Citations

Abstract Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2017. Since then, there have been major developments, including registration of new antiviral agents. Therefore, the Transplant Associated Virus Infections Forum, which consists of scientists, clinicians, regulators, and industry representatives, has produced an updated version of these definitions that incorporates recent knowledge with the aim of supporting clinical research and drug development. This also includes an update regarding the definition of resistant and refractory CMV infections previously published in 2019. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts among clinicians, scientists, regulators, and industry representatives can provide a platform for this work.

Abstract BACKGROUND Treatment and clinical management decisions for children with NF1-OPGs remain challenging as most existing data are retrospective and have not included standardized visual outcomes. In this study, we prospectively enrolled newly diagnosed NF1-OPGs and performed standardized neuro-oncology and ophthalmology assessments in order to develop evidence-based guidelines for monitoring and treatment. METHODS Children with NF1-OPG on MRI who were evaluated by both a study ophthalmologist and neuro-oncologist/NF1 expert within 1 month of radiologic diagnosis were eligible for enrollment. All subjects attempted quantitative visual acuity using Teller acuity cards (TAC) as well as ATS-HOTV testing. The neuro-oncologist/NF1 expert provided reasons for obtaining the MRI as well as initiating treatment, if applicable. Descriptive statistics calculated the success rate of acquiring TAC and reasons to obtain the MRI. RESULTS Two-hundred fifty subjects from 22 institutions were enrolled and had at least one visit beyond baseline (Median age 3.1 years, range 0.1–16.8; 53% female). TAC was successfully acquired in both eyes (N=195, 78%) and at least one eye in (N=206, 82%). ATS-HOTV was successfully acquired in both eyes (N=97, 39%) and at least one eye in (N=98, 39%). The two most common reasons to obtain an MRI were screening due to a diagnosis of NF1 (N=99, 39%) and ophthalmologic concern (N=81, 32%). At enrollment, continued observation occurred in a majority of subjects (N=221, 88%) while treatment with chemotherapy was initiated in only 11% (N=29). Twenty-nine (11%) subjects initially observed transitioned to treatment after enrollment (range: 2.5–25 months) thus far. DISCUSSION We present a prospective multicenter study of children with newly diagnosed NF1-OPGs. The ability to acquire quantitative visual acuity was higher than anticipated. The frequency of NF1-OPGs requiring treatment is lower than previously reported. Regression models of clinical and MRI features that prompted immediate treatment with chemotherapy versus observation will be discussed.

Abstract BACKGROUND NF1-OPGs are amorphous tumors involving either single or multiple locations (optic nerve, chiasm, tract) along the anterior visual pathway (AVP). In this prospective study, we investigated how volumetric MRI measures of the AVP as well as other clinical variables are associated with treatment decisions in children with newly diagnosed NF1-OPGs. METHODS Children with newly diagnosed NF1-OPG whose MRI included a T1-weighted volumetric sequence without significant artifact at their enrollment visit were eligible for inclusion. All subjects underwent a quantitative ophthalmic exam to determine if visual acuity (VA) was normal. The neuro-oncologist/NF1 expert determined whether the subject would be observed or undergo treatment at that baseline visit. Volumetric MRI analysis was automatically performed using a deep learning network that measured AVP volume (mm3). Non-parametric group comparisons and multivariable logistic regression models evaluated the impact of age at enrollment, sex, NF1 inheritance type, AVP volume, and VA on the decision for immediate treatment with chemotherapy versus observation. RESULTS One-hundred twenty-three subjects met inclusion criteria. Subjects assigned to observation (N=112, 44% female) and subjects immediately treated with chemotherapy (N=11, 80% female) at enrollment were of similar age (2.7 and 2.8 years, respectively) and inheritance (p > 0.05). Abnormal VA was present more often in the treatment group (46%) compared to the observation group (17%, p <0.001). AVP volume was significantly greater in the treatment group (4,181.1mm3) compared to the observation group (1,819.8mm3, p <0.001). AVP volume, sex, and VA reached significance in univariable regression, however, in the multivariable regression model only the AVP volume (p < 0.001) was significantly associated with treatment initiation. DISCUSSION Children with greater NF1-OPG AVP volumes are treated more often compared with those with lower volumes. Volumetric measures of NF1-OPGs are a valuable metric in understanding treatment patterns and are positioned to help inform clinical decision making.

OBJECTIVE It is not clear whether there is an additive effect of social factors in keeping patients with cervical spondylotic myelopathy (CSM) from achieving both a minimum clinically important difference (MCID) in outcomes and satisfaction after surgery. The aim of this study was to explore the effect of multiple social factors on postoperative outcomes and satisfaction. METHODS This was a multiinstitutional, retrospective study of the prospective Quality Outcomes Database (QOD) CSM cohort, which included patients aged 18 years or older who were diagnosed with primary CSM and underwent operative management. Social factors included race (White vs non-White), education (high school or below vs above), employment (employed vs not), and insurance (private vs nonprivate). Patients were considered to have improved from surgery if the following criteria were met: 1) they reported a score of 1 or 2 on the North American Spine Society index, and 2) they met the MCID in patient-reported outcomes (i.e., visual analog scale [VAS] neck and arm pain, Neck Disability Index [NDI], and EuroQol-5D [EQ-5D]). RESULTS Of the 1141 patients included in the study, 205 (18.0%) had 0, 347 (30.4%) had 1, 334 (29.3%) had 2, and 255 (22.3%) had 3 social factors. The 24-month follow-up rate was > 80% for all patient-reported outcomes. After adjusting for all relevant covariates (p < 0.02), patients with 1 or more social factors were less likely to improve from surgery in all measured outcomes including VAS neck pain (OR 0.90, 95% CI 0.83–0.99) and arm pain (OR 0.88, 95% CI 0.80–0.96); NDI (OR 0.90, 95% CI 0.83–0.98); and EQ-5D (OR 0.90, 95% CI 0.83–0.97) (all p < 0.05) compared to those without any social factors. Patients with 2 social factors (outcomes: neck pain OR 0.86, arm pain OR 0.81, NDI OR 0.84, EQ-5D OR 0.81; all p < 0.05) or 3 social factors (outcomes: neck pain OR 0.84, arm pain OR 0.84, NDI OR 0.84, EQ-5D OR 0.84; all p < 0.05) were more likely to fare worse in all outcomes compared to those with only 1 social factor. CONCLUSIONS Compared to those without any social factors, patients who had at least 1 social factor were less likely to achieve MCID and feel satisfied after surgery. The effect of social factors is additive in that patients with a higher number of factors are less likely to improve compared to those with only 1 social factor.

OBJECTIVE The aim of this study was to identify predictors of the best 24-month improvements in patients undergoing surgery for cervical spondylotic myelopathy (CSM). For this purpose, the authors leveraged a large prospective cohort of surgically treated patients with CSM to identify factors predicting the best outcomes for disability, quality of life, and functional status following surgery. METHODS This was a retrospective analysis of prospectively collected data. The Quality Outcomes Database (QOD) CSM dataset (1141 patients) at 14 top enrolling sites was used. Baseline and surgical characteristics were compared for those reporting the top and bottom 20th percentile 24-month Neck Disability Index (NDI), EuroQol-5D (EQ-5D), and modified Japanese Orthopaedic Association (mJOA) change scores. A multivariable logistic model was constructed and included candidate variables reaching p ≤ 0.20 on univariate analyses. Least important variables were removed in a stepwise manner to determine the significant predictors of the best outcomes (top 20th percentile) for 24-month NDI, EQ-5D, and mJOA change. RESULTS A total of 948 (83.1%) patients with 24-month follow-up were included in this study. For NDI, 204 (17.9%) had the best NDI outcome and 200 (17.5%) had the worst NDI outcome. Factors predicting the best NDI outcomes included symptom duration less than 12 months (OR 1.5, 95% CI 1.1–1.9; p = 0.01); procedure other than posterior fusion (OR 1.5, 95% CI 1.03–2.1; p = 0.03); higher preoperative visual analog scale neck pain score (OR 1.2, 95% CI 1.1–1.3; p < 0.001); and higher baseline NDI (OR 1.06, 95% CI 1.05–1.07; p < 0.001). For EQ-5D, 163 (14.3%) had the best EQ-5D outcome and 169 (14.8%) had the worst EQ-5D outcome. Factors predicting the best EQ-5D outcomes included arm pain–only complaints (compared to neck pain) (OR 1.9, 95% CI 1.3–2.9; p = 0.002) and lower baseline EQ-5D (OR 167.7 per unit lower, 95% CI 85.0–339.4; p < 0.001). For mJOA, 222 (19.5%) had the best mJOA outcome and 238 (20.9%) had the worst mJOA outcome. Factors predicting the best mJOA outcomes included lower BMI (OR 1.03 per unit lower, 95% CI 1.004–1.05; p = 0.02; cutoff value of ≤ 29.5 kg/m 2 ); arm pain–only complaints (compared to neck pain) (OR 1.7, 95% CI 1.1–2.5; p = 0.02); and lower baseline mJOA (OR 1.6 per unit lower, 95% CI 1.5–1.7; p < 0.001). CONCLUSIONS Compared to the worst outcomes for EQ-5D, the best outcomes were associated with patients with arm pain–only complaints. For mJOA, lower BMI and arm pain–only complaints portended the best outcomes. For NDI, those with the best outcomes had shorter symptom durations, higher preoperative neck pain scores, and less often underwent posterior spinal fusions. Given the positive impact of shorter symptom duration on outcomes, these data suggest that early surgery may be beneficial for patients with CSM.

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening, stem cell disorder that renders red blood cells vulnerable to complement-mediated hemolysis. This study describes the health-related quality of life (HRQoL) and symptom-specific functional impairment of patients with PNH in a real-world setting. Methods: US-based adults with PNH treated with a parenterally administered complement inhibitor (PACI) for ≥6 months completed an online, cross-sectional, observational survey; a subset of patients also participated in individual semi-structured qualitative interviews after completing the survey. The survey included the PROMIS® 29+2 Profile v2.1 (PROMIS 29+2) to measure HRQoL. The FACIT Fatigue, Neuro-QOL Item Bank v2.0 Cognitive Function Short Form, and PROMIS Item Bank v1.0 Dyspnea Functional Limitations 10a Short Form measured functional impairment associated with specific symptoms of PNH. For each patient with PNH who completed the online survey, up to 3 age- (+/- 3 years) and sex-matched adults without PNH also completed the survey. The HRQoL and functional impairment of the PNH sample was compared to that of general population (GP) sample using independent samples t-tests or Mann-Whitney tests. To further explore the experiences of patients with PNH, the association between HRQoL/functional impairment and fatigue severity was investigated. Patients with PNH were grouped according to their self-reported fatigue severity over the past 7 days (very mild or mild vs moderate, severe, or very severe [no patients reported no fatigue]). Differences in scores across these 2 groups were tested. Data from the qualitative interviews were coded using thematic analysis to explore key concepts related to HRQoL and impairment due to PNH symptoms. Data collection began in March 2023; results are based on interim data. Results: Demographic characteristics of the study samples (PNH survey sample: N=31, GP survey sample: N=62, PNH interview sample: N=10) are shown in Table 1. Patients were treated for PNH with eculizumab, pegcetacoplan, or ravulizumab, with an average duration of current PACI treatment of 3.4 years. Compared to the age and sex-matched GP sample, patients with PNH had significantly higher median scores on the PROMIS 29+2 fatigue domain (GP: 48.70 vs PNH: 57.10, p=0.041) and PROMIS Dyspnea Functional Limitations short form (GP: 40.70 vs PNH: 48.60, p=0.036), indicating that patients with PNH experience more fatigue and dyspnea limitations than the GP sample. Patients with PNH also had significantly lower median scores on the PROMIS 29+2 ability to participate in social roles/activities domain (GP: 53.50 vs PNH: 44.20, p=0.013), indicating greater role/activity limitations among patients with PNH. Compared to the GP sample, patients with PNH had numerically lower (i.e., worse) median PROMIS 29+2 cognitive functioning domain scores (GP: 50.00 vs PNH: 46.30, p=0.058) and FACIT Fatigue scores (GP: 39.50 vs PNH: 30.00, p=0.057). Within the PNH sample, statistically significant associations (p&lt;0.05) were observed between fatigue severity and HRQoL/functional impairment for all outcomes except for the PROMIS 29+2 sleep disturbance and cognitive functioning domains (Table 2). Patients with more severe fatigue had worse HRQoL and more functional impairment than patients with less severe fatigue. Interview participants described fatigue-related functional impairments in their physical, social, and cognitive functioning. Fatigue made daily activities (e.g., cooking, cleaning, going for a walk) difficult and sometimes impossible. Planning social activities in advance was also challenging as patients could not predict how they would feel on any given day, and often found they had to miss, postpone, or cancel social engagements. Finally, patients described experiencing “brain fog” including difficulty concentrating, forgetfulness, and delayed cognitive processing. Conclusions: Despite receiving treatment for PNH, patients experienced deficits in areas of HRQoL related to fatigue, participation in social roles, cognitive function, and functional limitations due to dyspnea, relative to a sample of GP adults. During follow-up interviews, patients emphasized the deep and broad impacts that fatigue and cognitive functioning had, making daily activities and their social lives very difficult.

Background: CLL is the most prevalent adult leukemia with a highly heterogenous genetic landscape leading to extremely varied clinical outcomes. Previously, CLL patients with immunoglobulin heavy chain variable region ( IGHV) mutated status and presence of deletion 13q14 [del(13q)] were identified as favorable-risk with most patients remaining on lifetime observation. However, other intrinsic factors contributing to CLL disease progression and leading to treatment initiation remain unknown. Our goal was to identify patients at high-risk of progression with added predictive value (APV) beyond IGHV-status and presence of del(13q). Methods: Flow cytometry was used to sort CD19+CD5+ malignant cells in peripheral blood from CLL patients at Huntsman Cancer Institute at University of Utah and triple sequencing generated (tumor whole transcriptome and paired tumor-normal whole exome data). We used SPECTRA, a novel dimension reduction transcriptome approach, to derive a set of independent, intrinsic, quantitative transcriptome tumor variables from 249 CLL patients with quality-controlled transcriptome sequence data. From this set, 182 treatment-naïve (TN) patients with quality-controlled clinical variables were used as a discovery cohort set to derive a SPECTRA-based risk score for TTFT using multivariable Cox proportional hazards modeling. Event time was date of patient specimen acquisition to initiation of frontline therapy with patients censored at last follow-up or death. Gaussian mixture modeling (GMM) was performed to identify evidence for distinct risk groups within the quantitative risk score. GMM-risk groups, and further stratifications by IGHV mutational and del(13q) status, were used in hazard ratios (HR) and to illustrate differences in Kaplan-Meier time-to-event curves. An independent publicly available dataset of 548 TN CLL patients with clinical and transcriptome data for CD19+ enriched cells was used for replication. Results: SPECTRA produced 19 quantitative spectra variables to describe most of the expression variation across the 249 CLL patients. In multivariable Cox modeling for TTFT, 7 spectra were significant and retained in a final model, which GMM separated into a bi-modal distribution and defined high (N=83) and low-risk (N=99) groups (HR=5.7, 95% confidence interval [CI] 3.4-9.7). In a post-hoc model including IGHV mutational and del(13q) status, the spectra-risk score showed significant APV beyond both factors (p&lt;0.001 for both). The discovery study timeframe was 6.3 years (y) and included 109 IGHV-mutated and 75 del(13q) patients. In the IGHV-mutated patients, median TTFT (mTTFT) was significantly shorter for spectra-high risk patients (3.1y) vs. spectra-low risk patients (median not reached [NR]; p&lt;0.001). Similarly, in the del(13q) patients, mTTFT was significantly shorter in high-risk patients (3.3y) compared to median NR for spectra-low (p&lt;0.001) ( Figure). Importantly, stratification of patients into low- and high-risk SPECTRA scores provided significant additional information for prediction of TTFT than IGHV mutational and del(13q) status ( Figure). For validation, we applied the same spectra-risk score to the independent data set containing 301 IGHV-mutated and 278 del(13q) CLL patients. In the replication set, the mTTFT in the IGHV-mutated patients who were spectra-high was 3.3y vs. 11.2y in spectra-low (p&lt;0.001). Similarly, in the replication set of del(13q) patients, spectra-high-risk patients had a mTTFT of 2.7y vs. 10.7y for spectra-low (p&lt;0.001). Conclusion: A transcriptome risk score utilizing novel SPECTRA variables identified a substantial subset of CLL patients with IGHV-mutated status and presence of del(13q) who have uncharacteristically short TTFT, but who would be classified as favorable risk under current best practice stratification. Future directions include validating our results with external patient cohorts from Mayo Clinic and investigating the genetic and transcriptomic profile of SPECTRA low- and high-risk cohorts to determine targetable pathways for treatment.

OBJECTIVE The aim of this study was to explore the preoperative patient characteristics that affect surgical decision-making when selecting an anterior or posterior operative approach in patients diagnosed with cervical spondylotic myelopathy (CSM). METHODS This was a multi-institutional, retrospective study of the prospective Quality Outcomes Database (QOD) Cervical Spondylotic Myelopathy module. Patients aged 18 years or older diagnosed with primary CSM who underwent multilevel (≥ 2-level) elective surgery were included. Demographics and baseline clinical characteristics were collected. RESULTS Of the 841 patients with CSM in the database, 492 (58.5%) underwent multilevel anterior surgery and 349 (41.5%) underwent multilevel posterior surgery. Surgeons more often performed a posterior surgical approach in older patients (mean 64.8 ± 10.6 vs 58.5 ± 11.1 years, p < 0.001) and those with a higher American Society of Anesthesiologists class (class III or IV: 52.4% vs 46.3%, p = 0.003), a higher rate of motor deficit (67.0% vs 58.7%, p = 0.014), worse myelopathy (mean modified Japanese Orthopaedic Association score 11.4 ± 3.1 vs 12.4 ± 2.6, p < 0.001), and more levels treated (4.3 ± 1.3 vs 2.4 ± 0.6, p < 0.001). On the other hand, surgeons more frequently performed an anterior surgical approach when patients were employed (47.2% vs 23.2%, p < 0.001) and had intervertebral disc herniation as an underlying pathology (30.7% vs 9.2%, p < 0.001). CONCLUSIONS The selection of approach for patients with CSM depends on patient demographics and symptomology. Posterior surgery was performed in patients who were older and had worse systemic disease, increased myelopathy, and greater levels of stenosis. Anterior surgery was more often performed in patients who were employed and had intervertebral disc herniation.

OBJECTIVE The authors sought to compare 3-level anterior with posterior fusion surgical procedures for the treatment of multilevel cervical spondylotic myelopathy (CSM). METHODS The authors analyzed prospective data from the 14 highest enrolling sites of the Quality Outcomes Database CSM module. They compared 3-level anterior cervical discectomy and fusion (ACDF) and posterior cervical laminectomy and fusion (PCF) surgical procedures, excluding surgical procedures crossing the cervicothoracic junction. Rates of reaching the minimal clinically important difference (MCID) in patient-reported outcomes (PROs) were compared at 24 months postoperatively. Multivariable analyses adjusted for potential confounders elucidated in univariable analysis. RESULTS Overall, 199 patients met the inclusion criteria: 123 ACDF (61.8%) and 76 PCF (38.2%) patients. The 24-month follow-up rates were similar (ACDF 90.2% vs PCF 92.1%, p = 0.67). Preoperatively, ACDF patients were younger (60.8 ± 10.2 vs 65.0 ± 10.3 years, p < 0.01), and greater proportions were privately insured (56.1% vs 36.8%, p = 0.02), actively employed (39.8% vs 22.8%, p = 0.04), and independently ambulatory (14.6% vs 31.6%, p < 0.01). Otherwise, the cohorts had equivalent baseline modified Japanese Orthopaedic Association (mJOA), Neck Disability Index (NDI), numeric rating scale (NRS)–arm pain, NRS–neck pain, and EQ-5D scores (p > 0.05). ACDF patients had reduced hospitalization length (1.6 vs 3.9 days, p < 0.01) and a greater proportion had nonroutine discharge (7.3% vs 22.8%, p < 0.01), but they had a higher rate of postoperative dysphagia (13.5% vs 3.5%, p = 0.049). Compared with baseline values, both groups demonstrated improvements in all outcomes at 24 months (p < 0.05). In multivariable analyses, after controlling for age, insurance payor, employment status, ambulation status, and other potential clinically relevant confounders, ACDF was associated with a greater proportion of patients with maximum satisfaction on the North American Spine Society Patient Satisfaction Index (NASS) (NASS score of 1) at 24 months (69.4% vs 53.7%, OR 2.44, 95% CI 1.17–5.09, adjusted p = 0.02). Otherwise, the cohorts shared similar 24-month outcomes in terms of reaching the MCID for mJOA, NDI, NRS–arm pain, NRS–neck pain, and EQ-5D score (adjusted p > 0.05). There were no differences in the 3-month readmission (ACDF 4.1% vs PCF 3.9%, p = 0.97) and 24-month reoperation (ACDF 13.5% vs PCF 18.6%, p = 0.36) rates. CONCLUSIONS In a cohort limited to 3-level fusion surgical procedures, ACDF was associated with reduced blood loss, shorter hospitalization length, and higher routine home discharge rates; however, PCF resulted in lower rates of postoperative dysphagia. The procedures yielded comparably significant improvements in functional status (mJOA score), neck and arm pain, neck pain–related disability, and quality of life at 3, 12, and 24 months. ACDF patients had significantly higher odds of maximum satisfaction (NASS score 1). Given comparable outcomes, patients should be counseled on each approach’s complication profile to aid in surgical decision-making.