PURPOSE:The purpose of this study was to analyze national trends in knee and shoulder arthroscopy to identify seasonal and annual variability using the Healthcare Cost and Utilization Project-Nationwide Ambulatory Surgery Sample (HCUP-NASS) dataset. METHODS:Estimated national rates of ambulatory knee and shoulder arthroscopy were analyzed using HCUP-NASS data from 2016 to 2021. Time trend plots were generated to identify potential seasonal trends in these procedures. RESULTS:There was a decreasing trend in the number of procedures (shoulder arthroscopy, rotator cuff repair [RCR], knee arthroscopy, meniscal repair [MR]/meniscectomy, and anterior cruciate ligament reconstruction [ACLR]) done from 2016 to 2021. There were an estimated 264,987 (95% confidence interval [CI] = 251,205 to 276,770) patients who underwent shoulder arthroscopy and 381,125 (95% CI = 362,555 to 399,696) patients who underwent knee arthroscopy in 2021, as compared with 345,892 (95% CI = 326,224 to 365,559) patients who underwent shoulder arthroscopy and 521,912 (95% CI = 496,905 to 546,919) patients who underwent knee arthroscopy in 2016. Male patients showed markedly higher rates of shoulder arthroscopy, RCR, knee arthroscopy, MR, and ACLR procedures as compared with female patients, whereas female patients showed markedly higher rates of knee arthroscopy done without MR and ACLR. Shoulder and knee arthroscopy rates peaked in the 55 to 75-year-old age group. In addition, both procedures were most frequently done in December and had the lowest utilization in the month of July. CONCLUSION:There was a nonlinear decrease in the estimates of shoulder arthroscopy, RCR, MR/meniscectomy, knee arthroscopy, and anterior cruciate ligament reconstruction procedures from 2016 to 2021, with peaks in 2016 and 2019, and a low point in 2020. There are notable variations in rates of knee and shoulder arthroscopy procedures by age and sex. CLINICAL RELEVANCE:Recent data on commonly done ambulatory orthopaedic arthroscopies are important for policy makers and for understanding utilization trends.

Preclinical studies showed a synergistic antileukemia activity with combination of selective XPO1 inhibitor selinexor (SEL) and venetoclax (VEN), with potential to overcome VEN resistance by reducing the anti-apoptotic protein MCL1. In an investigator-sponsored, open-label, phase Ib study (NCT03955783), adult patients with relapsed or refractory acute myeloid leukemia (R/R AML) were enrolled. After the dose-escalation phase, SEL 80 mg po weekly plus VEN 400 mg/day following ramp-up was deemed the recommended phase II dose. Responses were assessed with IWG2003 and ELN 2022 criteria. Nineteen patients with R/R AML were enrolled. Median age at enrollment was 67.2 (range, 21.1-83.8) years. Overall, patients received median of 3 (range, 1-5) prior lines of therapy. The most common grade 3-5 treatment emergent adverse events (TEAE) were anemia (39%), neutropenia (33%), febrile neutropenia (28%), and thrombocytopenia (28%). Overall, the response rate with SEL-VEN was 21%. Two (11%) patients, one with prior allo-HSCT and one with prior VEN and both treated with SEL 80 mg/week, experienced complete remissions, with duration of response of 7 and 9.1 months, respectively. After a median follow up of 3.0 (range, 0.6-15.4) months, median event-free survival was 2.4 (95% CI: 1.9-12.1) months and median overall survival was 6.4 (95% CI: 2.5-12.1) months. In conclusion, SEL-VEN was feasible and active in a heavily pretreated AML cohort, with no new toxicity signal, but survival outcomes remained poor. The second-generation XPO1-inhibitor eltanexor, combined with VEN may further improve outcomes in VEN resistant AML in an ongoing study (NCT06399640).

Supplemental Tables S1-S9 Supplemental Figures S1-S2

Dipeptidase-1 (DPEP1) is highly upregulated in colorectal cancer (CRC), with its enzymatic function linked to invasion and metastasis. More recently, DPEP1 was found to serve as a receptor for neutrophils when expressed by activated endothelial cells. It is unknown whether neutrophils bind to DPEP1-expressing CRC cells and whether this impacts features of CRC. Neutrophils have been shown to be tumor promoting in cancers including CRC, where they act to exclude CD8+ T cells. Herein, we show that neutrophils bind DPEP1-expressing CRC cells. In addition, DPEP1 is preferentially expressed in microsatellite-stable (MSS) CRCs, in which there are a paucity of CD8+ T cells, whereas DPEP1 is negatively correlated with microsatellite-unstable (MSI-H) CRCs, which are T cell rich and are more responsive to immunotherapy. Remarkably, carcinogen-treated Dpep1-null mice develop multiple, large, plaque-like, locally invasive adenocarcinomas and squamous cell cancers in the distal colon. These adenocarcinomas exhibit a marked reduction in neutrophils and an influx CD8+ T cells, along with reduced expression of mismatch repair proteins, consistent with features of MSI-H CRC. These results establish DPEP1’s importance in maintaining MSS CRC and its ability to shape the tumor microenvironment.

Introduction Measurement of repeatability and reproducibility (R&R) is necessary to realize the full potential of positron emission tomography (PET). Several studies have evaluated the reproducibility of PET using 18F-FDG, the most common PET tracer used in oncology, but similar studies using other PET tracers are scarce. Even fewer assess agreement and R&R with statistical methods designed explicitly for the task. 18F-(2S, 4R)-4-fluoro-glutamine (18F-Gln) is a PET tracer designed for imaging glutamine uptake and metabolism. This study illustrates high reproducibility and repeatability with 18F-Gln for in vivo research. Methods Twenty mice bearing colorectal cancer cell line xenografts were injected with ~9 MBq of 18F-Gln and imaged in an Inveon microPET. Three individuals analyzed the tumor uptake of 18F-Gln using the same set of images, the same image analysis software, and the same analysis method. Scans were randomly re-ordered for a second repeatability measurement 6 months later. Statistical analyses were performed using the methods of Bland and Altman (B&A), Gauge Reproducibility and Repeatability (Gauge R&R), and Lin’s Concordance Correlation Coefficient. A comprehensive equivalency test, designed to reject a null hypothesis of non-equivalence, was also conducted. Results In a two-way random effects Gauge R&R model, variance among mice and their measurement variance were 0.5717 and 0.024. Reproducibility and repeatability accounted for 31% and 69% of the total measurement error, respectively. B&A repeatability coefficients for analysts 1, 2, and 3 were 0.16, 0.35, and 0.49. One-half B&A agreement limits between analysts 1 and 2, 1 and 3, and 2 and 3 were 0.27, 0.47, and 0.47, respectively. The mean square deviation and total deviation index were lowest for analysts 1 and 2, while coverage probabilities and coefficients of the individual agreement were highest. Finally, the definitive agreement inference hypothesis test for equivalency demonstrated that all three confidence intervals for the average difference of means from repeated measures lie within our a priori limits of equivalence (i.e. ± 0.5%ID/g). Conclusions Our data indicate high individual analyst and laboratory-level reproducibility and repeatability. The assessment of R&R using the appropriate methods is critical and should be adopted by the broader imaging community.

BACKGROUND:Mutations in TP53 are common in gastroesophageal cancer and portend a poor prognosis. Tumor cells with TP53 mutations increasingly rely on ataxia-telangiectasia and Rad3-related (ATR) protein to respond to and repair DNA damage induced by cytotoxic chemotherapy. We aimed to assess the efficacy of ATR inhibitor, berzosertib, with irinotecan in patients harboring TP53-mutated, metastatic gastroesophageal cancer. METHODS:NCI 10211 is a phase II trial that enrolled patients with TP53-mutated, unresectable or metastatic gastroesophageal adenocarcinoma to receive berzosertib with irinotecan on day 1, 15 in 28-day cycles. Initially, patients who had progressed on at least 1 prior line of therapy were enrolled which was later amended to at least 2 prior lines of therapy. The primary outcome was objective response rate (ORR), and secondary outcomes included progression-free survival (PFS) and overall survival (OS). Nine patients underwent biopsy for correlative studies, which included assay evaluation of γH2AX, NBS1, and KAP1 p-Ser 824 expression. RESULTS:Of the 17 patients enrolled, 16 were evaluable for the primary endpoint of ORR. The ORR was 0%, disease control rate (DCR) of 56.2%, median PFS (mPFS) of 4.01 months, and median OS (mOS) of 6.21 months. The study did not meet its primary endpoint. The most common treatment-related adverse events were nausea (52.9%), anemia (41.2%), diarrhea (41.2%), and lymphopenia (41.2%) without any unexpected adverse events. CONCLUSION:This novel combination of ATR inhibitor berzosertib with irinotecan did not lead to objective responses in patients with TP53-mutated, advanced gastroesophageal adenocarcinoma. The combination regimen was well tolerated without unexpected adverse events. This trial was registered with ClinicalTrials.gov (NCT03641313).

Abstract Although amplifications and mutations in receptor tyrosine kinases (RTKs) act as bona fide oncogenes, in most cancers, RTKs maintain moderate expression and remain wild-type. Consequently, cognate ligands control many facets of tumorigenesis, including resistance to anti-RTK therapies. Herein, we show that the ligands for the RTKs MET and RON, HGF and HGFL, respectively, are synthesized as inactive precursors that are activated by cellular proteases. Our newly generated HGF/HGFL protease inhibitors could overcome both de novo and acquired cetuximab resistance in colorectal cancer (CRC). Conversely, HGF overexpression was necessary and sufficient to induce cetuximab resistance and loss of polarity. Moreover, HGF-induced cetuximab resistance could be overcome by the downstream MET inhibitor, crizotinib, and upstream protease inhibitors. Additionally, HAI-1, an endogenous inhibitor of HGF proteases, (i) was downregulated in CRC, (ii) exhibited increased genomic methylation that correlated with poor prognosis, (iii) HAI-1 expression correlated with cetuximab response in a panel of cancer cell lines, and (iv) exogenous addition of recombinant HAI-1 overcame cetuximab resistance in CC-HGF cells. Thus, we describe a targetable, autocrine HAI-1/Protease/HGF/MET axis in cetuximab resistance in CRC. Citation Format: Vivian Truong Jones, Ramona Graves-Deal, Zheng Cao, Galina Bogatcheva, Marisol A. Ramirez, Sarah J. Harmych, James N. Higginbotham, Claudia C. Wahoski, Neeraj Joshi, Joseph T. Roland, Gregory D. Ayers, Qi Liu, Robert J. Coffey, James W. Janetka, Bhuminder Singh. Autocrine HGF maturation as a targetable regulatory step in cetuximab resistance in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2001.

Abstract The first-line treatment for metastatic melanoma is immune checkpoint blockade (ICB), but it fails in many patients and may have serious adverse events. We showed that rigosertib (RGS), a RAS-pathway inhibitor, promotes CD40 upregulation on melanoma cells and synergizes with ICB in preclinical melanoma models. However, residual disease still occurred with uncontrolled ERK activation. Our present study explores the efficacy of RGS plus trametinib (T), a MEK1/2 inhibitor, to overcome ICB resistance. The concurrent RGS+T+αPD1 resulted in an additive effect to suppress ICB-resistant NRASmut 1014 tumor growth, and 44.4% (4/9) tumors completely regressed after 2 weeks of treatment. The RGS+T regimen promoted CD8+ T cell responses in the tumor microenvironment (TME) and extended the time to αPD1 resistance (p<0.0001). Combining RGS+T with agonist CD40 (aCD40) resulted in increased CD8+ T cells, natural killer cells, and M1 macrophages in the TME, with a reduction of myeloid-like CD11b+PD-L1+ regulatory B cells in the tumors (~70%, p<0.0001) and tumor-draining lymph nodes (~40%, p<0.0001). CRISPR/dCas9-based overexpression of CD40 (CD40-OE) in 1014 melanoma cells reduced in vivo tumor growth and successfully turned the ICB-resistant tumors into responders to αPD1 (p=0.025), which further regressed with aCD40+αPD1 (p<0.001). Our preclinical data support the therapeutic use of RAS/RAF/PI3K inhibition plus CD40 agonism for metastatic melanoma patients who do not respond to ICB.