CAR memory-like NK cells targeting the membrane proximal domain of mesothelin demonstrate promising activity in ovarian cancer.

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecological cancers. Cytokine-induced memory-like (CIML) natural killer (NK) cells have shown promising results in preclinical and early-phase clinical trials. In the current study, CIML NK cells demonstrated superior antitumor responses against a panel of EOC cell lines, increased expression of activation receptors, and up-regulation of genes involved in cell cycle/proliferation and down-regulation of inhibitory/suppressive genes. CIML NK cells transduced with a chimeric antigen receptor (CAR) targeting the membrane-proximal domain of mesothelin (MSLN) further improved the antitumor responses against MSLN-expressing EOC cells and patient-derived xenograft tumor cells. CAR arming of the CIML NK cells subtanstially reduced their dysfunction in patient-derived ascites fluid with transcriptomic changes related to altered metabolism and tonic signaling as potential mechanisms. Lastly, the adoptive transfer of MSLN-CAR CIML NK cells demonstrated remarkable inhibition of tumor growth and prevented metastatic spread in xenograft mice, supporting their potential as an effective therapeutic strategy in EOC.

In vivo imaging using surface enhanced spatially offset raman spectroscopy (SESORS): balancing sampling frequency to improve overall image acquisition.

In the field of optical imaging, the ability to image tumors at depth with high selectivity and specificity remains a challenge. Surface enhanced resonance Raman scattering (SERRS) nanoparticles (NPs) can be employed as image contrast agents to specifically target cells in vivo; however, this technique typically requires time-intensive point-by-point acquisition of Raman spectra. Here, we combine the use of "spatially offset Raman spectroscopy" (SORS) with that of SERRS in a technique known as "surface enhanced spatially offset resonance Raman spectroscopy" (SESORRS) to image deep-seated tumors in vivo. Additionally, by accounting for the laser spot size, we report an experimental approach for detecting both the bulk tumor, subsequent delineation of tumor margins at high speed, and the identification of a deeper secondary region of interest with fewer measurements than are typically applied. To enhance light collection efficiency, four modifications were made to a previously described custom-built SORS system. Specifically, the following parameters were increased: (i) the numerical aperture (NA) of the lens, from 0.2 to 0.34; (ii) the working distance of the probe, from 9 mm to 40 mm; (iii) the NA of the fiber, from 0.2 to 0.34; and (iv) the fiber diameter, from 100 µm to 400 µm. To calculate the sampling frequency, which refers to the number of data point spectra obtained for each image, we considered the laser spot size of the elliptical beam (6 × 4 mm). Using SERRS contrast agents, we performed in vivo SESORRS imaging on a GL261-Luc mouse model of glioblastoma at four distinct sampling frequencies: par-sampling frequency (12 data points collected), and over-frequency sampling by factors of 2 (35 data points collected), 5 (176 data points collected), and 10 (651 data points collected). In comparison to the previously reported SORS system, the modified SORS instrument showed a 300% improvement in signal-to-noise ratios (SNR). The results demonstrate the ability to acquire distinct Raman spectra from deep-seated glioblastomas in mice through the skull using a low power density (6.5 mW/mm2) and 30-times shorter integration times than a previous report (0.5 s versus 15 s). The ability to map the whole head of the mouse and determine a specific region of interest using as few as 12 spectra (6 s total acquisition time) is achieved. Subsequent use of a higher sampling frequency demonstrates it is possible to delineate the tumor margins in the region of interest with greater certainty. In addition, SESORRS images indicate the emergence of a secondary tumor region deeper within the brain in agreement with MRI and H&E staining. In comparison to traditional Raman imaging approaches, this approach enables improvements in the detection of deep-seated tumors in vivo through depths of several millimeters due to improvements in SNR, spectral resolution, and depth acquisition. This approach offers an opportunity to navigate larger areas of tissues in shorter time frames than previously reported, identify regions of interest, and then image the same area with greater resolution using a higher sampling frequency. Moreover, using a SESORRS approach, we demonstrate that it is possible to detect secondary, deeper-seated lesions through the intact skull.

Amino acid homeostasis is a target of metformin therapy.

OBJECTIVE: Unexplained changes in regulation of branched chain amino acids (BCAA) during diabetes therapy with metformin have been known for years. Here we have investigated mechanisms underlying this effect. METHODS: We used cellular approaches, including single gene/protein measurements, as well as systems-level proteomics. Findings were then cross-validated with electronic health records and other data from human material. RESULTS: In cell studies, we observed diminished uptake/incorporation of amino acids following metformin treatment of liver cells and cardiac myocytes. Supplementation of media with amino acids attenuated known effects of the drug, including on glucose production, providing a possible explanation for discrepancies between effective doses in vivo and in vitro observed in most studies. Data-Independent Acquisition proteomics identified that SNAT2, which mediates tertiary control of BCAA uptake, was the most strongly suppressed amino acid transporter in liver cells following metformin treatment. Other transporters were affected to a lesser extent. In humans, metformin attenuated increased risk of left ventricular hypertrophy due to the AA allele of KLF15, which is an inducer of BCAA catabolism. In plasma from a double-blind placebo-controlled trial in nondiabetic heart failure (trial registration: NCT00473876), metformin caused selective accumulation of plasma BCAA and glutamine, consistent with the effects in cells. CONCLUSIONS: Metformin restricts tertiary control of BCAA cellular uptake. We conclude that modulation of amino acid homeostasis contributes to therapeutic actions of the drug.

Genetically encoded Runx3 and CD4+ intestinal epithelial lymphocyte deficiencies link SKG mouse and human predisposition to spondyloarthropathy.

Disturbances in immune regulation, intestinal dysbiosis and inflammation characterize ankylosing spondylitis (AS), which is associated with RUNX3 loss-of-function variants. ZAP70W163C mutant (SKG) mice have reduced ZAP70 signaling, spondyloarthritis and ileitis. In small intestine, Foxp3+ regulatory T cells (Treg) and CD4+CD8αα+TCRαß+ intraepithelial lymphocytes (CD4-IEL) control inflammation. TGF-ß and retinoic acid (RA)-producing dendritic cells and MHC-class II+ intestinal epithelial cells (IEC) are required for Treg and CD4-IEL differentiation from CD4+ conventional or Treg precursors, with upregulation of Runx3 and suppression of ThPOK. We show in SKG mouse ileum, that ZAP70W163C or ZAP70 inhibition prevented CD4-IEL but not Treg differentiation, dysregulating Runx3 and ThPOK. TGF-ß/RA-mediated CD4-IEL development, T-cell IFN-γ production, MHC class-II+ IEC, tissue-resident memory T-cell and Runx3-regulated genes were reduced. In AS intestine, CD4-IEL were decreased, while in AS blood CD4+CD8+ T cells were reduced and Treg increased. Thus, genetically-encoded TCR signaling dysfunction links intestinal T-cell immunodeficiency in mouse and human spondyloarthropathy.

De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma.

Mutations affecting isocitrate dehydrogenase (IDH) enzymes are prevalent in glioma, leukemia, and other cancers. Although mutant IDH inhibitors are effective against leukemia, they seem to be less active in aggressive glioma, underscoring the need for alternative treatment strategies. Through a chemical synthetic lethality screen, we discovered that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway, including dihydroorotate dehydrogenase (DHODH). We developed a genetically engineered mouse model of mutant IDH1-driven astrocytoma and used it and multiple patient-derived models to show that the brain-penetrant DHODH inhibitor BAY 2402234 displays monotherapy efficacy against IDH-mutant gliomas. Mechanistically, this reflects an obligate dependence of glioma cells on the de novo pyrimidine synthesis pathway and mutant IDH's ability to sensitize to DNA damage upon nucleotide pool imbalance. Our work outlines a tumor-selective, biomarker-guided therapeutic strategy that is poised for clinical translation.

Treatment of anger problems in previously deployed post-911 veterans: A randomized controlled trial.

BACKGROUND: Problems with anger and aggression affect many veterans who have deployed to a warzone, resulting in serious impairment in multiple aspects of functioning. Controlled studies are needed to improve treatment options for these veterans. This randomized controlled trial compared an individually delivered cognitive behavioral therapy adapted from Novaco's Anger Control Therapy to a manualized supportive therapy to control for common therapeutic factors. METHODS: Ninety-two post-911 veterans deployed during Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), or Operation New Dawn (OND) with moderate to severe anger problems were randomized to receive the cognitive behavioral intervention (CBI) or the supportive intervention (SI). Anger, aggression, multiple areas of functioning and quality of life were assessed at multiple time points inclu\ding 3- and 6-month follow-up. RESULTS: Hierarchical linear modeling (HLM) analyses showed significant treatment effects favoring CBI for anger severity, social and interpersonal functioning, and quality of life. The presence of a PTSD diagnosis did not affect outcomes. CONCLUSIONS: CBI is an effective treatment for OEF/OIF/OND veterans with anger problems following deployment, regardless of PTSD diagnosis.

Mediation of Interleukin-23 and Tumor Necrosis Factor-Driven Reactive Arthritis by Chlamydia-Infected Macrophages in SKG Mice.

OBJECTIVE: ZAP-70W163C BALB/c (SKG) mice develop reactive arthritis (ReA) following infection with Chlamydia muridarum. Since intracellular pathogens enhance their replicative fitness in stressed host cells, we examined how myeloid cells infected with C muridarum drive arthritis. METHODS: SKG, Il17a-deficient SKG, and BALB/c female mice were infected with C muridarum or C muridarum luciferase in the genitals. C muridarum dissemination was assessed by in vivo imaging or genomic DNA amplification. Macrophages were depleted using clodronate liposomes. Anti-tumor necrosis factor (anti-TNF) and anti-interleukin-23p19 (anti-IL-23p19) were administered after infection or arthritis onset. Gene expression of Hspa5, Tgtp1, Il23a, Il17a, Il12b, and Tnf was compared in SKG mice and BALB/c mice. RESULTS: One week following infection with C muridarum, macrophages and neutrophils were observed to have infiltrated the uteri of mice and were also shown to have carried C muridarum DNA to the spleen. C muridarum load was higher in SKG mice than in BALB/c mice. Macrophage depletion was shown to reduce C muridarum load and prevent development of arthritis. Compared with BALB/c mice, expression of Il23a and Il17a was increased in the uterine and splenic neutrophils of SKG mice. The presence of anti-IL-23p19 during infection or Il17a deficiency suppressed arthritis. Tnf was overexpressed in the joints of SKG mice within 1 week postinfection, and persisted beyond the first week. TNF inhibition during infection or at arthritis onset suppressed the development of arthritis. Levels of endoplasmic reticulum stress were constitutively increased in the joints of SKG mice but were induced, in conjunction with immunity-related GTPase, by C muridarum infection in the uterus. CONCLUSION: C muridarum load is higher in SKG mice than in BALB/c mice. Whereas proinflammatory IL-23 produced by neutrophils contributes to the initiation of C muridarum-mediated ReA, macrophage depletion reduces C muridarum dissemination to other tissues, tissue burden, and the development of arthritis. TNF inhibition was also shown to suppress arthritis development. Our data suggest that enhanced bacterial dissemination in macrophages of SKG mice drives the TNF production needed for persistent arthritis.

The Role of Guilt and Shame in Psychosocial Functioning in a Sample of Women With Borderline Personality Disorder.

Individuals diagnosed with borderline personality disorder (BPD) experience significant and pervasive impairment in interpersonal, social, and vocational functioning, and accumulating evidence suggests that impairments in functioning often persist despite significant decreases in symptom severity. Previous research indicates that shame-proneness and guilt-proneness are associated with symptoms of BPD that can affect functioning (such as aggression toward others), but very few studies have examined the impact of shame-proneness and guilt-proneness on validated measures of psychosocial functioning. Forty women with BPD completed measures of shame-proneness and guilt-proneness, psychosocial functioning, and BPD symptom severity. Results from multiple regression analyses indicate that women with BPD who tend to experience higher levels of shame-proneness and lower levels of guilt-proneness report poor performance in school and work settings and in interpersonal relationships. Strengths of the study include the use of a validated measure of functioning as the primary outcome. Limitations and future directions are discussed.

Moral injury as a unique predictor of suicidal ideation in a veteran sample with a substance use disorder.

OBJECTIVE: Suicide among military veterans accounts for 22.2% of all suicide deaths in the United States per year, and veterans with a substance use disorder (SUD) are at an even higher risk for death by suicide. This prevalence has led to increased efforts to identify and investigate both potential risks and protective factors for veterans. This study examines relationships between depression symptomology, exposure to potentially morally injurious events, posttraumatic stress disorder (PTSD) diagnosis, and suicidal ideation, with the primary aim of examining exposure to moral injurious events as a risk factor for suicide in veterans with SUD. METHOD: An inpatient sample of 40 veterans with an active SUD admitted for suicidal ideation was evaluated to examine differences in suicidal ideation, depression symptomology, and exposure to morally injurious events in participants with and without a PTSD diagnosis. Further, exposure to morally injurious events and depression symptomology were examined as predictors of suicidal ideation. RESULTS: Analyses revealed that exposure to morally injurious events (d = 1.72) and depression symptomology (d = 0.72) were higher in participants with a PTSD diagnosis compared to those without a diagnosis, though no significant differences emerged between the two groups on suicidality. A hierarchical regression analysis indicated that only exposure to morally injurious events significantly accounted for variance in suicidality (ß = .31, p = .04, 95% confidence interval [.01, .37]). CONCLUSIONS: These results suggest that although PTSD may be associated with exposure to morally injurious events and depression symptoms, exposure to morally injurious events may potentially lead to higher suicide risk among veterans above and beyond PTSD and depressive symptoms. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Fall Prevention Knowledge, Attitudes, and Behaviors: A Survey of Emergency Providers.

INTRODUCTION: Falls are a frequent reason geriatric patients visit the emergency department (ED). To help providers, the Geriatric Emergency Department Guidelines were created to establish a standard of care for geriatric patients in the ED. We conducted a survey of emergency providers to assess 1) their knowledge of fall epidemiology and the geriatric ED guidelines; 2) their current ED practice for geriatric fall patients; and 3) their willingness to conduct fall-prevention interventions. METHODS: We conducted an anonymous survey of emergency providers including attending physicians, residents, and physician assistants at a single, urban, Level 1 trauma, tertiary referral hospital in the northeast United States. RESULTS: We had a response rate of 75% (102/136). The majority of providers felt that all geriatric patients should undergo screening for fall risk factors (84%, 86/102), and most (76%, 77/102) answered that all geriatric patients screened and at risk for falls should have an intervention performed. While most (80%, 82/102) answered that geriatric falls prevention was very important, providers were not willing to spend much time on screening or interventions. Less than half (44%, 45/102) were willing to spend 2-5 minutes on a fall risk assessment and prevention, while 46% (47/102) were willing to spend less than 2 minutes. CONCLUSION: Emergency providers understand the importance of geriatric fall prevention but lack knowledge of which patients to screen and are not willing to spend more than a few minutes on screening for fall interventions. Future studies must take into account provider knowledge and willingness to intervene.

The Relationship Among Shame, Nonsuicidal Self-Injury, and Suicidal Behaviors in Borderline Personality Disorder.

Shame has been individually linked to nonsuicidal self-injury and suicidal ideation and behavior and is highly prevalent in individuals with borderline personality disorder. The current study investigated the relationship between shame, nonsuicidal self-injury, and suicidal ideation in a sample of women with borderline personality disorder. Participants were 40 women recruited from a Women's Dialectical Behavior Therapy Partial Hospital Program in a psychiatric hospital in New England as part of a larger, six-month treatment development study. Results indicated that shame-proneness predicts nonsuicidal self-injury and suicidal ideation and behavior above and beyond the severity of borderline personality disorder symptoms, suggesting that shame may be an important treatment target for individuals with borderline personality disorder. Clinical implications, limitations, and future directions are discussed.

Acute Shame Predicts Urges for Suicide but not for Substance Use in a Veteran Population.

OBJECTIVE: There is an urgent need to identify ways to reduce rates of suicide among Veterans with a substance use disorder. Since co-occurring disorders can make diagnosis and treatment complex, it is useful for the mental health field to examine common factors that may underlie both problems. One common factor that underlies both substance use and suicidal behavior is shame. This brief report presents data collected in an experimental study examining shame as an acute risk factor for suicide and substance use in Veterans. METHOD: Thirty-eight Veterans admitted to an inpatient Veterans Affairs Medical Center unit with suicidal ideation completed measures on depression, hopelessness, addiction, and suicidality. Participants were randomized to either a shame mood induction group or a control group, and completed pre- and postexperiment measures on urges for suicide, urges for substance use, and level of shame. RESULTS: Results indicate that an acute increase in shame resulted in an increase in an urge for suicide, but was not associated with changes in urges for substance use. CONCLUSIONS: Acute feelings of shame may be a risk factor for increases in suicidal ideation. Limitations and suggestions for future directions are discussed.

Evaluation of Self-Compassion Focused Group Treatment for Co-Occurring PTSD and Substance Use in Veterans with Posttraumatic Guilt: A Case Study.

Co-occurring posttraumatic stress disorder (PTSD) and substance use disorders (SUD) following combat exposure affects a significant proportion of military veterans. Guilt and shame are common to PTSD-SUD, suggesting a possible role as a mechanism underlying both disorders. Cultivating self-compassion (SC) among veterans is a logical approach to treating guilt and shame. The purpose of this article is threefold: (a) present scientific theories of SC in the veteran population with emphasis on PTSD, substance use, and guilt and shame; (b) present a case study that highlights how self-compassion-focused treatment (SCFT) can be utilized in a group format with veterans with PTSD-SUD and posttraumatic guilt; and (c) discuss implications of our findings for refining SCFT within a group intervention setting among this population and for future research.

Older Adult Falls in Emergency Medicine: 2019 Update.

"Standing-level falls represent the most frequent cause of trauma-related death in older adults and a common emergency department (ED) presentation. However, these patients rarely receive guideline-directed screening and interventions during or following an episode of care. Reducing injurious falls in an aging society begins with prehospital evaluations and continues through definitive risk assessments and interventions that usually occur after ED care. Although ongoing obstacles to ED-initiated, evidence-based older adult fall-reduction strategies include the absence of a compelling emergency medicine evidence basis, innovations under way include validation of pragmatic screening instruments and incorporation of contemporary technology to improve fall detection rates."

Older Adult Falls in Emergency Medicine-A Sentinel Event.

Standing-level falls represent the most frequent cause of trauma-related death in older adults and a common emergency department presentation. However, these patients rarely receive guideline-directed screening and interventions during or following an episode of care. Reducing injurious falls in an aging society begins with prehospital evaluations and continues through risk assessments and interventions that occur after emergency department care. Although obstacles to emergency department-initiated, evidence-based older adult fall reduction strategies include the absence of a compelling emergency medicine evidence basis, innovations underway include validation of screening instruments and incorporation of contemporary technology like smart phones to improve fall detection rates.

A Contextual Behavior Science Framework for Understanding How Behavioral Flexibility Relates to Anxiety.

There is a growing literature focusing on the emerging idea that behavioral flexibility, rather than particular emotion regulation strategies per se, provides greater promise in predicting and influencing anxiety-related psychopathology. Yet this line of research and theoretical analysis appear to be plagued by its own challenges. For example, middle-level constructs, such as behavioral flexibility, are difficult to define, difficult to measure, and difficult to interpret in relation to clinical interventions. A key point that some researchers have made is that previous studies examining flexible use of emotion regulation strategies (or, more broadly, coping) have failed due to a lack of focus on context. That is, examining strategies in isolation of the context in which they are used provides limited information on the suitability, rigid adherence, or effectiveness of a given strategy in that situation. Several of these researchers have proposed the development of new models to define and measure various types of behavioral flexibility. We would like to suggest that an explanation of the phenomenon already exists and that we can go back to our behavioral roots to understand this phenomenon rather than focusing on defining and capturing a new process. Indeed, thorough contextual behavioral analyses already yield a useful account of what has been observed. We will articulate a model explaining behavioral flexibility using a functional, contextual framework, with anxiety-related disorders as an example.

Metformin selectively targets redox control of complex I energy transduction.

Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD+ couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD+ couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled.

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial.

BACKGROUND: Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. METHODS: In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0-1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. FINDINGS: Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m2. The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4-19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250-602). Two patients enrolled at a higher dose of 1000 mg/m2, and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3-4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3-4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1-3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. INTERPRETATION: A maximum tolerated dose of CPI-613 was established at 500 mg/m2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. FUNDING: Comprehensive Cancer Center of Wake Forest Baptist Medical Center.