Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence ...demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (−2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.
•End of treatment HD-MTX did not increase risk of CNS relapse compared with intercalated delivery and caused fewer delays to R-CHOP therapy.•CNS relapse rates in this large analysis of HD-MTX-treated patients were similar to published cohorts receiving minimal CNS prophylaxis.
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Background
Harvard Pilgrim Health Care expanded coverage for non-invasive prenatal testing (NIPT) to include all pregnant, single-gestation women aged < 35 years, through a performance-based ...risk-sharing (PBRS) agreement with Illumina to offset costs from coverage expansion. NIPT analyzes cell-free DNA fragments from a maternal blood sample to screen for fetal aneuploidies and is considered a more accurate screening method than conventional serum biochemical screening and nuchal translucency ultrasound-based approaches.
Objective
This study assessed the impact of NIPT coverage expansion on prenatal screening strategies and payer expenditures.
Methods
This was a real-world comparison of utilization and expenditures of prenatal screening and diagnostic testing in pregnant women aged < 35 years pre- (1 March 2016–28 February 2018) and post- (1 March 2018–30 September 2019) coverage expansion. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were estimated to compare changes in utilization of conventional and NIPT-based prenatal screening methods. Change in per member per month (PMPM) expenditures in $US year 2020 were assessed post-coverage expansion using a budget impact model.
Results
A total of 5041 and 4109 distinct pregnancies were identified in pre- and post-coverage expansion periods, respectively. Mean ± standard deviation maternal age was consistent between pre- and post-coverage expansion periods (30.35 ± 3.35 and 30.33 ± 3.28, respectively). Screening orders for conventional methods decreased, with an adjusted IRR in the post-expansion period of 0.87 (95% CI 0.85–0.90) times the rate in the pre-expansion period; orders for NIPT increased, with an adjusted IRR in the post-expansion period of 1.41 (95% CI 1.32–1.51) times the rate in the pre-expansion period. Invasive diagnostic testing was low at baseline (1.0%) and did not change post-coverage expansion. The change in PMPM is estimated at $US0.026 post-coverage expansion.
Conclusion
The PBRS agreement to expand NIPT coverage for women aged < 35 years was associated with an increase in NIPT utilization, decreases in conventional screening methods, and a modest increase in PMPM expenditures.
Introduction: Guidelines from the American Society of Hematology recommend consideration of outpatient management, rather than hospitalization, for patients with pulmonary thromboembolism (PTE) with ...low risk of complication. The simplified Pulmonary Embolism Severity Index (sPESI) is frequently used for PTE risk stratification and selection for outpatient management, where an sPESI of 0 is associated with a low risk of recurrent thromboembolism, non-fatal bleeding, and death. Prior to developing an outpatient care pathway for low risk PTE at a large, public academic medical center, we sought to assess the potential clinic volume by determining the number of patients seen at our institution with low risk acute PTE. We also sought to capture other features that may preclude outpatient management including renal impairment, thrombocytopenia, and obesity, which may prevent direct oral anticoagulant (DOAC) use, and lack of insurance, which may impede access to affordable anticoagulation and clinic follow-up.
Methods: We retrospectively identified patients with acute PTE by reviewing computed tomography (CT) of the chest with contrast or CT angiography performed during a one-year period (Oct 1, 2018 to Sept 30, 2019) using CPT codes. Imaging reports were manually reviewed to determine if acute PTE was present. sPESI variables were collected: age >80, history of cancer, history of cardiopulmonary disease, heart rate (HR) ≥110bpm, systolic blood pressure (SBP) <100mmHg, and oxygen saturation (O 2) <90%. Medical history variables were identified using ICD-10 codes. Vital sign values were determined by identifying peak or nadir as appropriate within 24 hours of encounter initiation. Additional demographic and clinical variables collected included sex, weight, body mass index (BMI), insurance status, serum creatinine, platelet count, and length of stay for admitted patients. Readmission was determined by reviewing documentation within 30 days of initial encounter. Values were reported using frequencies with percentages and means with standard deviation and/or range. Comparisons were performed using chi squared tests and t tests as appropriate.
Results: Of 587 CT chest imaging studies identified, 199 (34%) demonstrated acute PTE (Figure 1). The majority (n=174, 87%) had an sPESI of 1 or greater. Points were more frequently gained due to SBP <100mmHg (n=109, 63%), HR ≥110bpm (n=105, 60%), and O 2 ≤90% (n=90, 52%). History of cancer was present in 54 patients (31%) and history of cardiopulmonary disease in 81 patients (47%), with a total of 113 patients (65%) having a history of either. Only 25 patients (13%) had a low risk sPESI score of 0. Two patients with sPESI of 0 were excluded from further analysis due to age <18 and transfer to an outside hospital. Table 1 includes a comparison of the demographic and clinical features of all patients with acute PTE versus those with sPESI of 0.
Of those patients with a low risk sPESI, 3 patients (13%) had another indication for hospital admission aside from acute PTE (Figure 1). Three patients (13%) had a BMI greater than 40kg/m 2 and a weight greater than 120 kilograms. No patients had significant renal impairment, with a serum creatinine ranging between 0.5-1.5mg/dL. No patients had significant thrombocytopenia. Three patients (13%) were uninsured, 1 of whom was admitted for another indication.
The majority of patients with sPESI of 0 were admitted (n=19, 83%) with an average length of stay of 1.8 days (SD 1.6, range 0.2-7.4). Two patients were discharged from the emergency department (ED), and 2 patients were diagnosed and managed by an outpatient provider without contact with the ED or hospital. Only 1 patient was readmitted to the hospital within 30 days for reasons unrelated to PTE.
Conclusions: Our results indicate that the annual volume for a low risk PTE outpatient management pathway at a large, public medical center would be low, with only 20 patients meeting eligibility per sPESI in 12 months. Patients were frequently disqualified for vital sign abnormalities, but over half were ineligible due to comorbidities. This quantification will allow our institution and others that are similar to gauge the potential resource allotment needed for low risk pathway development. In addition, we demonstrate that 10% of eligible patients were uninsured, emphasizing that access to affordable anticoagulation and follow-up is necessary when developing outpatient PTE care models.
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No relevant conflicts of interest to declare.
Introduction:
Central nervous system (CNS) relapse in diffuse large B-cell lymphoma (DLBCL) is uncommon but is associated with poor outcomes. In selected high risk patients (pts), high dose ...methotrexate (HDMTX) is often used as CNS prophylaxis with frontline (1L) DLBCL therapy despite uncertain efficacy, optimum dose and timing of delivery. A recent UK study (Wilson et al 2020) showed that intercalated HDMTX (i-HDMTX) was associated with increased toxicity and R-CHOP delays compared to end of treatment (EOT) delivery. Although hypothesis generating, the study size was insufficient to determine whether EOT was non-inferior in terms of CNS relapse risk.
Methods:
We conducted an international, multicentre retrospective analysis of consecutive DLBCL or high grade BCL pts between 2007-20 from 47 centers in Europe, Australia and N. America. Pts were included if they received R-CHOP or R-CHOP-like 1L therapy with curative intent as well as HDMTX CNS prophylaxis (≥1 cycle). Concurrent intrathecal (IT) prophylaxis was permitted. Pts with known CNS involvement at baseline and those treated with more intensive protocols (e.g. R-DA-EPOCH) were excluded. i-HDMTX was defined as any pt receiving a HD-MTX cycle before the final R-CHOP cycle. CNS relapse events were excluded if occurring after first systemic lymphoma relapse/progression.
Time to event endpoints were measured from diagnosis to first event or censor and analysed using Kaplan-Meier and Cox regression methods. Time to CNS relapse was analysed using competing risk Fine and Gray method (for death and non-synchronous systemic relapse). To mitigate for possible immortality bias in the EOT arm, a landmark analysis for pts alive and free from progression at 6 months was conducted. We aimed to exclude a 5% difference in 2-year (y) CNS relapse rates.
Results:
1,384 pts were analysed. 750 received i-HDMTX and 634 received EOT HDMTX. Key baseline characteristics are summarised in Table 1. Median follow up was 37.9 months. 44.2% had high CNS IPI (4-6) with no significant difference between i-HDMTX and EOT groups (45.1% vs 43.1%, p=0.087). ≥2 cycles of HDMTX were used in 86.6% with no difference between groups (85.6% vs 87.9%, p=0.22). Concurrent IT prophylaxis use was higher for EOT pts (55.6% vs 38.1% p<0.0001).
78 CNS relapses (42 i-HDMTX, 36 EOT) were observed: parenchymal in 41 (53%), parenchymal and leptomeningeal in 16 (21%) and isolated leptomeningeal in 21 (27%). There was no significant difference in 2y CNS relapse rates between i-HDMTX and EOT in all pts: 5.2% vs 3.9%, adjusted hazard ratio (HR) 0.92 (95% CI 0.58-1.47), p=0.74, 2y difference -0.2% (-2.0-2.5) or landmark analysis: 2.8% vs 4.1%, HR: 0.93 (0.56-1.55), p=0.79, 2y difference: -0.3% (-1.8-2.2%) (Fig 1a/b). Exploratory analyses focusing on pts with isolated CNS relapse (n=57) demonstrated similar results (2y rates 3.6% vs 3.0%, p=0.99). On multivariable analysis (MVA) of risk factors for CNS relapse, renal/adrenal involvement was the only variable associated with increased CNS relapse risk (adjusted HR 1.74 (1.03-2.92), p=0.038). Notably, IT prophylaxis was not associated with reduction in CNS relapse.
In 600 high CNS IPI (4-6) pts, there was no difference in CNS relapse risk between i-HD-MTX and EOT (3y rates 9.4% vs 8.6%, HR 0.92 (95% CI 0.52-1.62)). In a composite high risk group including CNS IPI 4-6 and/or any of the following: ≥3 extranodal sites, renal, adrenal, testicular or breast involvement (n=885) there was no difference in 3y CNS relapse rates between groups (i-HDMTX 7.6% vs EOT 7.4%, HR 0.94 (0.58-1.53)).
Progression-free survival (PFS) and overall survival (OS) in the i-HDMTX and EOT groups were as follows: 3y PFS 70.7% vs 76.7% (p=0.098), 3y OS 79.9% vs 87.0% (p=0.0016). However, there were no PFS/OS differences between groups on landmark analysis (n=1259) (Fig 1c).
On analysis of pts experiencing ≥1 R-CHOP delay of ≥7 days, use of i-HDMTX was the only factor on MVA associated with increased delays (p<0.0001).
Discussion:
We found no evidence that EOT delivery increases CNS relapse risk when compared to i-HDMTX in this large analysis of pts treated with 1L R-CHOP. Delays to R-CHOP cycles were increased with i-HDMTX. Findings in a high risk subgroup were unchanged and rates of CNS relapse in this HDMTX treated group were similar to published comparable high risk cohorts receiving infrequent CNS prophylaxis. Where HDMTX prophylaxis is used, delivery could be deferred until R-CHOP completion.
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Wilson: Takeda: Other: Conference fees; Janssen: Other: Conference fees; Abbvie: Honoraria. Eyre: Janssen: Honoraria; Secura Bio: Consultancy, Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Beigene: Honoraria, Research Funding. Ahearne: Pfizer: Research Funding; Takeda: Honoraria; Roche: Honoraria. Schorb: Roche: Research Funding; Riemser Pharma GmbH: Honoraria, Research Funding; AbbVie: Research Funding. Ku: Antegene: Consultancy; Roche: Consultancy; Genor Biopharma: Consultancy. Narkhede: Genentech/Roche: Research Funding; Gilead: Research Funding; Genmab: Other: Medical writing support, Research Funding; TG Therapeautics: Research Funding. Lewis: AstraZeneca: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties; Novartis: Patents & Royalties; Roche: Consultancy, Honoraria. Øvlisen: Abbvie: Other: Travel expenses. Santarsiere: Janssen: Honoraria. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Roulin: Janssen: Other: Travel and meetings. Manos: Bristol-Myers Squibb: Other: Travel and meetings. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lopez-Garcia: Roche: Other: Speaker Honoraria, Travel and accommodation grants; Janssen: Other: Speaker Honoraria, Advisor, Travel and accommodation grants, Research Funding; Abbvie: Other: Speaker Honoraria, Advisor, Travel and accommodation grants; Celgene: Other: Speaker Honoraria; Fresenius: Other: Speaker Honoraria; Novonordisk: Other: Speaker Honoraria. El-Galaly: ROCHE Ltd: Ended employment in the past 24 months; Abbvie: Other: Speakers fee. Cheah: Beigene: Consultancy, Honoraria, Other: advisory; AbbVie: Research Funding; Celgene: Research Funding; AstraZeneca: Consultancy, Honoraria, Other: advisory; Loxo/Lilly: Consultancy, Honoraria, Other: advisory; TG Therapeutics: Consultancy, Honoraria, Other: advisory; Roche: Consultancy, Honoraria, Other: advisory and travel expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: advisory; MSD: Consultancy, Honoraria, Other: advisory, Research Funding; Gilead: Consultancy, Honoraria, Other: advisory; Ascentage pharma: Consultancy, Honoraria, Other: advisory. Ferreri: Gilead, Novartis, Juno, PletixaPharm, Roche, Incyte: Membership on an entity's Board of Directors or advisory committees; BMS, Beigene, Pharmacyclics, Hutchison Medipharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis, Pfizer: Research Funding. Fox: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: speaker fees. Cwynarski: Gilead: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Atara: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Kite, a Gilead Company: Consultancy, Other: travel to scientific conferences, Speakers Bureau; Janssen: Consultancy, Other: travel to scientific conferences; Roche: Consultancy, Other: travel to scientific conferences, Speakers Bureau; BMS/Celgene: Other: travel to scientific conferences. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Other: Travel Support; KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Janssen: Honoraria, Other: Travel Support; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Accurate predictions of the pathogenicity of mutations associated with genetic diseases are key to the success of precision medicine. Inherited missense mutations in the myocilin (MYOC) gene, within ...its olfactomedin (OLF) domain, constitute the strongest genetic link to primary open-angle glaucoma via a toxic gain of function, and thus MYOC is an attractive precision-medicine target. However, not all mutations in MYOC cause glaucoma, and common variants are expected to be neutral polymorphisms. The Genome Aggregation Database (gnomAD) lists ∼100 missense variants documented within OLF, all of which are relatively rare (allele frequency <0.001%) and nearly all are of unknown pathogenicity. To distinguish disease-causing OLF variants from benign OLF variants, we first characterized the most prevalent population-based variants using a suite of cellular and biophysical assays, and identified two variants with features of aggregation-prone familial disease variants. Next, we considered all available biochemical and clinical data to demonstrate that pathogenic and benign variants can be differentiated statistically based on a single metric: the thermal stability of OLF. Our results motivate genotyping MYOC in patients for clinical monitoring of this widespread, painless and irreversible ocular disease.
The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a ...randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF
) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines.
A recently developed radioimmunoassay (RIA) for measuring insulin-like growth factor (IGF-I) in a variety of fish species was used to investigate the correlation between growth rate and circulating ...IGF-I concentrations of barramundi (
Lates calcarifer), Atlantic salmon (
Salmo salar) and Southern Bluefin tuna (
Thunnus maccoyii). Plasma IGF-I concentration significantly increased with increasing ration size in barramundi and IGF-I concentration was positively correlated to growth rates obtained in Atlantic salmon (
r
2=0.67) and barramundi (
r
2=0.65) when fed a variety of diet formulations. IGF-I was also positively correlated to protein concentration (
r
2=0.59). This evidence suggested that measuring IGF-I concentration may provide a useful tool for monitoring fish growth rate and also as a method to rapidly assess different aquaculture diets. However, no such correlation was demonstrated in the tuna study probably due to seasonal cooling of sea surface temperature shortly before blood was sampled. Thus, some recommendations for the design and sampling strategy of nutritional trials where IGF-I concentrations are measured are discussed.
Computed tomographic (CT) enterography combines the improved spatial and temporal resolution of multi-detector row CT with large volumes of ingested neutral enteric contrast material to permit ...visualization of the small bowel wall and lumen. Adequate luminal distention can usually be achieved with oral hyperhydration, thereby obviating nasoenteric intubation and making CT enterography a useful, well-tolerated study for the evaluation of diseases affecting the mucosa and bowel wall. Unlike routine CT, which has been used to detect the extraenteric complications of Crohn disease such as fistula and abscess, CT enterography clearly depicts the small bowel inflammation associated with Crohn disease by displaying mural hyperenhancement, stratification, and thickening; engorged vasa recta; and perienteric inflammatory changes. As a result, CT enterography is becoming the first-line modality for the evaluation of suspected inflammatory bowel disease. CT enterography has also become an important alternative to traditional fluoroscopy in the assessment of other small bowel disorders such as celiac sprue and small bowel neoplasms.
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