Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma.

BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide. METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1. RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9). CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).

CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells.

A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982).

A socially polymorphic Formica ant species exhibits a novel distribution of social supergene genotypes.

Most supergenes discovered so far are young, occurring in one species or a few closely related species. An ancient supergene in the ant genus Formica presents an unusual opportunity to compare supergene-associated phenotypes and the factors that influence the persistence of polymorphism in different species. We investigate the genetic architecture of social organization in Formica francoeuri, an ant species native to low- and mid-elevation semiarid regions of southern California, and describe an efficient technique for estimating mode of social organization using population genomic data. Using this technique, we show that F. francoeuri exhibits polymorphism in colony social organization and that the phenotypic polymorphism is strongly associated with genotypes within the Formica social supergene region. The distribution of supergene haplotypes in F. francoeuri differs from that of related species Formica selysi in that colonies with multiple queens contain almost exclusively workers that are heterozygous for alternative supergene haplotypes. Moreover, heterozygous workers exhibit allele-specific expression of the polygyne-associated haplotype at the candidate gene Knockout, which is thought to influence social organization. We also report geographic population structure and variation in worker size across a large fraction of the species range. Our results suggest that, although the Formica supergene is conserved within the genus, the mechanisms that maintain the supergene and its associated polymorphisms differ among species.

Is the Proportion of Patients with "Successful" Outcomes After Two-stage Revision for Prosthetic Joint Infection Different When Applying the Musculoskeletal Infection Society Outcome Reporting Tool Compared with the Delphi-based Consensus Criteria?

BACKGROUND: There are a variety of criteria for defining successful treatment after two-stage exchange arthroplasty for prosthetic joint infection (PJI). To accurately assess current practices and improve techniques, it is important to first establish reliable, clinically relevant, reproducible criteria for defining persistent infection and "successful" outcomes. QUESTION/PURPOSE: Is the proportion of patients considered to have successful management of PJI after two-stage resection arthroplasty smaller using 2019 Musculoskeletal Infection Society Outcome Reporting Tool (MSIS ORT) criteria than when using a Delphi-based criterion? METHODS: Patients were retrospectively identified by Current Procedural Technology codes for resection arthroplasty with placement of an antibiotic spacer for infected THA or TKA between April 1, 2011 and January 1, 2018 at a tertiary academic institution. The initial review identified 180 procedures during this time period. Nine patients had documented transition of care outside the system, 16 did not meet the MSIS criteria for chronic PJI, and 34 patients were excluded for lack of documented 2-year follow-up. The mean follow-up duration of the final cohort of 121 procedures in 120 patients was approximately 3.7 ± 1.7 years. Forty percent (49 of 121) of the procedures were performed on the hip and 60% (72 of 121) were performed on the knee. The mean time from primary THA or TKA to explantation was 4.6 years. The mean age of the patients at the time of explantation was 66 years. The mean time from spacer placement to replantation was 119 days. The final 121 patient records were reviewed by a single reviewer and outcomes were subsequently assigned to "successful" and "unsuccessful" outcomes based on the MSIS ORT and Delphi-based consensus criterion, two previously published and validated multidimensional definition schemes. Chi-squared and t-test analyses were performed to identify differences between "successful" and "unsuccessful" outcomes with respect to patient baseline characteristics using each outcome-reporting criterion. RESULTS: Overall, the MSIS ORT classified a smaller proportion of patients as having a "successful" treatment outcome after two-stage exchange arthroplasty for PJI than the Delphi-based consensus method did (MSIS: 55% [63 of 114], Delphi: 70% [71 of 102]; relative risk 0.79 [0.65-0.98]; p = 0.03). However, there were no differences when stratified by hips (MSIS: 55% [26 of 47], Delphi: 74% [29 of 39]; relative risk 0.74 [0.54-1.02]; p = 0.07) and knees (MSIS: 55% [37 of 67], Delphi: 67% [42 of 63]; relative risk 0.83 [0.63-1.09]; p = 0.19). Notably, the disease of 16% of the patients (19 of 121) was not classifiable per the Delphi method because these patients never underwent reimplantation. CONCLUSION: The present study demonstrated that the MSIS criteria detect fewer instances of "successful" infection management after two-stage resection arthroplasty for PJI than the Delphi method in this cohort. Based on these findings, researchers and surgeons should aim for standardized reporting after intervention for PJI to allow for a better comparison of outcomes across different studies and ultimately allow for improved techniques and approaches to the treatment of PJI. LEVEL OF EVIDENCE: Level III, diagnostic study.

CYP2J19 mediates carotenoid colour introgression across a natural avian hybrid zone.

It has long been of interest to identify the phenotypic traits that mediate reproductive isolation between related species, and more recently, the genes that underpin them. Much work has focused on identifying genes associated with animal colour, with the candidate gene CYP2J19 identified in laboratory studies as the ketolase converting yellow dietary carotenoids to red ketocarotenoids in birds with red pigments. However, evidence that CYP2J19 explains variation between red and yellow feather coloration in wild populations of birds is lacking. Hybrid zones provide the opportunity to identify genes associated with specific traits. Here we investigate genomic regions associated with colour in red-fronted and yellow-fronted tinkerbirds across a hybrid zone in southern Africa. We sampled 85 individuals, measuring spectral reflectance of forecrown feathers and scoring colours from photographs, while testing for carotenoid presence with Raman spectroscopy. We performed a genome-wide association study to identify associations with carotenoid-based coloration, using double-digest RAD sequencing aligned to a short-read whole genome of a Pogoniulus tinkerbird. Admixture mapping using 104,933 single nucleotide polymorphisms (SNPs) identified a region of chromosome 8 that includes CYP2J19 as the only locus with more than two SNPs significantly associated with both crown hue and crown score, while Raman spectra provided evidence of ketocarotenoids in red feathers. Asymmetric backcrossing in the hybrid zone suggests that yellow-fronted females mate more often with red-fronted males than vice versa. Female red-fronted tinkerbirds mating assortatively with red-crowned males is consistent with the hypothesis that converted carotenoids are an honest signal of quality.

What Happens to Unused Opioids After Total Joint Arthroplasty? An Evaluation of Unused Postoperative Opioid Disposal Practices.

BACKGROUND: This study evaluates the fate of unused opioids after total hip arthroplasty (THA) and total knee arthroplasty (TKA) at our facility. METHODS: Medication disposal after primary elective THA and TKA was classified as appropriate (in accordance with United States Food and Drug Administration guidelines) or inappropriate for all patients undergoing these procedures during the second half of the fiscal year 2015. RESULTS: In total, 199 THAs and 144 TKAs met inclusion criteria. Total pills prescribed were 55,635. Approximately 8925 (16%) of pills were unused. About 39.9% of patients disposed of unused opioids appropriately, while 60.1% of patients reported still having (18.5%), not knowing where they were (8.2%), or other (33.4%). There was no significant association with the type of opioid prescribed. CONCLUSION: A large volume of unused opioids were improperly disposed of after total joint arthroplasty.

Spatially Resolved Electric-Field Manipulation of Magnetism for CoFeB Mesoscopic Discs on Ferroelectrics.

Electric-field control of magnetism in ferromagnetic/ferroelectric multiferroic heterostructures is a promising way to realize fast and nonvolatile random-access memory with high density and low-power consumption. An important issue that has not been solved is the magnetic responses to different types of ferroelectric-domain switching. Here, for the first time three types of magnetic responses are reported induced by different types of ferroelectric domain switching with in situ electric fields in the CoFeB mesoscopic discs grown on PMN-PT(001), including type I and type II attributed to 109°, 71°/180° ferroelectric domain switching, respectively, and type III attributed to a combined behavior of multiferroelectric domain switching. Rotation of the magnetic easy axis by 90° induced by 109° ferroelectric domain switching is also found. In addition, the unique variations of effective magnetic anisotropy field with electric field are explained by the different ferroelectric domain switching paths. The spatially resolved study of electric-field control of magnetism on the mesoscale not only enhances the understanding of the distinct magnetic responses to different ferroelectric domain switching and sheds light on the path of ferroelectric domain switching, but is also important for the realization of low-power consumption and high-speed magnetic random-access memory utilizing these materials.

Superior therapeutic efficacy of nab-paclitaxel over cremophor-based paclitaxel in locally advanced and metastatic models of human pancreatic cancer.

BACKGROUND: Albumin-bound paclitaxel (nab-paclitaxel, nab-PTX) plus gemcitabine (GEM) combination has demonstrated efficient antitumour activity and statistically significant overall survival of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) compared with GEM monotherapy. This regimen is currently approved as a standard of care treatment option for patients with metastatic PDAC. It is unclear whether cremophor-based PTX combined with GEM provide a similar level of therapeutic efficacy in PDAC. METHODS: We comprehensively explored the antitumour efficacy, effect on metastatic dissemination, tumour stroma and survival advantage following GEM, PTX and nab-PTX as monotherapy or in combination with GEM in a locally advanced, and a highly metastatic orthotopic model of human PDAC. RESULTS: Nab-PTX treatment resulted in significantly higher paclitaxel tumour plasma ratio (1.98-fold), robust stromal depletion, antitumour efficacy (3.79-fold) and survival benefit compared with PTX treatment. PTX plus GEM treatment showed no survival gain over GEM monotherapy. However, nab-PTX in combination with GEM decreased primary tumour burden, metastatic dissemination and significantly increased median survival of animals compared with either agents alone. These therapeutic effects were accompanied by depletion of dense fibrotic tumour stroma and decreased proliferation of carcinoma cells. Notably, nab-PTX monotherapy was equivalent to nab-PTX plus GEM in providing survival advantage to mice in a highly aggressive metastatic PDAC model, indicating that nab-PTX could potentially stop the progression of late-stage pancreatic cancer. CONCLUSIONS: Our data confirmed that therapeutic efficacy of PTX and nab-PTX vary widely, and the contention that these agents elicit similar antitumour response was not supported. The addition of PTX to GEM showed no survival advantage, concluding that a clinical combination of PTX and GEM may unlikely to provide significant survival advantage over GEM monotherapy and may not be a viable alternative to the current standard-of-care nab-PTX plus GEM regimen for the treatment of PDAC patients.

Fluorophore-Induced Plasmonic Current Generation from Copper Nanoparticle Films.

We describe the process of generating a fluorophore-induced plasmonic current (FIPC) from copper nanoparticle films. Previous work and the literature have shown that excited near-field fluorophores are able to plasmonically couple with metal nanoparticle films (MNFs), inducing surface plasmons in the films. These induced surface plasmons are then in turn able to generate a directly measurable electrical current across the film. These generated currents have been quantified and detected in noble metal films, such as those made from Ag and Au, but due to the cost of such films, there has been a push to use lower cost materials for FIPC. Previous work has detailed the use of gold, silver, and aluminum films for these purposes, and in this paper, we will subsequently examine the ability of thermally deposited copper films to generate FIPC when in close proximity to excited near-field fluorophores. We report the effects of copper film thickness, the effects of light polarization and solution conductance, and the effects of metal-enhanced fluorescence (MEF) emission on the generation of plasmonic current.

Chronic pelvic pain and dysmenorrhea disguising a rare submucosal leiomyoma of the urinary bladder.

Representing 0.43% of all urinary bladder neoplasms, leiomyomas are rare mesenchymal tumours with a benign pathophysiology. There have only been approximately 250 cases published on this subject, necessitating further inquiry into this disease and effective management protocols. Treatment options may include a broad spectrum of surgical interventions, from minimally invasive resection to radical cystectomy, depending on the location, size and symptoms associated with the tumour. To date, few cases of leiomyoma have resulted in recurrence after removal, and zero have reported malignant transformation. Described here in detail is a woman in her early 40s who presented with a history of chronic pelvic pain and irregular vaginal bleeding. The urology team completed further evaluation after imaging discovered a concerning bladder lesion. Eventually, she underwent transurethral resection, with the subsequent pathology revealing a rare diagnosis of leiomyoma in the urinary bladder.

Penile Osteosarcoma: A Rare Extraosseous Site.

Primary penile extraosseous osteosarcoma (EOS) ranks the most uncommon amongst the differential penile masses, with only nine cases reported so far. In this report, we share the management of a 67-year-old Hispanic male who presented with a painful mass over his distal penile shaft and glans for the last two months. After initial imaging and complete blood investigations, he underwent partial penectomy. Histology revealed high-grade sarcoma, with osteoid production, favoring high-grade extra-skeletal osteosarcoma, with tumor necrosis involving approximately 5% of the tumor volume. The patient had bilateral palpable inguinal lymphadenopathy, which was seen even on a pre-op CT scan. The patient thus underwent bilateral robotic superficial and deep inguinal standard template lymph node dissection three weeks after his partial penectomy. His pathology was negative for malignancy in all examined lymph nodes. At his last follow-up, five months post his primary surgery, he had been doing well without concerns for recurrence.

Ovarian Serous Cystadenoma of the Epididymis: A Case Report.

Paratesticular cystadenomas remain a very rare entity, typically presenting as a painless mass, often indistinguishable from the testicle. As such, the predominant management seems to be complete excision via various approaches, which often proves curative. Given its rarity, post-operative surveillance has not been standardized; most patients and providers elect a more conservative surveillance approach. Based on the available literature, this seems appropriate, given the lack of morbidity or recurrence associated with these types of tumors.

Neutron activation data for the analysis of archaeological and geological hematite in Missouri and Illinois, U.S.A.

Hematite, and more broadly ochre, have long been used by humans throughout history for a variety of applications. In prehistoric North America the use of hematite is as old as its first migrants. This data article includes data related to the analysis of archaeological hematite in the American Bottom region in Missouri and Illinois, U.S.A. The data include archaeological samples dating from the Late Archaic Period (3000 - 1000 BCE) to the Middle Woodland Period (150 BCE - 400 CE) from nine sites within the general St. Louis area (n = 69), as well as 29 samples from Verkamp Rockshelter in the iron-rich region of the Meramec River Valley. The data is supplemented with geological samples collected from five raw deposits in southeastern Missouri (n = 70). Data was acquired through Neutron Activation Analysis to assess provenance of all archaeological samples. Following the irradiation of samples, data was normalized for iron content before statistical analysis. A variety of multivariate statistical routines, including principal component and cluster analyses were then employed to assess possible origin locales for all archaeological samples. This data article also includes maps, tables, and figures to assist in understanding the analysis conducted.

Fluorophore-Induced Plasmonic Current Generation from Aluminum Nanoparticle Films.

In this paper we demonstrate fluorophore induced plasmonic current (FIPC) from aluminum nanoparticle films. It has been previously shown that near-field excited fluorophores are able to plasmonically couple with metal nanoparticle films (MNF's) and induce surface plasmons, which in turn leads to a direct measurable electrical current through the MNF. These currents have been detected and quantified in noble metal MNF's, however due to future envisioned cost considerations there has been a push to adapt FIPC for use with less expensive metals. Subsequently, we observe that plasmonic aluminum films are able to produce these current changes when in close proximity to excited fluorophores, and the magnitude of the current changes are respective to the magnitude of the extinction coefficients of the fluorophores themselves. These findings also further support recent literature reports showing the inverse relationship between metal-enhanced fluorescence (MEF) and FIPC.

Prostatic artery embolization for bladder outlet obstruction in the setting of prior posterior urethroplasty.

This case presents a patient with a remote history of complex posterior urethral repair related to a prior motorcycle accident who presented to the urology clinic in urinary retention with associated lower urinary tract symptoms. Due to his altered anatomy, traditional outlet procedures were deferred due to significant reported risks of post treatment urinary incontinence. Decision was made to proceed with prostatic artery embolization, and at follow up he reported resolution of his urinary retention and significant symptomatic improvement in his voiding without development of urinary incontinence.

Synchronous Metastatic Clear Cell Renal Cell Carcinoma to the Gallbladder With Metachronous Contralateral Recurrence.

Renal cell carcinoma (RCC) classically metastasizes to the lungs, bones, adrenals, lymph nodes, liver, and brain. RCC metastasis to the gallbladder is rare occurring in less than 1% of metastases. We present a case of a 60-year-old male who at initial diagnosis of his large left renal mass was incidentally found to have a gallbladder mass. He underwent simultaneous open radical nephrectomy and cholecystectomy with pathology confirming solitary metastatic clear cell RCC (ccRCC). The patient chose surveillance and was without evidence of disease for three years. At three years, imaging showed a 2 cm contralateral renal mass which was cryoablated percutaneously. This case demonstrates not only the importance of a thorough review of initial and surveillance imaging but also of maintaining a broad differential for other solid organ masses in the setting of a primary RCC of the kidney.

Quantitative Systems Pharmacology Modeling of Avadomide-Induced Neutropenia Enables Virtual Clinical Dose and Schedule Finding Studies.

Avadomide is a cereblon E3 ligase modulator and a potent antitumor and immunomodulatory agent. Avadomide trials are challenged by neutropenia as a major adverse event and a dose-limiting toxicity. Intermittent dosing schedules supported by preclinical data provide a strategy to reduce frequency and severity of neutropenia; however, the identification of optimal dosing schedules remains a clinical challenge. Quantitative systems pharmacology (QSP) modeling offers opportunities for virtual screening of efficacy and toxicity levels produced by alternative dose and schedule regimens, thereby supporting decision-making in translational drug development. We formulated a QSP model to capture the mechanism of avadomide-induced neutropenia, which involves cereblon-mediated degradation of transcription factor Ikaros, resulting in a maturation block of the neutrophil lineage. The neutropenia model was integrated with avadomide-specific pharmacokinetic and pharmacodynamic models to capture dose-dependent effects. Additionally, we generated a disease-specific virtual patient population to represent the variability in patient characteristics and response to treatment observed for a diffuse large B-cell lymphoma trial cohort. Model utility was demonstrated by simulating the avadomide effect in the virtual population for various dosing schedules and determining the incidence of high-grade neutropenia, its duration, and the probability of recovery to low-grade neutropenia.

Design and Implementation of a Musculoskeletal Ultrasound Curriculum for Physical Medicine and Rehabilitation Residents: Pilot Data on Improvement of Palpation Accuracy in Physical Examination.

Studies have shown that physical medicine and rehabilitation residents have poor surface anatomy palpation accuracy, suggesting that new methods of teaching musculoskeletal (MSK) examination need to be found. This study describes the design of a novel MSK ultrasound course that integrated ultrasonography skills with palpation skills. Ultrasound was used to teach, validate, and refine physical medicine and rehabilitation residents' palpation of MSK structures. Surface anatomy palpation is intimately related to ultrasonography as clinicians should use palpation to guide their ultrasound examination rather than purely follow an algorithm. This study assessed whether the ultrasound course improved physical medicine and rehabilitation resident palpation accuracy at 12 upper limb structures. Palpation accuracy was tested at the beginning of their residency training and retested several weeks after completion of the ultrasound course's upper limb component, to assess retention of skill. There was significant improvement (P < 0.05) in 9 of 12 sites from pretesting to posttesting. Mean postcourse palpation accuracy was within 1 cm for 8 of 12 structures. This study demonstrates that an integrated MSK ultrasound and palpation curriculum improves palpation accuracy at multiple MSK structures and this improvement is retained. Physical medicine and rehabilitation residencies should consider integrating palpation skills into their ultrasound curriculum to improve the caliber of their trainees.

Open-label, Phase I Study of Nivolumab Combined with nab-Paclitaxel Plus Gemcitabine in Advanced Pancreatic Cancer.

PURPOSE: Assess safety and efficacy of nivolumab plus nab-paclitaxel and gemcitabine in patients with locally advanced/metastatic pancreatic cancer in a two-part, open-label, phase I trial. PATIENTS AND METHODS: Fifty chemotherapy-naive patients received nab-paclitaxel 125 mg/m2 plus gemcitabine 1,000 mg/m2 (days 1, 8, and 15) and nivolumab 3 mg/kg (days 1 and 15) in 28-day cycles. The primary endpoints were dose-limiting toxicities (DLTs; part 1) and grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (parts 1/2). Secondary efficacy endpoints were progression-free survival (PFS), overall survival (OS), and response. Assessment of programmed cell death-ligand 1 (PD-L1) expression was an exploratory endpoint; additional biomarkers were assessed post hoc. RESULTS: One DLT (hepatitis) was reported in part 1 among six DLT-evaluable patients; 48 of 50 patients experienced grade 3/4 TEAEs and 18 discontinued treatment due to TEAEs. One grade 5 TEAE (respiratory failure) was reported. Median [95% confidence interval (CI)] PFS/OS was 5.5 (3.25-7.20 months)/9.9 (6.74-12.16 months) months, respectively [median follow-up for OS, 13.6 months (95% CI, 12.06-23.49 months)]. Overall response rate (95% CI) was 18% (8.6%-31.4%). Median PFS/OS was 5.5/9.7 months (PD-L1 <5%) and 6.8/11.6 months (PD-L1 ≥5%), respectively. Proportion of peripheral Ki67+ CD8+/CD4+ cells increased significantly from baseline to cycle 3; median peak on-treatment Ki67+ CD8+ T-cell values were higher in responders than in nonresponders. CONCLUSIONS: The safety profile of nivolumab plus nab-paclitaxel and gemcitabine at standard doses in advanced pancreatic cancer was manageable, with no unexpected safety signals. Overall, the clinical results of this study do not support further investigation.