fractions with concurrent capecitabine 1650 mg/m 2 /d) alone or in combination with IPI (1 mg/kg IV at day 7), following 3 cycles of NIVO (3 mg/kg IV Q2W, starting on day 14). Surgical resection was performed 10-12 weeks post CRT. The primary endpoint was surgical safety and feasibility (Clavien-Dindo Classification) of neoadjuvant CRT with sequential IPI and NIVO following surgical resection. Secondary outcome was complete response rate (clinical and pathological). Results: Between June 2020 and November 2023, 145 patients were screened and 80 randomly assigned to CRT (n=30) or CRT+IPI/NIVO (n=50). The primary endpoint (any surgical complication) did not differ between the 2 groups (78% vs. 77%). The reoperation rate (≥Grade IIIb) was comparable low in both groups (8% vs. 7%). No new safety signals were identified. The rate of major pathological response (MPR) and complete response (CR) was also comparable high in both arms (38% vs. 37% and 30% vs. 22%, respectively). Conclusions: Neoadjuvant IPI/NIVO can be safely applied concomitant with CRT in patients with RC, as it does not increase the rate of reoperation or surgical complications. The validity of the encouraging CR rate needs to be elucidated over time. Further translational analyses will elucidate mechanistic insight regarding improved fraction, dosing and timing of CRT and ICI. Clinical trial information: NCT04124601 .

P0852 Influence of a gluten-free dietary intervention on the gut microbiome and inflammation in inflammatory bowel disease: results from murine experiments and protocol of a prospective proof-of-concept human study as part of the miGut-Health project

Abstract Background A significant number of inflammatory bowel disease (IBD) patients report an improvement of gastrointestinal symptoms under a gluten-free diet (GFD), despite not suffering from celiac disease. In a recent prospective pilot study, we detected a significant downregulation of proinflammatory cytokines and chemokines on the mucosal level, as well as slight compositional changes of the luminal microbiome after implementation of an eight-week GFD intervention in PSC-IBD patients (1). For a further characterization, we established murine models of IBD, investigating the influence of a GFD on colitis susceptibility, gut microbiota, and intestinal inflammation (Part A). Subsequently, a proof-of-concept human study was implemented as part of the miGut Health project for clinical correlation (Part B). Methods A) C57BL/6 mice are either bred and kept under standard diet (SD, containing wheat) or GFD followed by induction of dextran sodium sulfate (DSS) colitis, a murine model for ulcerative colitis. Relative loss of bodyweight and mean endoscopic colitis score are measured. For characterization of the microbiota impact, murine stool transplantation into germ free mice and 16s RNA analyzes are performed. B) An investigator-initiated prospective clinical trial with one interventional arm in IBD patients will be performed at the University Medical Center Hamburg-Eppendorf to investigate a 1.5-year long wheat protein-free diet in patients with inflammatory bowel disease (IBD) including ulcerative colitis (UC), Crohn’s disease (CD) and PSC-associated IBD (PSC-IBD), n=20 each. Effects of the GFD on intestinal cell composition and state, intestinal fecal and mucosal microbiota composition will be assessed as well as the dietary impact on IBD activity using colonoscopy and biomarkers of intestinal inflammation and on symptoms and health-related quality of life. Results A) Gluten aggravates murine DSS-colitis and long-term GFD (LT-GFD) protects mice from gluten aggravated colitis susceptibility. More importantly, preliminary data in germ-free settings support that this effect is mediated through microbiota alterations during the LT-GFD. 16s RNA sequencing data from murine stool showed different relative bacterial abundance. B) The study protocol received formal ethical approval by the ethics committee of the Hamburg Medical Association, Hamburg, Germany. Patient recruitment has started and is ongoing. Conclusion These primary results underline a potential role of gut microbiota modulation for the positive effect of a GFD on gastrointestinal symptoms in IBD. Long-term tolerability and efficacy of the dietary intervention in IBD patients remain to be seen.

Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastases.

Natural killer (NK) cells can control metastasis through cytotoxicity and IFN-γ production independently of T cells in experimental metastasis mouse models. The inverse correlation between NK activity and metastasis incidence supports a critical role for NK cells in human metastatic surveillance. However, autologous NK cell therapy has shown limited benefit in treating patients with metastatic solid tumors. Using a spontaneous metastasis mouse model of MHC-I+ breast cancer, we found that transfer of IL-15/IL-12-conditioned syngeneic NK cells after primary tumor resection promoted long-term survival of mice with low metastatic burden and induced a tumor-specific protective T cell response that is essential for the therapeutic effect. Furthermore, NK cell transfer augments activation of conventional dendritic cells (cDCs), Foxp3-CD4+ T cells and stem cell-like CD8+ T cells in metastatic lungs, to which IFN-γ of the transferred NK cells contributes significantly. These results imply direct interactions between transferred NK cells and endogenous cDCs to enhance T cell activation. We conducted an investigator-initiated clinical trial of autologous NK cell therapy in six patients with advanced cancer and observed that the NK cell therapy was safe and showed signs of effectiveness. These findings indicate that autologous NK cell therapy is effective in treating established low burden metastases of MHC-I+ tumor cells by activating the cDC-T cell axis at metastatic sites.

Syngeneic natural killer cell therapy activates dendritic and T cells in metastatic lungs and effectively treats low-burden metastases

Natural killer (NK) cells can control metastasis through cytotoxicity and IFN-γ production independently of T cells in experimental metastasis mouse models. The inverse correlation between NK activity and metastasis incidence supports a critical role for NK cells in human metastatic surveillance. However, autologous NK cell therapy has shown limited benefit in treating patients with metastatic solid tumors. Using a spontaneous metastasis mouse model of MHC-I+ breast cancer, we found that transfer of IL-15/IL-12-conditioned syngeneic NK cells after primary tumor resection promoted long-term survival of mice with low metastatic burden and induced a tumor-specific protective T cell response that is essential for the therapeutic effect. Furthermore, NK cell transfer augments activation of conventional dendritic cells (cDCs), Foxp3-CD4+ T cells and stem cell-like CD8+ T cells in metastatic lungs, to which IFN-γ of the transferred NK cells contributes significantly. These results imply direct interactions between transferred NK cells and endogenous cDCs to enhance T cell activation. We conducted an investigator-initiated clinical trial of autologous NK cell therapy in six patients with advanced cancer and observed that the NK cell therapy was safe and showed signs of effectiveness. These findings indicate that autologous NK cell therapy is effective in treating established low burden metastases of MHC-I+ tumor cells by activating the cDC-T cell axis at metastatic sites.

The BEnefit of LONGitudinal Micro-Incisions Prior to Paclitaxel-Coated Balloon Angioplasty (BELONG Study) in Patients With Lower Extremity Arterial Disease: Clinical Outcomes at 12 Months.

Angioplasty of lower extremity arteries with calcification may result in flow-limiting dissection requiring bail-out stenting with unfavorable long-term outcomes. Vessel preparation prior to angioplasty may improve immediate results of the angioplasty and long-term patency. This prospective study assessed the 12-month outcomes of patients who underwent novel vessel preparation catheter, the FLEX Vessel Prep™ System (FLEX VP), prior to drug-coated balloon angioplasty (DCB-PTA). This investigator-initiated single-arm prospective trial enrolled patients with symptomatic lower extremity peripheral artery disease with de novo, restenotic, or in-stent stenosis of the superficial femoral or popliteal arteries. Target lesions were prepared using FLEX VP that created 12 longitudinal micro-incisions before drug-coated balloon angioplasty. Forty-three lesions in 41 patients were treated in this study with an average lesion length of 118 mm (10-291 mm), average stenosis of 82% (40-100%), and an occlusion rate of 27.9% with an average occlusion length of 89 mm (10-272 mm). Calcification was observed in 85.7% of the lesions, with 66.7% of lesions demonstrating grade 3 or 4 of the Peripheral Arterial Calcification Scoring System. After FLEX VP and DCB-PTA, 92.7% of patients were absent of flow-limiting dissections. Stenting occurred in 39% (16/41) patients (median stent length 40 mm) for residual stenosis (15 patients) and flow-limiting dissection (1 patient). There was one death prior to the 12-month follow-up, not related to the index procedure. Freedom from clinically driven target lesion revascularization at 12 months was 97.5% (39/40). Rutherford classification shifted from 41.5% Class ≥3 at baseline to 95% Class ≤1 at 12 months. There were no amputations at 12 months. Vessel preparation with longitudinal micro-incisions of complex and calcified lesions prior to angioplasty was associated with few flow-limiting dissections. The majority of stents were placed to treat focal residual stenosis, using the shortest available stent length at the time of the study (40 mm) for the majority. Only one stent was needed to treat a flow-limiting dissection. The 97.5% freedom from clinically driven target lesion revascularization (CDTLR) and symptom relief at 12 months suggest that vessel preparation via FLEX VP provides value in maintaining long-term outcomes in patients with highly calcified superficial femoral artery (SFA) or popliteal lesions. Vessel preparation with longitudinal micro-incisions is a short and efficient intervention associated with promising clinical outcomes and patency rate 12 months after treatment of long and calcified occlusions or stenosis of the femoral and popliteal arteries. This innovative vessel preparation provides post-procedure less residual stenosis and more favorable dissection morphology, decreasing the placement of stent and especially their length. Vessel preparation by longitudinal incisions also favors optimal distribution of anti-restenotic drug in the lesion and thus prevents further intervention due to restenosis.

Usefulness and safety of remimazolam in upper gastrointestinal endoscopy: A comparative study between elderly and non-elderly patients.

In gastroenterology, sedation demand is increasing, although elderly patients are more prone to experiencing adverse events. Remimazolam, a novel ultra-short-acting benzodiazepine, may reduce recovery time after endoscopic procedures. This study was a secondary analysis of the investigator-initiated trial, which investigated the efficacy and safety of remimazolam in gastrointestinal endoscopy (REM-IICT JP01). Remimazolam sedation was administered during upper gastrointestinal endoscopy. Patients were divided into two groups: 45 non-elderly and 11 elderly patients (aged ≥65 years). The primary outcome was sedation success. Secondary outcomes included the dose required for sedation, time to awakening, time to regain the ability to walk, and occurrence of adverse events. Endoscopic sedation was successful in 95.6% of the non-elderly group and 100% of the elderly group. The total dose of remimazolam was significantly higher in the non-elderly group (4.0 [3.0-8.0] mg) than in the elderly group (3.0 [2.0-3.0] mg; p<0.01). The time to awakening was 0.0 (0.0-10.0) min in the non-elderly group compared to 0.0 (0.0-30.0) min (p=0.98) in the elderly group. The time to regain the ability to walk was significantly longer in the elderly group (5.0 [0.0-60.0] min) than in the non-elderly group (5.0 [0.0-30.0] min; p=0.03). During the procedure, adverse events included hypotension in two cases (4.4%) in the non-elderly group and hypoxemia in one case (9.0%) in the elderly group. Upper gastrointestinal endoscopy with remimazolam was effective and safe, regardless of age.

Investigator-Initiated Clinical Pharmacokinetic Studies in Resource-Limited Settings: Minimal Requirements and Practical Guidance.

Clinical pharmacology studies are critical for determining the efficacy and safety of drugs. Due to the resource-intensive nature of these studies, most have been conducted in high-income countries, leading to a significant gap in clinical pharmacology data for patients in low- and middle-income countries. This paper provides an overview of the minimal requirements for performing a clinical pharmacology investigator-initiated trial (IIT), including pharmacokinetic sampling. We identify common challenges in resource-limited settings and propose strategies to overcome them. This guideline covers regulatory approval, participant recruitment, drug storage, sample collection and handling, transport, bioanalytical analysis, and data management tailored to the constraints of resource-limited settings. Strategies are proposed to minimize resource demands, including simplified study designs, the use of technologies like whole blood microsampling, and opportunities for collaboration. The goal is to provide practical guidance for those seeking to perform a clinical pharmacology IIT in resource-limited settings to improve safe and effective drug treatment for patients worldwide. Beyond the scope of this guideline is a detailed step-by-step guide on how to perform clinical pharmacology studies.

Comparative Study of Remimazolam and Midazolam During Sedated Upper Gastrointestinal Endoscopy: A Propensity Score Matching Analysis.

This study aimed to compare the use of remimazolam and midazolam in upper gastrointestinal endoscopy in Japan as a sub-analysis of data from an investigator-initiated clinical trial of remimazolam. Patients in two groups were matched using propensity score matching. We evaluated the time from the end of the gastrointestinal endoscopy until discharge, the time from the end of the procedure until awakening, and adverse events. Overall, 36 participants from the clinical trial population who underwent upper gastrointestinal endoscopy using remimazolam and 199 patients who underwent the procedure with midazolam during the same period were included in this study. Following propensity score matching, 34 patients in both groups were matched. The median time from the end of the procedure until awakening was 27.0 min (23.0-40.5 min) in the midazolam group (Group M) and 0 min (0-5.0 min) in the remimazolam group (Group R); the median time from the end of the upper gastrointestinal endoscopy until discharge was 39.0 min (35.0-52.5 min) in Group M and 5.0 min (0-5.0 min) in Group R (p < 0.01). Reported adverse events were hypotension and hypoxemia in one patient in Group R. Compared with midazolam, remimazolam significantly shortened the time to patient awakening and duration until the patient could leave the endoscopy room. Trial Registration: The main study (REM-IICT JP1) is registered with the Japan Registry of Clinical Trails: jRCT2031200360.

Effect and safety of ethanolamine oleate in sclerotherapy in patients with difficult-to-resect venous malformations: A multicenter, single-arm study.

To evaluate the effect and safety of sclerotherapy in patients with difficult-to-resect venous malformations treated with ethanolamine oleate. This investigator-initiated clinical trial employed a multicenter, single-arm design and was conducted in Japan. Overall, 44 patients with difficult-to-resect venous malformations were categorized into two cohorts: 22 patients with cystic-type malformations and 22 patients with diffuse-type malformations, including children (<15 years old). Adult patients received injections of 5% ethanolamine oleate solution, double diluted with contrast or normal saline, with a maximum dose of 0.4 mL/kg. The same method of administration was used for children (<15 years old). The maximum volume of the prepared solution in one treatment was 30 mL. Treatment effect was assessed by evaluating the difference in lesion volume using magnetic resonance imaging as a primary endpoint and differences in pain using a visual analog scale as a key secondary endpoint. Among the 45 patients who consented, one was excluded owing to potential intracranial involvement of venous malformations during screening. Regarding the primary outcome, 26 of 44 patients (59.1%, 95% confidence interval: 44.41-72.31%) achieved ≥ 20% reduction in malformation volume, with 16 patients having cystic lesions (72.7%, 51.85-86.85%) and 10 patients having diffuse lesions (45.5%, 26.92-65.34%). Both cohorts showed significant improvement in self-reported pain scores associated with lesions 3 months post-sclerotherapy. No death or serious adverse events occurred. Hemoglobinuria was observed in 23 patients (52%), a known drug-related adverse event. Prompt initiation of haptoglobin therapy led to full recovery within a month for these patients. Ethanolamine oleate shows potential as a therapeutic sclerosing agent for patients with difficult-to-resect venous malformations.

Efficacy and safety of a 72-h infusion of prostacyclin (1 ng/kg/min) in mechanically ventilated patients with pulmonary infection and endotheliopathy-protocol for the multicenter randomized, placebo-controlled, blinded, investigator-initiated COMBAT-ARF trial.

Acute respiratory failure (ARF) is common in critically ill patients, and 50% of patients in intensive care units require mechanical ventilation [3, 4]. The COVID-19 pandemic revealed that COVID-19 infection induced ARF caused by damage to the microvascular pulmonary endothelium. In a randomized clinical trial, mechanically ventilated COVID-19 patients with severe endotheliopathy, as defined by soluble thrombomodulin (sTM) ≥ 4 ng/mL, were randomized to evaluate the effect of a 72-h infusion of low-dose prostacyclin 1 ng/kg/min or placebo. Twenty-eight-day mortality was 21.9% versus 43.6% in the prostacyclin and the placebo groups, respectively (RR 0.50; CI 0.24 to 0.96 p = .06). The aim of the current trial is to investigate if this beneficial effect and safety of prostacyclin also are present in any patient with suspected pulmonary infection requiring mechanical ventilation and concomitant severe endotheliopathy. This is a multi-center, randomized, blinded, clinical investigator-initiated phase 3 trial in mechanically ventilated patients with suspected pulmonary infection and severe endotheliopathy, as defined by sTM ≥4 ng/mL. Patients are randomized 1:1 to a 72-h infusion of low-dose prostacyclin (iloprost) 1 ng/kg/min or placebo (an equal volume of saline). Four-hundred fifty patients will be included. The primary endpoint is 28-day all-cause mortality. Secondary endpoints include 90-day mortality, days alive without vasopressor, mechanical ventilation, and renal replacement therapy in the ICU within 28 and 90 days, and the number of serious adverse reactions or serious adverse events within the first 7 days. This trial will investigate the efficacy and safety of prostacyclin vs. placebo for 72-hours in mechanically ventilated patients with any suspected pulmonary infection and severe endotheliopathy, as defined by sTM ≥4 ng/mL. Trial endpoints focus on the potential effect of prostacyclin to reduce 28-day all-cause mortality.

First-in-human trial of a self-expandable, temporary dilation system for intracranial atherosclerotic disease in patients presenting with acute ischemic stroke

BackgroundIntracranial atherosclerotic disease (ICAD) significantly contributes to ischemic stroke, especially among Asian populations. Large vessel occlusion (LVO) due to underlying ICAD accounts for 15–35% of acute ischemic stroke cases requiring...

68Ga-MY6349 PET/CT imaging to assess Trop2 expression in multiple types of cancer.

Background Considering trophoblast cell surface antigen 2 (Trop2) is overexpressed in a wide range of human epithelial cancers, it presents an attractive target for the diagnosis and treatment of multiple types of cancer. Herein, we have developed a Trop2-specific radiotracer, 68Ga-MY6349, and present a prospective, investigator-initiated trial to explore the clinical values of 68Ga-MY6349 PET/CT. Methods In this translational study, 90 patients with 15 types of cancer, who underwent 68Ga-MY6349 PET/CT, were enrolled prospectively. Among them, 78 patients underwent paired 68Ga-MY6349 and 18F-FDG PET/CT, and 12 patients with prostate cancer underwent paired 68Ga-MY6349 and 68Ga-PSMA-11 PET/CT. Results Among the 90 patients across 15 types of cancer, 68Ga-MY6349 uptake in tumors was generally high but heterogeneous, varying among lesions, patients, and cancer types. Trop2 expression level determined by immunohistochemistry was highly correlated with 68Ga-MY6349 uptake at primary and metastatic tumor sites. 68Ga-MY6349 PET/CT showed higher tumor uptake (quantified by SUVmax) than 18F-FDG PET/CT in certain types of cancer, including breast (7.2 vs. 5.4, P < 0.001), prostate (9.2 vs. 3.0, P < 0.001), and thyroid cancers (8.5 vs. 3.7, P < 0.001). When compared with 68Ga-PSMA-11, 68Ga-MY6349 PET/CT exhibited comparable lesion uptake (12.2 vs. 12.5, P = 0.223) but a better tumor-to-background contrast (15.8 vs. 12.2, P < 0.001) for primary and metastatic prostate cancer, allowing visualization of more metastatic lesions. Conclusion 68Ga-MY6349 PET/CT is a non-invasive method for comprehensively assessing Trop2 expression in tumors, which can improve the diagnosis and staging for cancer patients, and aid in the decision-making for Trop2-targeted therapies and advancing personalized treatment.

A real-world, prospective, observational, investigator initiated trial to evaluate early discharge following Angio-Seal™ vascular closure device in patients undergoing percutaneous coronary intervention

BackgroundCardiac catheterization procedures such as percutaneous coronary intervention (PCI) are widely used but with complications of access site bleeding. Manual compression (MC)is the well accepted technique to control bleeding but time consuming (15-20 min); vascular closure devices (VCDs) are used increasingly as an alternative to MC and require <5 min for deployment.We aimed to document the real-world experience with a bioabsorbable collagen closure device (Angio-Seal™) with absorbable traction suture in patients undergoing PCI. ObjectiveThe primary objective was time (hours) to discharge from hospital after the procedure; to document the incidence of vascular access site complications, time to ambulation and time to hemostasis were the secondary objectives. MethodThis was a prospective, observational, investigator-initiated clinical trial wherein adult patients who underwent PCI procedure through femoral access route, with deployment of Angio-Seal™ femoral closure device were included. ResultsAmongst the 100 patients enrolled, 68 % were males. systemic hypertension (63 %), and type-2 diabetes mellitus (37 %) were the major comorbidities reported. Mean overall time from the end of procedure to hemostasis was 2.32 ± 0.99min. Time to ambulation was 156.08 ± 36.81min and to hospital discharge was 25.21 ± 4.49 h, One subject experienced hematoma. No other complications particularly pertaining to vascular access site were observed. ConclusionAngio-Seal™ is an effective and safe VCD and results in early ambulation, rapid hemostasis, and discharge in patients undergoing PCI.

Development of a Serum Metabolome-Based Test for Early-Stage Detection of Multiple Cancers.

Detection of cancer at the early stage currently offers the only viable strategy for reducing disease-related morbidity and mortality. Various approaches for multi-cancer early detection are being explored, which largely rely on capturing signals from circulating analytes shed by tumors into the blood. The fact that biomarker concentrations are limiting in the early stages of cancer, however, compromises the accuracy of these tests. We, therefore, adopted an alternate approach that involved interrogation of the serum metabolome with machine learning-based data analytics. Here, we monitored for modulations in metabolite patterns that correlated with the presence or absence of cancer. Results obtained confirmed the efficacy of this approach by demonstrating that it could detect a total of 15 cancers in women with an average accuracy of about 99%. To further increase the scope of our test, we conducted an investigator-initiated clinical trial involving a total of 6445 study participants, which included both cancer patients and non-cancer volunteers. Our goal here was to maximize the number of cancers that could be detected, while also covering cancers in both females and males. Metabolites extracted from individual serum samples were profiled by ultra-performance liquid chromatography coupled to a high-resolution mass spectrometer using an untargeted protocol. After processing, the data were analyzed by our cancer detection machine-learning algorithm to differentiate cancer from non-cancer samples. Results revealed that our test platform could indeed detect a total of 30 cancers, covering both females and males, with an average accuracy of ~98%. Importantly, the high detection accuracy remained invariant across all four stages of the cancers. Thus, our approach of integrating untargeted metabolomics with machine learning-powered data analytics offers a powerful strategy for early-stage multi-cancer detection with high accuracy. Registration No: CTRI/2023/03/050316.

Efficacy and safety of adrenomedullin for acute ischemic stroke (AMFIS): a phase 2, randomized, double-blinded, placebo-controlled, clinical trial

Adrenomedullin has angiogenic and vasoprotective effects in acute ischemic stroke (AIS). This investigator-initiated trial aimed to evaluate the safety, efficacy, and optimal administration of adrenomedullin in treating AIS. In this single-center, multi-cohort, double-blinded, randomized, placebo-controlled, Phase II trial, patients with AIS received pulsed adrenomedullin (9ng/kg/min for 8h daily over 7 days) or placebo in the first-half cohort, and continuous-pulsed adrenomedullin (9ng/kg/min for 72h during the first 3 days and 8h daily between Day 4-7) or placebo in the second-half cohort. We included male and female patients aged 20-90 years with newly confirmed ischemic lesions on diffusion-weighted magnetic resonance imaging, and for whom protocol treatment could be initiated within 24h of symptom onset. The primary safety endpoint was the occurrence of intervention-related severe adverse events. For the primary efficacy endpoint, the least square means and 95% confidence intervals of National Institutes of Health Stroke Scale (NIHSS) scores up to 7 days post-intervention initiation were calculated using generalized estimating equation models. This trial was registered at Japan Registry of Clinical Trials, jRCT2051190092. Between January 16, 2020, and November 14, 2021, 60 patients were enrolled (median [interquartile range] age, 75 [66-81] years; NIHSS score, 3 [2-4]; 21 [35.0%] females). Neither intervention-related serious adverse events nor severe adverse events were observed in patients receiving adrenomedullin. No life-threatening adverse events or deaths were reported. The least square means (95% confidence intervals) of the changes in NIHSS scores from pre-treatment to Day 7 were-0.76 (-1.43 to-0.09) in the adrenomedullin group (-1.08 [-2.17 to 0.00] in the pulsed adrenomedullin group and-0.42 [-1.12 to 0.29] in the continuous-pulsed adrenomedullin group) and-1.08 (-2.11 to-0.05) in the placebo group. Adrenomedullin was well tolerated in patients with non-severe, non-embolic AIS, although its beneficial effects were not demonstrated. It is necessary to show the efficacy of adrenomedullin in further clinical trials. Japan Agency for Medical Research and Development.

Prospective screening and proposed treatment algorithm for immune checkpoint inhibitor induced myositis in neoadjuvant-treated rectal cancer patients: data from the phase II CHINOREC trial

Abstract Background Myositis is an infrequent (&amp;lt;1%) but potentially life-threatening (case fatality rate 40-50%) immune-related adverse event (irAEs) of immune checkpoint inhibitors (ICI), such as ipilimumab (IPI) and nivolumab (NIVO). The true incidence is likely to be underestimated and may not be representative for curative neoadjuvant treatment approaches in gastrointestinal (GI) cancers, especially in combination with chemoradiotherapy (CRT). Currently, the summary of product characteristics (SmPC) does not suggest any pre-emptive screening or surveillance. Methods The CHINOREC study is an ongoing prospective, randomized, open-label, multicenter, phase II investigator-initiated trial (IIT). Patients with intermediate to locally advanced rectal cancer (LARC) receive either neoadjuvant CRT alone or in combination with a single dose of IPI and 3 cycles of NIVO, following surgical resection. Patients are monitored at baseline and throughout the whole study period for myotoxicity biomarkers, including cardiac troponin T (cTnT) and cardiac troponin I (cTnI). Findings From 06/2020 to 11/2023, 80 patients have been enrolled of whom 50 patients were randomized to the CRT+IPI/NIVO arm. Six patients (12%) developed biopsy-verified myositis. Myositis treatment was promptly implemented using a pragmatic step-up approach. Patients received glucocorticoids (GC) with concomitant intravenous immunoglobulin (IVIG). If myotoxicity biomarkers did not improve, patients received infliximab (INFLIXI) and/or plasma exchange (PLEX). Although all patients had strikingly elevated cTnT (median peak 284 ng/L, 95% CI 39-3097), cTnI levels remained largely normal, correlating with a negative cardiac magnetic resonance (CMR). All patients underwent successful tumor surgery without any major surgical complication. As of today, all patients' creatine kinase (CK) and myoglobin (MB) levels have normalized and they are tumor free without any major sequela. Interpretation Longitudinal biomarker screening (cTnT/cTnI) for ICI-induced myotoxicities is pivotal in curative neoadjuvant-treated cancer patients to initiate an early counter treatment in a holistic step-up approach, without compromising oncological principles.

Safety and tolerability of a Muse cell-based product in neonatal hypoxic-ischemic encephalopathy with therapeutic hypothermia (SHIELD trial).

Hypoxic-ischemic encephalopathy (HIE), associated with high mortality and neurological sequelae, lacks established treatment except therapeutic hypothermia. Clinical-grade multilineage-differentiating stress-enduring (Muse) cells (CL2020) demonstrated safety and efficacy in nonclinical HIE rat models, thereby leading to an investigator-initiated clinical trial to evaluate CL2020 safety and tolerability in neonatal HIE as a single-center open-label dose-escalation study with 9 neonates with moderate-to-severe HIE who received therapeutic hypothermia. Each patient received a single intravenous injection of CL2020 cells between 5 and 14 days of age. The low-dose (3 patients) and high-dose (6 patients) groups received 1.5 × 106 and 1.5 × 107 cells/dose, respectively. The occurrence of any adverse event within 12 weeks following CL2020 administration was the primary endpoint of this trial. No significant changes in physiological signs including heart rate, blood pressure, and oxygen saturation were observed during or after administration. The only adverse event that may be related to cell administration was a mild γ-glutamyltransferase level elevation in one neonate, which spontaneously resolved without any treatment. All patients enrolled in the trial survived, and normal developmental quotients (≥ 85) in all 3 domains of the Kyoto Scale of Psychological Development 2001 were observed in 67% of the patients in this trial. CL2020 administration was demonstrated to be safe and tolerable for neonates with HIE. Considering the small number of patients, a randomized controlled confirmatory study is warranted to verify these preliminary findings and evaluate the efficacy of this therapy.

From the Beginning of the Korean Gynecologic Oncology Group to the Present and Next Steps.

The Korean Gynecologic Oncology Group (KGOG) was established in 2002 and is the only organization in Korea conducting multi-center clinical trials for gynecologic cancers. Since its re-establishment as a non-profit organization in 2021, KGOG has grown significantly, now including 207 gynecologic oncology specialists from 76 hospitals. This growth is a testament to the dedication and hard work of all those involved in the organization. KGOG is committed to maximizing the activation of multi-center clinical research through policies that support patients with rare diseases and gynecologic cancer research, focusing on strengthening institutional capacity, equalizing participation opportunities, and enhancing information sharing. A significant milestone for KGOG was becoming a member of the US Gynecologic Oncology Group (GOG) in 2005, allowing participation in GOG clinical trials. KGOG later joined the Gynecologic Cancer InterGroup (GCIG) and strengthened its capabilities by hosting the first Endometrial Cancer Consensus Conference-Clinical Research (ECCC-CR) in 2023. KGOG holds biannual meetings and symposia, as well as 224 operating committee meetings annually to review the discussions of the Tumor Site Committee. KGOG has conducted 156 investigator-initiated trial (IIT) or sponsor-initiated trial (SIT) studies as KGOG-led or participated in research. Currently, 18 studies are registered, and 10 are in preparation. To date, 68 papers have been published. KGOG conducts six national projects and collaborates with external organizations such as the NRG Oncology Foundation, Gynecologic Oncology Group Partners (GOG-P), GCIG, East Asian Gynecologic Oncology Trial group (EAGOT), and the Japanese Gynecologic Oncology Group (JGOG). Through collaboration with renowned international research institutions, KGOG has significantly expanded the scope of its research, achieving noteworthy clinical outcomes. This report not only introduces the history and recent status of KGOG but also presents the exciting future direction of the organization, filled with potential breakthroughs and advancements in gynecologic oncology research.