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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).

Abstract Background While consensus guidelines regarding VTE prophylaxis for hospital inpatients have been available for more than 15 years, the number of US inpatients who are potentially eligible for prophylaxis is unknown. Such data are required for estimating the potential costs and benefits of prophylaxis in reducing VTE incidence. Objective To estimate the number of Y2002 US acute-care hospital inpatients who are potentially eligible for VTE prophylaxis. Methods We applied the 7th (2004) American College of Chest Physician (ACCP) Consensus Conference VTE prophylaxis guidelines (Geerts et al. Chest2004;126:338S–400S) to inpatients with hospital discharge International Classification of Disease (ICD-9) codes for major surgery or medical illness identified from the Healthcare Utilization and Cost Database (HCUP), a national acute-care hospital database supported by the US Agency for Health Care Quality Research. Results Of a total of 37.8 million inpatients discharged from US acute-care hospitals in Y2002, 13.4 million (35%) met ACCP guideline criteria for VTE prophylaxis (Table). Table. Inpatients Discharged from US Acute-Care Hospitals with ACCP Guideline Defined Risk of VTE in Y2002 Surgical VTE Risk N Highest risk surgery 744,465 High risk surgery 3,031,318 Moderate risk surgery 2,019,696 Surgical subtotal 5,795,479 Medical VTE Risk N Heart failure 1,867,576 Cancer 1,017,356 Stroke 515,370 Other medical conditions 4,196,343 Medical subtotal 7,596,645 Grand Total 13,392,124 Among the 37.8 million Y2002 discharged inpatinets, 7.7 million were defined by HCUP criteria as having had a major operative procedure. When ACCP surgical risk criteria were applied to this population, 1.9 (25%) were at low VTE risk, while 5.8 million (75%) were at moderate (26%), high (39%) or highest (10%) VTE risk. Among the patients without a major operative procedure, 7.6 million met the ACCP criteria for VTE prophylaxis based on medical illness risk factors. Conclusions In total, 13.4 million US residents meet ACCP criteria for VTE prophylaxis annually due to hospitalization for either major surgery or medical illness. Given that almost 60% of all VTE events occurring in the community are related to recent acute-care hospitalization, providing universal, safe and effective VTE prophylaxis to this population affords an important opportunity to significantly reduce the incidence of VTE. These data provide support for developing and monitoring compliance with hospital-wide guidelines for VTE prevention.

Abstract Background The total annual number of VTE events and related deaths in the US is unknown, largely because the complete spectrum of disease (including asymptomatic events and sudden deaths) occurring in the community is under-recognized. Objective To estimate the total annual number of non-fatal and fatal deep vein thrombosis (DVT) and pulmonary embolism (PE) events (incident and recurrent) in the US. Methods We developed an incidence-based model that included both hospital- and community-acquired VTE events as well as death from recognized and unrecognized VTE. We estimated the annual number of community-acquired events using the average age-, sex-, and event-specific incidence rates in Olmsted County, MN (1966–1990) and Y2000 US census data. We estimated the annual number of hospital-acquired events using patient age and Y2002 International Classification of Disease (ICD-9) discharge diagnosis codes for major surgery types or acute medical illnesses within the Healthcare Utilization and Cost Database, which includes major discharge diagnoses from all US acute-care hospitals. Patients were included in the hospital model if they were deemed at risk of VTE according to current American College of Chest Physicians definitions. The hospital at-risk population was divided into categories according to type of surgery or medical diagnosis on admission. We estimated the annual number of VTE events based on the published probability of VTE with and without prophylaxis, and US prophylaxis rates, by risk group. Fatal and recurrent events were estimated based on published data. The effects of VTE and prophylaxis rate uncertainty on our estimates were tested using sensitivity analyses. Results The estimated total annual number of symptomatic VTE events in the US exceeded 600,000, (DVT, n=376,365; PE, n=237,058. Table). Table. Annual Number of Non-Fatal and Fatal, Community- and Hospital-Acquired Symptomatic VTE Events in the US Event Type Community Hospital Total Non-Fatal ---------n---------- DVT 108,240 268,125 376,365 PE 85,358 151,700 237,058 Total 193,598 419,825 613,423 Fatal DVT 649 1,609 2,258 PE 105,902 188,210 294,112 Total 106,550 189,819 296,370 VTE-related deaths were estimated at 296,370 annually. Of these deaths, 21,223 (7%) patients were diagnosed with VTE and treated, 101,032 (34%) were sudden fatal PE and 174,115 (59%) followed undetected PE. Approximately two-thirds of symptomatic VTE events were hospital-acquired and one-third were community-acquired. Conclusions Our study confirms that VTE is a major US health problem. Given that effective VTE prophylaxis and expert consensus prophylaxis guidelines are widely available, these data suggest that universal, safe and effective prophylaxis could significantly reduce US VTE incidence and related deaths. Future studies should address the impact of universal VTE prophylaxis on VTE incidence and survival.

Background: Atrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described. Methods: We assessed factors associated with a 1-year increase in the Atrial Fibrillation Effect on Quality-of-Life score of 1 SD (≥18 points; 3× clinically important difference), among outpatients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I registry. Results: Overall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 versus 74, P =0.3), equally likely to be female (44% versus 48%, P =0.3), but more likely to have newly diagnosed AF at baseline (18% versus 8%; P =0.0004), prior antiarrhythmic drug use (52% versus 40%, P =0.005), baseline antiarrhythmic drug use (34.8% versus 26.8%, P =0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% versus 2.0%, P =0.003; cardioversion: 12.2% versus 5.9%, P =0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR, 2.41; P =0.01) and increased baseline diastolic blood pressure (adjusted OR, 1.23 per 10-point increase and >65 mm Hg; P =0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/transient ischemic attack, chronic obstructive pulmonary disease, and peripheral arterial disease were less likely to improve ( P <0.05 for each). Conclusions: In this national registry of patients with AF, potentially treatable AF risk factors are associated with large hrQoL improvement, whereas less reversible conditions appeared negatively associated with hrQoL improvement. Understanding which patients are most likely to have large hrQoL improvement may facilitate targeting interventions for high-value care that optimizes patient-reported outcomes in AF. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01165710.

Abstract Background: Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. Biomarkers that can help monitor the progression of PD or response to disease-modifying agents will be invaluable in making appropriate therapeutic decisions. Further, biomarkers that could be used to distinguish PD from other related disorders with PD-like symptoms will be useful for accurate diagnosis and treatment. C-Abl tyrosine kinase is activated in PD resulting in increased phosphorylation of the tyrosine residue at position 39 (Y39) of a-synuclein (a-syn) (pY39 a-syn), which contributes to the death of dopaminergic neurons. Because pY39 a-syn may be pathogenic, monitoring pY39 a-syn could allow us to diagnose presymptomatic PD and help monitor disease progression and response to treatment. We sought to investigate if increased phosphorylation of pY39 a-syn can be detected in the cerebrospinal fluid (CSF) of PD patients by targeted mass spectrometry. Methods: Here, we report a two-step enrichment method in which phosphotyrosine peptides were first enriched with an anti-phosphotyrosine antibody followed by a second round of enrichment by titanium dioxide (TiO2) beads to detect EGVLpYVGSK sequence derived from tyrosine 39 region of α- and β-synuclein (aβ-syn). Accurate quantification was achieved by adding a synthetic heavy version of pY39 aβ-syn peptide before enzymatic digestion. Results: Using the developed enrichment methods and optimized parallel reaction monitoring (PRM) assays, we detected pY39 aβ-syn peptide in human CSF and demonstrated that the ratio of pY39 aβ-syn to Y39 aβ-syn was significantly increased in the CSF of patients with PD.Conclusions: We anticipate that this optimized two-step enrichment-based PRM detection method will help monitor c-Abl activation in PD patients and can also be used to quantify other phosphotyrosine peptides of low abundance in biological samples.

Abstract Purpose: NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in non–small cell lung cancer (NSCLC), indicating its association with the clinical benefit of immune checkpoint inhibitors (ICI). We hypothesized that NOTCH mutation in NSCLC might be a robust predictor of immunotherapeutic efficacy. Experimental Design: Multiple-dimensional data including genomic, transcriptomic, and clinical data from cohorts of NSCLC internal and public cohorts involving immunotherapeutic patients were analyzed. Polymorphism Phenotyping v2 (PolyPhen-2) system was performed to determine deleterious NOTCH mutation (del-NOTCHmut). Further investigation on molecular mechanism was performed in The Cancer Genome Atlas (TCGA) data via CIBERSORT and gene set enrichment analysis. Results: Our 3DMed cohort (n = 58) and other four cohorts (Rizvi, POPLAR/OAK, Van Allen, and MSKCC; n = 1,499) uncovered marked correlation between NOTCH1/2/3 mutation and better ICI outcomes in EGFR/ALKWT population, including objective response rate (2.20-fold, P = 0.001), progression-free survival [HR, 0.61; 95% confidence interval (CI), 0.46–0.81; P = 0.001], and overall survival (HR, 0.56; 95% CI, 0.32–0.96; P = 0.035). Del-NOTCHmut exhibited better predictive function than non-deleterious NOTCH mutation, potentially via greater transcription of genes related to DNA damage response and immune activation. Del-NOTCHmut was not linked with prognosis in TCGA cohorts and chemotherapeutic response, but was independently associated with immunotherapeutic benefit, delineating the predictive, but not prognostic, utility of del-NOTCHmut. Conclusions: This work distinguishes del-NOTCHmut as a potential predictor to favorable ICI response in NSCLC, highlighting the importance of genomic profiling in immunotherapy. More importantly, our results unravel a possibility of personalized combination immunotherapy as adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.

Abstract Context Glucagon increases energy expenditure; consequently, glucagon receptor agonists are in development for the treatment of obesity. Obesity negatively affects the reproductive axis, and hypogonadism itself can exacerbate weight gain. Therefore, knowledge of the effects of glucagon receptor agonism on reproductive hormones is important for developing therapeutics for obesity; but reports in the literature about the effects of glucagon receptor agonism on the reproductive axis are conflicting. Objective The objective of this work is to investigate the effect of glucagon administration on reproductive hormone secretion in healthy young men. Design A single-blinded, randomized, placebo-controlled crossover study was conducted. Setting The setting of this study was the Clinical Research Facility, Imperial College Healthcare NHS Trust. Participants Eighteen healthy eugonadal men (mean ± SEM: age 25.1 ± 1.0 years; body mass index 22.5 ± 0.4 kg/m2; testosterone 21.2 ± 1.2 nmol/L) participated in this study. Intervention An 8-hour intravenous infusion of 2 pmol/kg/min glucagon or rate-matched vehicle infusion was administered. Main Outcome Measures Luteinizing hormone (LH) pulsatility; LH, follicle-stimulating hormone (FSH), and testosterone levels were measured. Results Although glucagon administration induced metabolic effects (insulin area under the curve: vehicle 1065 ± 292 min.µU/mL vs glucagon 2098 ± 358 min.µU/mL, P &lt; .001), it did not affect LH pulsatility (number of LH pulses/500 min: vehicle 4.7 ± 0.4, glucagon 4.2 ± 0.4, P = .22). Additionally, there were no significant differences in circulating LH, FSH, or testosterone levels during glucagon administration compared with vehicle administration. Conclusions Acute administration of a metabolically active dose of glucagon does not alter reproductive hormone secretion in healthy men. These data are important for the continued development of glucagon-based treatments for obesity.