Imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial.

BACKGROUND: Delta-like ligand 3 (DLL3) is aberrantly expressed on the surface of small-cell lung cancer (SCLC) and neuroendocrine prostate cancer cells. We assessed the safety and feasibility of the DLL3-targeted imaging tracer [89Zr]Zr-DFO-SC16.56 (composed of the anti-DLL3 antibody SC16.56 conjugated to p-SCN-Bn-deferoxamine [DFO] serving as a chelator for zirconium-89) in patients with neuroendocrine-derived cancer. METHODS: We conducted an open-label, first-in-human study of immunoPET-CT imaging with [89Zr]Zr-DFO-SC16.56. The study was done at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Patients aged 18 years or older with a histologically verified neuroendocrine-derived malignancy and an Eastern Cooperative Oncology Group performance status of 0-2 were eligible. An initial cohort of patients with SCLC (cohort 1) received 37-74 MBq [89Zr]Zr-DFO-SC16.56 as a single intravenous infusion at a total mass dose of 2·5 mg and had serial PET-CT scans at 1 h, day 1, day 3, and day 7 post-injection. The primary outcomes of phase 1 of the study (cohort 1) were to estimate terminal clearance half-time, determine whole organ time-integrated activity coefficients, and assess the safety of [89Zr]Zr-DFO-SC16.56. An expansion cohort of additional patients (with SCLC, neuroendocrine prostate cancer, atypical carcinoid tumours, and non-small-cell lung cancer; cohort 2) received a single infusion of [89Zr]Zr-DFO-SC16.56 at the same activity and mass dose as in the initial cohort followed by a single PET-CT scan 3-6 days later. Retrospectively collected tumour biopsy samples were assessed for DLL3 by immunohistochemistry. The primary outcome of phase 2 of the study in cohort 2 was to determine the potential association between tumour uptake of the tracer and intratumoural DLL3 protein expression, as determined by immunohistochemistry. This study is ongoing and is registered with ClinicalTrials.gov, NCT04199741. FINDINGS: Between Feb 11, 2020, and Jan 30, 2023, 12 (67%) men and six (33%) women were enrolled, with a median age of 64 years (range 23-81). Cohort 1 included three patients and cohort 2 included 15 additional patients. Imaging of the three patients with SCLC in cohort 1 showed strong tumour-specific uptake of [89Zr]Zr-DFO-SC16.56 at day 3 and day 7 post-injection. Serum clearance was biphasic with an estimated terminal clearance half-time of 119 h (SD 31). The highest mean absorbed dose was observed in the liver (1·83 mGy/MBq [SD 0·36]), and the mean effective dose was 0·49 mSv/MBq (SD 0·10). In cohort 2, a single immunoPET-CT scan on day 3-6 post-administration could delineate DLL3-avid tumours in 12 (80%) of 15 patients. Tumoural uptake varied between and within patients, and across anatomical sites, with a wide range in maximum standardised uptake value (from 3·3 to 66·7). Tumour uptake by [89Zr]Zr-DFO-SC16.56 was congruent with DLL3 immunohistochemistry in 15 (94%) of 16 patients with evaluable tissue. Two patients with non-avid DLL3 SCLC and neuroendocrine prostate cancer by PET scan showed the lowest DLL3 expression by tumour immunohistochemistry. One (6%) of 18 patients had a grade 1 allergic reaction; no grade 2 or worse adverse events were noted in either cohort. INTERPRETATION: DLL3 PET-CT imaging of patients with neuroendocrine cancers is safe and feasible. These results show the potential utility of [89Zr]Zr-DFO-SC16.56 for non-invasive in-vivo detection of DLL3-expressing malignancies. FUNDING: National Institutes of Health, Prostate Cancer Foundation, and Scannell Foundation.

Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer.

PURPOSE: Patients with microsatellite instability high/mismatch repair deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab. We define the genomic features, clinical course, and response to immune checkpoint blockade (ICB) in patients with MSI-H/dMMR and TMB-H prostate cancers without MSI (TMB-H/MSS). METHODS: We sequenced 3,244 tumors from 2,257 prostate cancer patients. MSI-H/dMMR prostate cancer was defined as MSIsensor score ≥10 or MSIsensor score ≥3 and <10 with a deleterious MMR alteration. TMB-H was defined as ≥10 mutations/megabase. PSA50 and RECIST responses were assigned. Overall survival (OS) and radiographic progression-free survival (rPFS) were compared using log rank test. RESULTS: 63 (2.8%) men had MSI-H/dMMR and 33 (1.5%) had TMB-H/MSS prostate cancers. Patients with MSI-H/dMMR and TMB-H/MSS tumors more commonly presented with grade group 5 and metastatic disease at diagnosis. MSI-H/dMMR tumors had higher TMB, indel and neoantigen burden compared with TMB-H/MSS. 27 patients with MSI-H/dMMR and 8 patients with TMB-H/MSS tumors received ICB, none of whom harbored POLE mutations. 45% of MSI-H/dMMR patients had a RECIST response and 65% had a PSA50 response. No TMB-H/MSS patient had a RECIST response and 50% had a PSA50 response. rPFS tended to be longer in MSI-H/dMMR patients than in TMB-H/MSS patients who received immunotherapy. Pronounced differences in genomics, TMB or MSIsensor score were not detected between MSI-H/dMMR responders and non-responders. CONCLUSIONS: MSI-H/dMMR prostate cancers have greater TMB, indel and neoantigen burden compared with TMB-H/MSS prostate cancers, and these differences may contribute to more profound and durable responses to ICB.

Single-cell analysis of treatment-resistant prostate cancer: Implications of cell state changes for cell surface antigen-targeted therapies.

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)-a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single-cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to current and future antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.

Training and Verification Requirements for Interpretation of Cardiac CT and MRI: AJR Expert Panel Narrative Review.

The use of cardiac CT and MRI is rapidly expanding based on strong evidence from large international trials. The number of physicians competent to interpret cardiac CT and MRI may be unable to keep pace with the increasing demand. Societies and organizations have prescribed training requirements for interpreting cardiac CT and MRI, with recent updates focusing on the increased breadth of competency that is now required due to ongoing imaging advances. In this AJR Expert Panel Narrative Review, we discuss several aspects of cardiac CT and MRI training, focusing on topics that are uncertain or not addressed in existing society statements and guidelines, including determination of competency in different practice types in real-world settings and the impact of artificial intelligence on training and education. The article is intended to guide updates in professional society training requirements and also inform institutional verification processes.

A Framework for Integrating Telehealth Equitably across the cancer care continuum.

The COVID-19 pandemic placed a spotlight on the potential to dramatically increase the use of telehealth across the cancer care continuum, but whether and how telehealth can be implemented in practice in ways that reduce, rather than exacerbate, inequities are largely unknown. To help fill this critical gap in research and practice, we developed the Framework for Integrating Telehealth Equitably (FITE), a process and evaluation model designed to help guide equitable integration of telehealth into practice. In this manuscript, we present FITE and showcase how investigators across the National Cancer Institute's Telehealth Research Centers of Excellence are applying the framework in different ways to advance digital and health equity. By highlighting multilevel determinants of digital equity that span further than access alone, FITE highlights the complex and differential ways structural determinants restrict or enable digital equity at the individual and community level. As such, achieving digital equity will require strategies designed to not only support individual behavior but also change the broader context to ensure all patients and communities have the choice, opportunity, and resources to use telehealth across the cancer care continuum.

Transforming patient-centered cancer care using telehealth: the MATCHES Center.

Modern cancer care is costly and logistically burdensome for patients and their families despite an expansion of technology and medical advances that create the opportunity for novel approaches to care. Therefore, there is a growing appreciation for the need to leverage these innovations to make cancer care more patient centered and convenient. The Memorial Sloan Kettering Making Telehealth Delivery of Cancer Care at Home Efficient and Safe Telehealth Research Center is a National Cancer Institute-designated and funded Telehealth Research Center of Excellence poised to generate the evidence necessary to inform the appropriate use of telehealth as a strategy to improve access to cancer services that are convenient for patients. The center will evaluate telehealth as a strategy to personalize cancer care delivery to ensure that it is not only safe and effective but also convenient and efficient. In this article, we outline this new center's research strategy, as well as highlight challenges that exist in further integrating telehealth into standard oncology practice based on early experiences.

MRI in Patients with Cardiovascular Implantable Electronic Devices and Fractured or Abandoned Leads.

Purpose To examine the clinical effect of lead length and lead orientation in patients with cardiac implantable electronic devices (CIEDs) and lead fragments or abandoned leads undergoing 1.5-T MRI. Materials and Methods This Health Insurance Portability and Accountability Act-compliant retrospective study included patients with CIEDs and abandoned leads or lead fragments undergoing 1.5-T MRI from March 2014 through July 2020. CIED settings before and after MRI were reviewed, with clinically significant variations defined as a composite of the change in capture threshold of at least 50%, in sensing of at least 40%, or in lead impedance of at least 30% between before MRI and after MRI interrogation. Adverse clinical events were assessed at MRI and up to 30 days after. Univariable and multivariable analysis was performed. Results Eighty patients with 126 abandoned CIED leads or lead fragments underwent 107 1.5-T MRI examinations. Sixty-seven patients (median age, 74 years; IQR, 66-78 years; 44 male patients, 23 female patients) had abandoned leads, and 13 (median age, 66 years; IQR, 52-74 years; nine male patients, four female patients) had lead fragments. There were no reported deaths, clinically significant arrhythmias, or adverse clinical events within 30 days of MRI. Three patients with abandoned leads had a significant change in the composite of capture threshold, sensing, or lead impedance. In a multivariable generalized estimating equation analysis, lead orientation, lead length, MRI type, and MRI duration were not associated with a significant change in the composite outcome. Conclusion Use of 1.5-T MRI in patients with abandoned CIED leads or lead fragments of varying length and orientation was not associated with adverse clinical events. Keywords: Cardiac Assist Devices, MRI, Cardiac Implantable Electronic Device Supplemental material is available for this article. © RSNA, 2024.

Safety and Feasibility of Third-Party Cytotoxic T Lymphocytes for High-Risk Patients with Covid-19.

Cytotoxic T lymphocytes (CTLs) destroy virally infected cells and are critical for the elimination of viral infections such as those caused by the SARS-CoV-2 virus. Delayed and dysfunctional adaptive immune responses to SARS-CoV-2 are associated with poor outcomes. Treatment with allogeneic SARS-CoV-2-specific CTLs may enhance cellular immunity in high-risk patients and provide a safe, direct mechanism of treatment. Thirty high-risk ambulatory patients with COVID-19 were enrolled on a phase I trial to assess the safety of 3rd party, SARS-CoV-2-specific CTLs. Twelve Interventional patients, 6 of whom were immunocompromised, matched the human leukocyte antigen (HLA)-A*02:01 restriction of the CTLs and received a single infusion of one of four escalating doses of a product containing 68.5% SARS-CoV-2-specific CD8+ CTLs/total cells. Symptom improvement and resolution in these patients was compared to an Observational group of eighteen patients lacking HLA-A*02:01 who could receive standard of care. No dose-limiting toxicities were observed at any dosing level. Nasal swab PCR data showed ≥ 88% and >99% viral elimination from baseline in all patients at 4- and 14-days post-infusion. The CTLs did not interfere with the development of endogenous anti-SARS-CoV-2 humoral or cellular responses. T-cell receptor beta (TCR) analysis comparing SARS-CoV-2-specific T-cell responses derived from the CTL donor versus recipients showed persistence of donor-derived CTLs through the end of the 6-month follow-up period. Interventional patients consistently reported symptomatic improvement 2-3 days after infusion, whereas improvement was more variable in Observational patients. This study shows that SARS-CoV-2-specific CTLs are a potentially feasible cellular therapy for COVID-19 illness. (Clinicaltrials.gov #NCT04765449).

ACR Appropriateness Criteria® Workup of Pleural Effusion or Pleural Disease.

Pleural effusions are categorized as transudative or exudative, with transudative effusions usually reflecting the sequala of a systemic etiology and exudative effusions usually resulting from a process localized to the pleura. Common causes of transudative pleural effusions include congestive heart failure, cirrhosis, and renal failure, whereas exudative effusions are typically due to infection, malignancy, or autoimmune disorders. This document summarizes appropriateness guidelines for imaging in four common clinical scenarios in patients with known or suspected pleural effusion or pleural disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

A Phase 0 Study to Assess the Biodistribution and Pharmacokinetics of a Radiolabeled Antibody Targeting Human Kallikrein 2 in Participants with Metastatic Castration-Resistant Prostate Cancer.

Despite the inclusion of multiple agents within the prostate cancer treatment landscape, new treatment options are needed to address the unmet need for patients with metastatic castration-resistant prostate cancer (mCRPC). Although prostate-specific membrane antigen is the only cell-surface target to yield clinical benefit in men with advanced prostate cancer, additional targets may further advance targeted immune, cytotoxic, radiopharmaceutical, and other tumor-directed therapies for these patients. Human kallikrein 2 (hK2) is a novel prostate-specific target with little to no expression in nonprostate tissues. This first-in-human phase 0 trial uses an 111In-radiolabeled anti-hK2 monoclonal antibody, [111In]-DOTA-h11B6, to credential hK2 as a potential target for prostate cancer treatment. Methods: Participants with progressive mCRPC received a single infusion of 2 mg of [111In]-DOTA-h11B6 (185 MBq of 111In), with or without 8 mg of unlabeled h11B6 to assess antibody mass effects. Sequential imaging and serial blood samples were collected to determine [111In]-DOTA-h11B6 biodistribution, dosimetry, serum radioactivity, and pharmacokinetics. Safety was assessed within a 2-wk follow-up period from the time of [111In]-DOTA-h11B6 administration. Results: Twenty-two participants received [111In]-DOTA-h11B6 and are included in this analysis. Within 6-8 d of administration, [111In]-DOTA-h11B6 visibly accumulated in known mCRPC lesions, with limited uptake in other organs. Two treatment-emergent adverse events unrelated to treatment occurred, including tumor-related bleeding in 1 patient, which led to early study discontinuation. Serum clearance, biodistribution, and tumor targeting were independent of total antibody mass (2 or 10 mg). Conclusion: This first-in-human study demonstrates that tumor-associated hK2 can be identified and targeted using h11B6 as a platform as the h11B6 antibody selectively accumulated in mCRPC metastases with mass-independent clearance kinetics. These data support the feasibility of hK2 as a target for imaging and hK2-directed agents as potential therapies in patients with mCRPC.

When the one true faith trumps all: Low religious diversity, religious intolerance, and science denial.

Past theories have linked science denial to religiosity but have not explained its geographic variability. We hypothesize that it springs not only from religious intensity but also from religious intolerance, which depends greatly on the experience of religious diversity and hence on geography. The belief that one's religion trumps other faiths precipitates the stance that it trumps science too. This psychological process is most likely to operate in regions or countries with low religious heterogeneity. We measure the rejection of science not only in people's refusal to follow specific health recommendations, such as taking COVID-19 vaccines, but also in general measures of scientific engagement and attainment. We rule out alternative explanations, including reverse causality and spurious correlations, by conducting controlled experiments and running robustness checks on our statistical models.

High Self-Reported Prevalence of Kidney Stones in Trinidad and Tobago: Results of a Cross-Sectional Online Survey.

Introduction No data exist on the prevalence of kidney stone disease in Trinidad and Tobago. Local clinicians have noted that the disease is very common, and this study represents the first attempt to investigate the prevalence of urolithiasis in these islands. Objectives The objective is to estimate the prevalence of kidney stone disease in Trinidad and Tobago and to investigate the epidemiology of the disease. Methods An online survey using the online tool Survey Monkey was distributed among members of the public via instant messaging and social media. The survey captured data relating to the stone status and demographics of respondents. Results 1225 patients completed the survey of whom 46.5% were males and 53.5% were females. Respondents were equally distributed throughout the country. 16.74% of those surveyed indicated that they were currently affected by stones confirmed by imaging. Kidney stones were more common among Trinidadians of East Indian ancestry (20.6% vs 10.6%). Positive correlations were established between kidney stones and the presence of hypertension, diabetes, and gout. Persons with kidney stones were more likely to have a family member with the disease - 45.6% vs 31.4% among those without kidney stones. Conclusion This study demonstrates a high self-reported prevalence of kidney stones in Trinidad and Tobago.

Expert Perspectives on Controversies in Castration-Sensitive Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 1.

Purpose: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. Materials and Methods: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. Results: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. Conclusions: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

Expert Perspectives on Controversies in Metastatic Castration-Resistant Prostate Cancer Management: Narrative Review and Report of the First US Prostate Cancer Conference Part 2.

Background: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. Materials and Methods: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. Results: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. Conclusions: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.

Single Cell Analysis of Treatment-Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies.

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)--a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis (TMA) on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated, but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer (SCLC) subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to novel antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.

Cyclic Ion Mobility for Hydrogen/Deuterium Exchange-Mass Spectrometry Applications.

Hydrogen/deuterium exchange-mass spectrometry (HDX-MS) has emerged as a powerful tool to probe protein dynamics. As a bottom-up technique, HDX-MS provides information at peptide-level resolution, allowing structural localization of dynamic changes. Consequently, the HDX-MS data quality is largely determined by the number of peptides that are identified and monitored after deuteration. Integration of ion mobility (IM) into HDX-MS workflows has been shown to increase the data quality by providing an orthogonal mode of peptide ion separation in the gas phase. This is of critical importance for challenging targets such as integral membrane proteins (IMPs), which often suffer from low sequence coverage or redundancy in HDX-MS analyses. The increasing complexity of samples being investigated by HDX-MS, such as membrane mimetic reconstituted and in vivo IMPs, has generated need for instrumentation with greater resolving power. Recently, Giles et al. developed cyclic ion mobility (cIM), an IM device with racetrack geometry that enables scalable, multipass IM separations. Using one-pass and multipass cIM routines, we use the recently commercialized SELECT SERIES Cyclic IM spectrometer for HDX-MS analyses of four detergent solubilized IMP samples and report its enhanced performance. Furthermore, we develop a novel processing strategy capable of better handling multipass cIM data. Interestingly, use of one-pass and multipass cIM routines produced unique peptide populations, with their combined peptide output being 31 to 222% higher than previous generation SYNAPT G2-Si instrumentation. Thus, we propose a novel HDX-MS workflow with integrated cIM that has the potential to enable the analysis of more complex systems with greater accuracy and speed.