Citations

Abstract Purpose: Clear cell renal cell carcinoma (ccRCC) is frequently associated with inactivation of the von Hippel–Lindau tumor suppressor, resulting in activation of HIF-1α and HIF-2α. The current paradigm, established using mechanistic cell-based studies, supports a tumor promoting role for HIF-2α, and a tumor suppressor role for HIF-1α. However, few studies have comprehensively examined the clinical relevance of this paradigm. Furthermore, the hypoxia-associated factor (HAF), which regulates the HIFs, has not been comprehensively evaluated in ccRCC. Experimental Design: To assess the involvement of HAF/HIFs in ccRCC, we analyzed their relationship to tumor grade/stage/outcome using tissue from 380 patients, and validated these associations using tissue from 72 additional patients and a further 57 patients treated with antiangiogenic therapy for associations with response. Further characterization was performed using single-cell mRNA sequencing (scRNA-seq), RNA-in situ hybridization (RNA-ISH), and IHC. Results: HIF-1α was primarily expressed in tumor-associated macrophages (TAMs), whereas HIF-2α and HAF were expressed primarily in tumor cells. TAM-associated HIF-1α was significantly associated with high tumor grade and increased metastasis and was independently associated with decreased overall survival. Furthermore, elevated TAM HIF-1α was significantly associated with resistance to antiangiogenic therapy. In contrast, high HAF or HIF-2α were associated with low grade, decreased metastasis, and increased overall survival. scRNA-seq, RNA-ISH, and Western blotting confirmed the expression of HIF-1α in M2-polarized CD163-expressing TAMs. Conclusions: These findings highlight a potential role of TAM HIF-1α in ccRCC progression and support the reevaluation of HIF-1α as a therapeutic target and marker of disease progression.

AbstractIntroductionThe best management strategy for patients with atrial fibrillation (AF) with heart failure (HF) and preserved left ventricular ejection fraction (LVEF) is unknown.Methods and ResultsThis cohort study was conducted in Olmsted County, Minnesota, with resources of the Rochester Epidemiology Project. Patients with incident AF occurring between 2000 and 2014 with a prior or concurrent HF were included. Patients with LVEF ≥ 50% were designated as HF and preserved ejection fraction (HFpEF) and those with LVEF < 50% were designated as HF and reduced ejection fraction (HFrEF). Rhythm control in the first year after AF diagnosis was defined as prescriptions for an antiarrhythmic drug, catheter ablation, or maze procedure. The primary endpoint was all‐cause mortality. The secondary endpoints were cardiovascular death, cardiovascular hospitalization, and stroke or transient ischemic attack. Of 859 patients (age, 77.2 ± 12.1 years; 49.2%, female), 447 had HFpEF‐AF, and 412 had HFrEF‐AF. There was no difference in all‐cause mortality (10‐year mortality, 83% vs 79%; p = .54) or secondary endpoints between the HFpEF‐AF and HFrEF‐AF, respectively. Compared with the rate control strategy, rhythm control in HFpEF‐AF patients (n = 40, 15.9%) offered no survival benefits (adjusted HR, 0.70; 95% CI, 0.42–1.16; p = .16), whereas rhythm control in HFrEF‐AF patients (n = 52, 22.5%) decrease cardiovascular mortality (HR, 0.38; 95% CI, 0.17–0.86; p = .02).ConclusionsPatients with HFpEF‐AF and HFrEF‐AF had similar poor prognoses. Rhythm control strategy was seldom adopted in community care in patients with HF and AF. A rhythm control strategy may provide survival benefit for patients with HFrEF‐AF and the benefit of rhythm control in patients with HFpEF‐AF warrants further study.

Objective To investigate the prevalence of eustachian tube dysfunction (ETD) in elderly adults in the United States and its association with other upper aerodigestive inflammatory processes. Study Design Cross‐sectional study. Setting Population based. Subjects and Methods In total, 147,805 patients without malignancy were compared to 13,804 demographically matched patients with malignancy of the upper aerodigestive tract (UADT) by querying the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database for patients aged 66 to 99 years between 2003 and 2011. The prevalence of ETD and inflammatory diseases among these patients was compared. Association between ETD, other upper aerodigestive inflammatory processes, and UADT malignancies was evaluated. Results The prevalence of ETD was 5.44% among patients without malignancy and 9.08% in those with cancer (odds ratio [OR], 1.73; 95% CI, 1.63‐1.84). Patients with ETD in the control population were more likely (OR, 95% CI) to be diagnosed with chronic rhinitis (5.00, 4.70‐5.33), chronic sinusitis (4.20, 3.98‐4.43), allergic rhinitis (4.27, 4.08‐4.47), and gastroesophageal reflux disease (GERD) (2.42, 2.31‐2.53). Patients with ETD and chronic rhinitis (1.43, 1.24‐1.65), chronic sinusitis (1.57, 1.38‐1.78), and acute otitis media (1.33, 1.08‐1.65) were associated with higher rates of UADT malignancy. Conclusion Over 5% of patients older than 65 in the United States are diagnosed with ETD in the absence of UADT malignancy. Associations between ETD and chronic rhinitis, chronic sinusitis, allergic rhinitis, and GERD in the absence of UADT malignancy suggest that some patients may benefit from treatment of inflammatory disease as a cause of ETD.

OBJECTIVE Limited information is available about glycemic outcomes with a closed-loop control (CLC) system compared with a predictive low-glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS After 6 months of use of a CLC system in a randomized trial, 109 participants with type 1 diabetes (age range, 14–72 years; mean HbA1c, 7.1% [54 mmol/mol]) were randomly assigned to CLC (N = 54, Control-IQ) or PLGS (N = 55, Basal-IQ) groups for 3 months. The primary outcome was continuous glucose monitor (CGM)-measured time in range (TIR) for 70–180 mg/dL. Baseline CGM metrics were computed from the last 3 months of the preceding study. RESULTS All 109 participants completed the study. Mean ± SD TIR was 71.1 ± 11.2% at baseline and 67.6 ± 12.6% using intention-to-treat analysis (69.1 ± 12.2% using per-protocol analysis excluding periods of study-wide suspension of device use) over 13 weeks on CLC vs. 70.0 ± 13.6% and 60.4 ± 17.1% on PLGS (difference = 5.9%; 95% CI 3.6%, 8.3%; P &lt; 0.001). Time &gt;180 mg/dL was lower in the CLC group than PLGS group (difference = −6.0%; 95% CI −8.4%, −3.7%; P &lt; 0.001) while time &lt;54 mg/dL was similar (0.04%; 95% CI −0.05%, 0.13%; P = 0.41). HbA1c after 13 weeks was lower on CLC than PLGS (7.2% [55 mmol/mol] vs. 7.5% [56 mmol/mol], difference −0.34% [−3.7 mmol/mol]; 95% CI −0.57% [−6.2 mmol/mol], −0.11% [1.2 mmol/mol]; P = 0.0035). CONCLUSIONS Following 6 months of CLC, switching to PLGS reduced TIR and increased HbA1c toward their pre-CLC values, while hypoglycemia remained similarly reduced with both CLC and PLGS.

e20009 Background: Although treating B-Chronic Lymphocytic Leukemia (CLL) with small molecule inhibitors has shown promise, a lasting cure for this disease has yet to be found. Further treatments directed at key molecular targets in the CLL B cell need development for patients with adverse prognostic factors, and relapsed/refractory patients. We evaluated the impact of two novel drugs with non-overlapping mechanisms of action on CLL B cells: Voruciclib, a cyclin dependent kinase (CDK) inhibitor targeting CDKs 9, 6, 4, 1 and Venetoclax a BCL-2 inhibitor. To mimic the protective effect of the CLL micro-environment these experiments were done with CLL cells cocultured in the presence of bone marrow mesenchymal stromal cells (BMSC). Methods: Voruciclib, (MEI Pharma) and Venetoclax were tested for killing activity alone and in combination against CLL cells cocultured with healthy human bone marrow MSC. CLL B cells were from untreated patients stratified on risk of disease progression. Low risk had mutated and high risk patients had unmutated IVGH genetic status. CLL cells were cultured on BMSC’s with a series of escalating doses of individual drugs and drug combinations at fixed molar ratios then Annexin/PI stained for viability testing by flow cytometry. Killing curves generated for each drug/combination were analyzed by the combination index (C.I.) approach of Chou and Talalay with Calcusyn, characterizing interactions as synergistic, additive or inhibitory. C.I. value hierarchy classes synergy as moderate (0.7-0.9), synergistic (0.3-0.7), strong (0.1-0.3) and very strong (below 0.1). Results: CLL cells with unmutated IGVH status were more sensitive to Voruciclib than mutated IGVH both with and without BMSC’s. The combination Voruciclib +Venetoclax showed synergism for all patients regardless of risk; half strongly to very strongly (Table). Similar synergistic effects were seen with relapsed/refractory patients. Conclusions: Based on these preclinical data, Voruciclib + Venetoclax is a very promising combination to improve treatment of CLL patients. We speculate that CDK9 inhibition, which regulates transcription of Mcl-1, with Bcl-2 inhibition results in potent apoptosis induction in CLL B cells. [Table: see text]

3535 Background: Peripheral blood allows for a simple non-invasive method for isolating various cancer associated circulating stromal cells (CStCs) which may predict for cancer presence. Cancer Associated Macrophage-Like cells (CAMLs), a specific CStC, are phagocytic myeloid cells that derive from an immunological response to cancer and emanate from primary tumors. Using a filtration platform we screened the peripheral blood of untreated newly diagnosed cancer patients (n = 308) for CAMLs. In parallel, we screened patients with newly diagnosed non-malignant diseases, i.e. lupus, benign cysts, etc. (n = 39), and healthy control samples (n = 76). We found that CAMLs are highly prevalent (87%) in the blood of cancer patients, but uncommon in non-malignant conditions (20%) & absent in healthy individuals (0%). Methods: Anonymized peripheral blood were taken from 308 cancer patients after confirmation of invasive malignancy [stage I (n = 76), stage II (n = 73), stage III (n = 72), stage IV (n = 65) and unstaged non-metastatic (n = 22)] with pathologically confirmed lung (n = 65), pancreas (n = 53), breast (n = 52), prostate (n = 40), esophageal (n = 30), renal cell (n = 18), hepatocellular (n = 15), neuroblastoma (n = 10), melanoma (n = 8), and other (n = 17). Further, anonymized blood was taken from patients with untreated non-malignant conditions including benign breast masses (n = 19), lupus (n = 11), liver cirrhosis (n = 5), benign prostatic hyperplasia (BPH) (n = 3), and viral infection (n = 1); or from healthy control volunteers (n = 76). CAMLs were isolated from whole peripheral blood by the CellSieve™ microfiltration technique and defined as enlarged, multinuclear cells with cytokeratin and/or CD45/CD14 positive. Results: CAMLs were found in 87% of all cancer patients regardless of stage, ~5.4 CAMLs/7.5mL blood. Specifically, CAMLs were found in 80% of Stage I, 90% Stage II, 89% Stage III, and 97% Stage IV patients. No CAMLs were found in any healthy controls, but were found in 26% of benign breast masses, 18% of lupus, 0% of BPH and 0% of cirrhosis. In total, CAML sensitivity in cancer vs healthy was 87% (CI95% 82-90%), specificity = 100% (CI95% 95-100%), PPV = 100% (CI95% 100%), NPV = 67% (CI95% 58-71%). CAML sensitivity in cancer vs benign was 87% (CI95% 82-90%), specificity = 80% (CI95% 64-91%), PPV = 97% (CI95% 95-98%), NPV = 43% (CI95% 35-51%). Conclusions: CAMLs, a Circulating Stromal Cell subtype, is a sensitive blood based biomarker found in all stages of cancer that is rare in non-malignant conditions and absent in healthy individuals.

1512 Background: Tobacco smoking profoundly impacts LC risk; however, data are limited as to what extent SC prior to diagnosis impacts LC overall survival (OS) and lung cancer specific survival (LCSS). LC screening offers a possible teachable moment, but there is uncertainty of SC benefits after a lifetime of smoking. We use the ILCCO database to answer if SC prior to LC dx is associated with better OS and LCSS, considering time since smoking cessation (TSSC). Methods: Using individual data, analysis was performed on 17 ILCCO studies with available TSSC to estimate survival using univariable analysis and models of stage-adjusted and cumulative smoking-adjusted multivariable analysis. Adjusted Hazard Ratios (aHR) from Cox models, cubic spline smooth curves and Kaplan-Meier curves were created. Sensitivity analysis was performed for TSSC and LCSS on 13 studies. Results: Of 34649 patients, 14322 (41%) were current smokers 14273 (41%) ex-smokers and 6054 (18%) never smokers at diagnosis. We confirmed that ex-smokers (aHR 0.88 CI 0.86-0.91) and never smokers (aHR 0.76 CI 0.73-0.8) improved OS compared to current smokers. Amongst ex-smokers, < 2y TSSC (aHR 0.88 CI 0.82-0.94), 2-5y TSSC (aHR 0.83 CI 0.77-0.90) and > 5y TSSC (aHR 0.8 CI 0.76-0.84) had improved OS compared to CS. Sensitivity analysis showed a trend towards improved LCSS survival for < 2y TSSC (aHR 0.95 CI 0.86-1.05) and 2-5y TSSC (aHR 0.93 CI 0.83-1.04), whereas > 5y TSSC significantly improved LCSS by 15% (aHR 0.85 CI 0.78-0.92). To mimic the LC screening participants, in analysis of > 30 pack-years individuals, associations were strikingly strong: < 2y TSSC had improved OS by 14% (aHR 0.86 CI 0.80-0.93); 2-5y TSSC by 17% (aHR 0.83 CI 0.76-0.90); and > 5 TSSC by 22% (aHR 0.78 CI 0.74-0.83), compared to current smokers; for < 30 packs-years, a trend towards better OS was observed for < 2y TSSC (aHR 0.95 CI 0.92-1.02) and 2-5y TSSC (aHR 0.86 CI 0.74-1.01), whereas > 5y TSSC improved OS by 23% (aHR 0.77 CI 0.72-0.82). Conclusions: Among ex-smokers, the risk of overall death was reduced by 12% on < 2y TSSC, 17% on 2-5y TSSC and 20% > 5y TSSC, whereas for LCSS, the benefit was significant only for > 5y TSCC, compared to current smokers at time of diagnosis. Here we demonstrate that convincing screening participants to quit smoking at any point of their trajectory, even just prior to dx such as < 2y TSSC, improved OS, and LCSS benefit was present beyond 5y of quitting. These relationships are independent of pack-years, age, across all stages and other prognostic variables.

Abstract Introduction: Patients and their families and medical providers have assumed that psychologic stress impacts glucose control in T1D (Type 1 Diabetes) though studies providing confirmatory evidence in real world settings are, to our knowledge, lacking. We hypothesized that self-reported psychologic stress worsens glucose control in T1D. Method: We studied 20 adults with T1D on continuous glucose monitor (CGM), sensor augmented insulin pump (SAP) prospectively at 2 clinical research centers. Patients reported psychological stress through stress diaries for 5 weeks on a severity scale of 1-7 using hard copy logs including time of onset and offset of stress and severity. For analytic purpose, grades 1-4 are classified as mild and grades 5-7 as severe. Results: Baseline characteristics were age 44.9±15.0 years, F/M 12/8, HbA1c 6.8 ± 0.7%, and diabetes duration of 22.9±15.9 years. We analyzed glucose variability during days of stress versus days without stress. During a 24 hour period, patients experienced less hypoglycemia during days with stress versus days without stress (p value 0.03). During the 5 week period, patients reported 23 ± 19.5 events. We analyzed the impact of self-reported stress on CGM data streams after excluding stress events associated with missing CGM data, nocturnal events (from 12 MN to 6 AM, too few events) and events for which subjects did not provide duration of stress. Thus, we analyzed 19.5 ± 17 events per patient from 6AM to 12MN. From 6 AM to 12 MN, the episodes lasted 179 ± 255 minutes with 83 % episodes being mild/moderate and 17% moderate/ severe. Number of CGM readings during daytime stress episodes were 717± 1120 compared to 8768± 1238 during non-stress periods. Impact of stress from 6 AM to 12 MN (Mid-Night) on CGM glucose was analyzed using matched paired t test. Mean glucose (160.6±41.9 vs 148.3± 28.6) and SD (53.2 ±17.7 vs 56.1±14.6) did not show a difference; however % of time spent below 70 mg/dl was less (4 ± 5) in patients during stressful periods compared to times without stress (6.3± 5.5, P value 0.02). Conclusions: To our knowledge, this is the first study attempting to analyze the impact of self-reported stress using daily stress diaries on CGM data streams in T1D patients on SAP. The study revealed significant challenges experienced by patients in reporting adequate data. Self-reported stress was not associated with hyperglycemia. However, days of self-reported stress and periods during patients reported stress were characterized by less hypoglycemia on CGM data streams.

Abstract Background Hypothyroidism is known to be associated with adverse clinical outcomes in heart failure. The association between hypothyroidism and cardiac resynchronization therapy outcomes in patients with severe heart failure is not clear. Methods The study included 1,316 patients who received cardiac resynchronization therapy between 2002 and 2015. Baseline demographics and cardiac resynchronization therapy outcomes, including left ventricular ejection fraction, New York Heart Association class, appropriate implantable cardioverter-defibrillator therapy, and all-cause mortality, were collected from the electronic health record. Results Of the study cohort, 349 patients (26.5%) were classified as the hypothyroidism group. The median duration of follow-up was 3.6 years (interquartile range, 1.7-6.2). Hypothyroidism was associated with a greater all-cause mortality than euthyroidism (hazard ratio, 1.19; 95% CI, 1.01-1.38; P=0.04). In this group, the risk of appropriate implantable cardioverter-defibrillator therapy significantly increased in association with increased baseline thyroid-stimulating hormone level (hazard ratio, 1.27 per 5 mIU/L increase, 95% CI, 1.00-1.53, P=0.04). Conclusions Cardiac resynchronization therapy improves cardiac function in hypothyroid patients. Hypothyroidism has adverse effects on cardiac resynchronization therapy outcomes with reduced survival and increased implantable cardioverter-defibrillator therapies for ventricular arrhythmic events.

SummaryReduced‐intensity conditioning (RIC) allogeneic haematopoietic cell transplantation (allo‐HCT) is a curative option for select relapsed/refractory Hodgkin lymphoma (HL) patients; however, there are sparse data to support superiority of any particular conditioning regimen. We analyzed 492 adult patients undergoing human leucocyte antigen (HLA)‐matched sibling or unrelated donor allo‐HCT for HL between 2008 and 2016, utilizing RIC with either fludarabine/busulfan (Flu/Bu), fludarabine/melphalan (Flu/Mel140) or fludarabine/cyclophosphamide (Flu/Cy). Multivariable regression analysis was performed using a significance level of <0·01. There were no significant differences between regimens in risk for non‐relapse mortality (NRM) (P = 0·54), relapse/progression (P = 0·02) or progression‐free survival (PFS) (P = 0·14). Flu/Cy conditioning was associated with decreased risk of mortality in the first 11 months after allo‐HCT (HR = 0·28; 95% CI = 0·10–0·73; P = 0·009), but beyond 11 months post allo‐HCT it was associated with a significantly higher risk of mortality, (HR = 2·46; 95% CI = 0·1.32–4·61; P = 0·005). Four‐year adjusted overall survival (OS) was similar across regimens at 62% for Flu/Bu, 59% for Flu/Mel140 and 55% for Flu/Cy (P = 0·64), respectively. These data confirm the choice of RIC for allo‐HCT in HL does not influence risk of relapse, NRM or PFS. Although no OS benefit was seen between Flu/Bu and Flu/Mel 140; Flu/Cy was associated with a significantly higher risk of mortality beyond 11 months from allo‐HCT (possibly due to late NRM events).