Citations

Introduction: The relative performance of carotid artery stenting (CAS) and carotid endarterectomy (CEA) among Medicare beneficiaries in routine clinical practice has not been established. Objective: To compare the performance of CAS relative to CEA among Medicare beneficiaries. Methods: We linked Medicare data (2000-2009) to the Society for Vascular Surgery’s Vascular Registry (SVS-VR; 2005-2008) and to the NCDR® Carotid Artery Revascularization and Endarterectomy Registry (CARE; 2006-2008/9). Medicare patients aged ≥66 years undergoing CAS or CEA were followed from the procedure date for the outcomes of death, stroke/transient ischemic attack (TIA), peri-procedural myocardial infarction (MI) or a composite endpoint for these outcomes. We derived high-dimensional propensity scores using registry and Medicare data to control for patient-level factors and adjusted for provider-level factors including past-year CAS/CEA physician and hospital volume, hospital ownership, teaching affiliation, and hospital size in a Cox regression model comparing CAS to CEA. Results: Among 5,254 SVS-VR (1,999 CAS and 3,255 CEA) and 4,055 CARE (2,824 CAS and 1,231 CEA) patients, CAS patients were more often at higher surgical risk (SVS-VR: 96.7% vs. 44.5%; CARE: 71.3% vs. 44.7%) and had a higher comorbidity burden. Crude outcome risks for death and stroke/TIA were lower for CEA. Adjusting for patient-level factors drove estimates downwards for CAS relative to CEA but only after further adjustment for provider-level factors did the performance of CAS and CEA become comparable on all outcomes (figure 1). Conclusion: Performance of CAS and CEA among Medicare beneficiaries was comparable after accounting for patient- and provider-level factors, which is consistent with landmark trials. Further studies are needed to understand the role of heterogeneity in provider-level characteristics.

Abstract The role of maternal microbiome transmitted at birth in cancer control is poorly understood. We have developed the first germfree B6 mouse model of breast cancer to investigate the role of the maternal microbiome in controlling oncogenic/metastatic frequencies of pro-oncogenic mammary cells. In this model, a DNA barcoded, primitive normal mouse mammary epithelial cell encoding MMTV-PyMT oncogene, was transplanted in large numbers into conventional or germfree B6 mice. Next-gen sequencing analysis of the DNA barcodes in tissues enabled us to clonally track millions of cells and measure the frequency and growth dynamics of clones at the primary site and their systemic distribution in circulation and all vital organs, generating an unprecedented high-definition map of cancer progression. Our results show that in conventional B6 mice with maternal microbial transmission at-birth, a small fraction (~0.01%) of transplanted cells transform de novo and produce slow growing, late-onset benign tumors (mouse median survival of > 1 year). In contrast, in germfree B6 mice, a >10-fold higher frequency of cells transform de novo and generate early-onset, highly aggressive metastatic clones, and are frequently associated with features leading to early euthanasia or endpoint (i.e. sudden death, intracardiac metastasis, paralysis, swollen abdomen, early multiorgan aggressive metastasis) (median survival of ~4 months; p<0.005 vs conventional mice). However, postnatal intervention with healthy fecal implants reconstituted gut microbiota in germfree B6 mice and significantly restored protective effects against cancer progression and sudden death, as well as improved quality/duration of life (median survival of >1 year; p<0.005 vs germfree mice; p=ns vs conventional mice). We found maternal microbial transmission fully protected against systemic metastasis. GC-MS analysis identified significantly distinct primary tumor metabolome associated with conventional (non-metastatic) mice vs germfree (metastatic) mice. Metagenomic analysis of fecal samples from a subset of tumor bearing conventional (non-metastatic) mice vs fecal implanted (late-onset, less aggressive metastatic) germfree mice identified significant association between metastasis and altered microbial communities. These findings using novel germfree mouse model of metastasis and cellular DNA barcoding technology provide first direct evidence that diverse microbial communities transmitted at birth play a critical role in protecting the host from clonal de novo mammary cell transformation and progression to systemic disease and thereby improving quality and duration of life. Citation Format: Nagarajan Kannan, Syed Mohammed Musheer Aalam, Xiaojia Tang, Krishna Kalari, Purna Kashyap, Jun Chen, Stephen Johnson, Anguraj Sadanandam, Mark Sherman. Maternal microbiome protects host against clonal de novo transformation, early onset systemic metastasis, and sudden death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB226.

Abstract Background: A previous neoadjuvant study in patients with triple negative breast cancer (TNBC) demonstrated that low tumor infiltrating lymphocytes (TILs) after neoadjuvant chemotherapy is associated with a poor outcome. Activation of RAS/MAPK pathway has been associated with reduced TILs. Preclinical studies showed that MEK inhibitor enhances immune responses and is synergistic with anti PD-1/PD-L1 therapy in TNBC. Methods: The standard Phase I 3+3 study design was used. Patients with unresectable locally advanced or metastatic TNBC with ≤ 3 prior lines of therapy were enrolled. Patients received single agent binimetinib for 2 weeks prior to an addition of pembrolizumab. Dose level 0 was binimetinib at 45 mg oral twice daily continuously and dose level -1 was 30 mg twice daily. Pembrolizumab was given at a fixed dose of 200 mg every 3 weeks in both dose levels. The maximum tolerated dose (MTD) was defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) during the first 2 cycles in at least one-third of patients. Results: A total of 12 evaluable patients were enrolled in the phase I, 4 patients in dose level 0 and 8 patients in dose level -1. In dose level 0, among 3 out of 4 patients who were evaluable for DLT, 2 patients experienced DLTs, including grade (G) 3 nausea, vomiting, abdominal pain and G3 ALT elevation. Thus, the stopping rule was met and the dose level was adjusted to dose level -1. None of the first 3 patients in dose level -1 experienced a DLT. All three experienced other ≥ G3 AEs, including 1 G3 cardiac troponin T increased and 2 with G3 hypertension. 5 additional patients were accrued to dose level -1 and were evaluable for AEs. Three of these were evaluable for DLTs. One patient had G3 ALT/AST increase, deemed a DLT. However, this patient had liver metastasis and had G1 ALT/AST elevation at baseline. Her ALT/AST normalized in 3 weeks after treatment discontinuation and oral prednisone. Other ≥ G3 toxicities in the second group of 5 patients in dose level -1 include G3 hypertension (12.5%), nausea (12.5%), hypokalemia (12.5%), neutrophil count decrease (12.5%) dyspnea (12.5%), peripheral neuropathy (12.5%), and retinal detachment (12.5%). Since less than 1/3 of patients experienced DLT and there was no ≥ G4 AE at least possibly related to treatment over all cycles at any given dose level, the MTD was determined as dose level -1. Five patients are currently enrolled in the phase II section, and 10 more patients are needed. Objective response rate analysis will be performed once study enrollment is completed. Conclusions: The recommended phase II doses for pembrolizumab in combination with binimetinib are 200 mg every 3 weeks and 30 mg twice daily, respectively. The combination appears to be safe with manageable toxicities. Long term durable response has been observed. The phase 2 portion of this trial is currently on going. Citation Format: Saranya Chumsri, Jun He, David Hillman, Morgan Weidner, Morgan Weidner, Dana Haley, Aline Reis, Kathleen Tenner, Pooja Advani, Kostandinos Sideras, Alvaro Moreno-Aspitia, Edith Perez, Keith Knutson. Results of phase I study of pembrolizumab in combination with binimetinib in patients with unresectable locally advanced or metastatic triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT133.

Abstract Background: Mixed acinar neuroendocrine carcinoma (MANEC) of the pancreas is an extremely rare histopathologic subtype. MANEC is an amphicrine malignancy composed of at least 25% of acinar cell carcinoma (PACC) and neuroendocrine carcinoma (pNET). No standard systemic treatment is available for MANEC and current recommendations are derived from standard of care for PACC or pNET. Platinum based regimens have been approved for PACC while targeted agents (sunitinib and everolimus) are approved for pNET. This study aimed to investigate the antitumor effect and toxicities of both platinum based and targeted agents on a successfully first described patient derived xenograft (PDX) of metastatic MANEC of the pancreas. Methods: Several generations of PDX from a surgically resected metastatic MANEC of the pancreas was histologically validated. PDX-MANEC tumors were heterotopically implanted into NOD/SCID mice and randomized into 6 groups (4 mice each) as in table 1. The study continued for 3 weeks. Antitumor efficacy was determined based on change in the tumor volume. Toxicity was assessed change in mice weights. Results: Table 1 shows the changes in tumor volume and mouse weight in all study arms compared to controls end point. Only FOLFIRINOX and gemcitabine/cisplatin arms revealed overall decrease in tumor volume lower than starting volume in controls. All arms other than sunitinib, led to decrease in overall tumor volume compared to control tumor volumes over time. All treatment arms led to lower trending mouse weights (toxicities) except sunitinib, however only the everolimus arm had statistical significance. Conclusion: Both platinum-based regimens and everolimus revealed significant tumor control. No synergistic effect observed in sunitinib/everolimus. Preclinical studies are undergoing to investigate other effective and less toxic therapeutics for MANEC. Table 1.Delta in tumor volumes of PDX-MANEC-P after multiple platinum-based chemotherapy regimens and targeted therapeutics from the standard of care for other pancreatic cancer subtypes including PACC and pNET.ControlFOLFIRINOXGemcitabine and CisplatinSunitinibEverolimusSunitinib and EverolimusDelta in tumor volume in mm3 at the study end (mean ± standard deviation)3225 ± 2054-609.3 ± 351.8-654.7 ± 92.561583 ± 950.3-178.1 ± 61.58-160.8 ± 86.55P value (column group vs. control)<0.0010.0030.0950.0010.001Delta in mice weight in grams at the study end (mean ± standard deviation)0.84 ± 1.68-1.26 ± 0.84-8.5 ± 1.630.86 ± 1.22-2.2 ± 1.61-1.42 ± 1.27P value (column group vs. control)0.058<0.0010.9810.0070.050 Citation Format: Amro M. Abdelrahman, Jennifer A. Yonkus, Roberto Alva-Ruiz, Jennifer L. Leiting, Nellie A. Campbell, Lewis R. Roberts, Michael L. Kendrick, David M. Nagorney, Sean P. Cleary, Travis E. Grotz, Gregory J. Gores, Jun Yin, Rondell P. Graham, Thorvardur R. Halfdanarson, Rory L. Smoot, Mark J. Truty. Preclinical efficacy of platinum based chemotherapy regimens and targeted therapeutics in the first successful described patient derived xenograft model of mixed acinar neuroendocrine carcinoma of the pancreas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 413.

Abstract Purpose: Hepatocellular Carcinoma (HCC) is the leading cause of cancer-related mortality in Nigeria. HIV and viral hepatitis B (HBV) and C (HCV) co-infection are common in Nigeria that significantly accelerates liver disease progression including HCC. Aging-related DNA methylation signatures obtained in liquid biopsy, such as circulating cell-free DNA (ccfDNA) extracted from serum/plasma are promising minimally-invasive biomarkers that may inform HIV-associated HCC. We examined the epigenetic age acceleration (EpiAgeAccel) in ccfDNA in HCC patients with HIV. Methods: The study included three groups of participants: a) HIV positive with HCC (n=7); b) HIV positive and cancer-free (n=45); and c) HIV negative with HCC (n=33). Epigenetic age was estimated by Horvath's calculator using genome-wide ccfDNA methylation data profiled by Illumina EPIC array. EpiAgeAccel was computed as the residuals of a linear model of epigenetic age on chronological age, namely the unexplained portion of epigenetic age by chronological age. We used multiple linear regression to compare EpiAgeAccel between HIV/HCC groups, adjusting for sex, age, education, alcohol intake, and HBV/HCV infection. Results: Among HIV positive participants, there was a higher percentage of men (57% vs. 22%, p<0.001), HBV infection (29% vs. 11%, p=0.004), and HCV infection (57% vs. 2%, p<0.001) in the HCC group compared to the cancer-free group. EpiAgeAccel was 4.8 years higher in HIV positive patients with HCC compared to cancer-free HIV positives (p=0.02). Among HCC patients, EpiAgeAccel was 2.1 years higher in HIV positives compared to HIV negative but not statistically significant. Conclusion: Epigenetic age in ccfDNA is accelerated in HIV-positive HCC patients. EpiAgeAccel measured in ccfDNA may be developed into a surrogate biomarker for minimally invasive HCC detection among HIV-infected patients in low- and middle-income countries. Citation Format: Yinan Zheng, Claudia Hawkins, Edith Okeke, Mary Duguru, Emuobor Odeghe, Olufunmilayo Lesi, Yishu Qu, Kyeezu Kim, Brian Joyce, Jun Wang, Lewis Roberts, Demirkan Gursel, Abdulkareem Fatimah, Alani Akanmu, Godwin Imade, Jian-Jun Wei, Masha Kocherginsky, Kwang-Youn Kim, Oluwakemi Odukoya, Wasiu Adeyemo, Firas Wehbe, Chad Achenbach, Atiene Sagay, Folasade Ogunsola, Robert Murphy, Lifang Hou. Blood-Based Circulating Cell-Free DNA Epigenetic Age Is Accelerated Among HIV-Infected Patients with Hepatocellular Carcinoma in Nigeria [abstract]. In: Proceedings of the 9th Annual Symposium on Global Cancer Research; Global Cancer Research and Control: Looking Back and Charting a Path Forward; 2021 Mar 10-11. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2021;30(7 Suppl):Abstract nr 83.

Background: Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs). Design: Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions. Results: Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland ( p = 0.0034 and p < 0.001, respectively), with median difference of 3–4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients ( p < 0.001). Conclusions: Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies.

Abstract Androgen receptor (AR) is a major survival factor for prostate cancer. Inflammation is implicated in many cancer types, including prostate cancer. Activation of MAP3K7 (also termed TAK1) and downstream IκB kinase β (IKKβ) by proinflammatory cytokines such as TNFα stimulates NF-κB survival pathways. Paradoxically, MAP3K7 is often deleted in human prostate cancer. Here, we demonstrate that AR protein expression is lower in inflammatory tumor areas compared with non-inflammatory tissues in patients with prostate cancer. Map3k7 knockout increased AR protein levels and activity in the mouse prostate, and MAP3K7 and AR protein levels were inversely correlated in prostate cancer patient specimens. TNFα treatment increased AR protein ubiquitination and proteasomal degradation. Mechanistically, activation of IKKβ by TNFα induced phosphorylation and TRCP1/2 E3 ligase–mediated polyubiquitination and degradation of AR protein. TNFα suppressed prostate cancer proliferation, which could be rescued by blockade of AR degradation. These findings reveal a previously unrecognized tumor suppressive function of the inflammation-activated MAP3K7–IKKβ axis in degrading AR protein. Moreover, they suggest that aberrant elevation of AR protein could be a prognostic biomarker and therapeutic target for MAP3K7-deficient prostate cancer. Significance: This study identifies that MAP3K7–IKKβ signaling plays a tumor-suppressive role in prostate cancer by degrading AR, revealing potential prognostic and therapeutic strategies for MAP3K7-deficient tumors.

ABSTRACTThe purpose of this study was to determine the sex differences in the overall prevalence of radiographic femoroacetabular impingement (FAI) deformity patients presenting with hip pain and to identify the most common radiographic findings in male and female patients. A geographic database was used to identify patients between the age of 14 and 50 years with hip pain from 2000 to 2016. A chart and radiographic review was performed to identify patients with cam, pincer and mixed-type FAI. A total of 374 (449 hips) out of 612 (695 hips) male patients and 771 (922 hips) out of 1281 (1447 hips) female patients had radiographic features consistent with FAI. Ninety-four male hips (20.9%) and 45 female hips (4.9%) had cam type, 20 male hips (4.5%) and 225 female hips (24.4%) had pincer type and 335 male hips (74.6%) and 652 female hips (70.7%) had mixed type. The overall prevalence of radiographic findings consistent with FAI in male and female patients with hip pain was 61.1% and 60.2%, respectively. Mixed type was the most prevalent. The most common radiographic finding for cam-type FAI was an alpha angle &gt;55°, and the most common radiographic finding for pincer-type FAI was a crossover sign. Male patients were found to have a higher prevalence of cam-type deformities, whereas female patients were found to have a higher prevalence of pincer-type deformities.

Background: Insulin-like growth factor binding protein7 (IGFBP-7) and tissue inhibitor of metalloproteinase-2 (TIMP-2) reflect G1-cell cycle arrest and are used as biomarkers for AKI. Recent studies show that these biomarkers rise in ischemic conditions and suggest that they actually may limit the severity of AKI. We tested the hypothesis that renal vein [IGFBP-7]*[TIMP-2] correlate with reductions in renal blood flow (RBF) and post-stent single kidney (SK)-GFR changes in patients with RVD undergoing contrast-based imaging and stent revascularization Methods: Inpatient studies were performed during 150 mEq Na+ intake and ACE/ARB Rx in patients with hemodynamically severe RVD (n=29, Doppler velocity = 318 ± 100cm/sec, and eGFR= 34.7 ± 11.7 mL/ min) scheduled for renal artery stenting, and compared to essential hypertensive (EH) healthy controls (n=32). Cortical and medullary RBFs (by multidetector CT) and renal vein levels of IGFBP-7 and TIMP-2 were measured before renal artery stenting and 3 months later Results: Pre-stenting IGFBP-7 and TIMP-2 levels were elevated in RVD compared to EH (18.5±2. vs 15.7±1.5 and 97.4±23.1vs 62.7±9.2 ng/mL respectively, P <0.0001). Baseline renal vein levels of IGFBP-7 * TIMP-2 correlated inversely with pre-stent RBF (r= - 0.53, P=0.01) and directly with the change (%) in SK-GFR observed 3 months after stenting Conclusion: IGFBP-7 and TIMP-2 levels are elevated in patients with chronic RVD as a function of the baseline reduction in RBF, and associate with subsequent improvement in SK-GFR 3 months after revascularization. These data are consistent with renovascular occlusion inducing cell-cycle arrest that serves to protect kidney function.

High‐fat diets induce changes in the gut microbiome and induce nonalcoholic fatty liver disease. This study tested the hypothesis that high‐fat feeding increases certain predominant hind gut bacteria in a C57BL/6 mouse model of obesity. We found that a high‐fat diet produced significant increases in both body weight and body fat percentage in C57BL/6 mice compared with a control group fed a low‐fat diet. With an immunohistochemical approach, we found that these changes were associated with increases in lipid droplets, inflammatory cell infiltration and inducible nitric oxide synthase (iNOS) level in the livers of mice fed the high‐fat diet. In addition, plasma leptin and tumor necrosis factor (TNFα) levels were elevated in mice fed the high‐fat diet, indicative of chronic inflammation. Eight out of twelve bacterial species that typically predominate hind gut microbial ecology were detected in fecal samples by DNA analysis. The DNA amount of one of these species, Lactobacillus (L.) acidophilus , was 6900‐fold greater in high‐fat fed mice compared to controls. L. acidophilus can promote inflammatory production of cytokines such as TNFα, which was also elevated in high‐fat fed mice. These results suggest that changes in the hindgut microbiome which accompany high fat feeding may contribute to the development of steatohepatitis in obese mice.