Citations

Abstract Patients with multiple myeloma (MM) who do not respond to initial therapy have worse outcomes than primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not yet been studied. We reviewed patients with MM treated with triplet/quadruplet therapy at our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. We identified 1127 patients, of whom 1086 were evaluated for hematologic responses after 4 to 6 cycles. Of these, 93.3% (1013) had evidence of response, whereas 6.7% (73) had primary refractory disease. With a median overall survival (OS) of 51.3 months, patients with primary refractory disease had an increased risk of shorter survival in univariable and multivariable analyses (hazard ratio [HR], 3.5 [95% confidence interval (CI), 2.5-4.9]; HR, 4.3 [95% CI, 2.6-6.9], respectively). In the subgroup analysis of patients with primary refractory disease, those who received second-line autologous stem cell transplantation (ASCT) had increased second progression-free survival (20.9 vs 8.1 months; P < .01) and second OS (74.7 vs 31.3 months; P = .02) compared with patients who did not. We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population.

8056 Background: Multiple myeloma (MM) is preceded by monoclonal gammopathy of undetermined significance (MGUS). A transitional stage of smoldering multiple myeloma (SMM) can be identified between MGUS and MM. While MGUS carries a steady risk of progression of 1% per year, SMM is more heterogenous with nearly 40% of patients progressing in the first 5 years, 15% in the next 5 years, reaching the same low risk as MGUS after 10 years. SMM with its high risk of progression in the initial years after diagnosis presents a viable opportunity for early intervention. For implementing early intervention, the ability to identify SMM patients at the highest risk of progression is critical. This has led to the development of several risk stratification systems. Using these systems high risk SMM patients studied in phase 3 trials demonstrated delayed progression to MM and improved overall survival with early initiation of therapy. However, these approaches showed limited specificity exposing patients at lower risk of progression to therapy. To date, identifying high risk SMM patients and confirming disease stability in low risk SMM patients remain an important clinical need. Genomic instability has been shown to be a sensitive indicator of disease progression in cancer. Telomere dysfunction is an early event in genomic instability. The 3-dimensional spatial profiling of telomeres using TeloView technology allows for quantification of telomere dysfunction, and was shown to be instrumental in risk stratification of cancer patients generally, but particularly in selected hematological malignancies. Importantly, in a previous SMM proof-of-concept study telomeric parameters measured by TeloView technology was found to be significantly different between SMM patients who progressed to active MM within 2 years and those who remained stable for over 5 years. Methods: We analyzed a total of 162 SMM patients using TeloView technology. 88 patients were employed as training dataset in Receiver Operating Curve (ROC) modeling to develop a scoring model that stratifies individual SMM patients based on risk of progression to full stage MM. An additional cohort of 74 SMM patients was used for blind validation of the developed scoring model. Results: We report area-under-the-curve (AUC) in the ROC analysis of 0.8 (accuracy 80%) achieved by the scoring model developed using the training dataset. Furthermore, the independent blind validation achieved positive predictive value of 83% and negative predictive value of 71%, with sensitivity and specificity of 80% and 76% respectively. Conclusions: The result of this study supports presenting TeloView as an accurate prognostic biomarker which appears able to stratify SMM patients into their respective risk groups with high sensitivity and specificity. This will potentially allow for evidence-based treatment decisions for high risk SMM patients and confident monitoring of stable patients.

Importance Scoring systems for Stevens-Johnson syndrome and epidermal necrolysis (EN) only estimate patient prognosis and are weighted toward comorbidities and systemic features; morphologic terminology for EN lesions is inconsistent. Objectives To establish consensus among expert dermatologists on EN terminology, morphologic progression, and most-affected sites, and to build a framework for developing a skin-directed scoring system for EN. Evidence Review A Delphi consensus using the RAND/UCLA appropriateness criteria was initiated with a core group from the Society of Dermatology Hospitalists to establish agreement on the optimal design for an EN cutaneous scoring instrument, terminology, morphologic traits, and sites of involvement. Findings In round 1, the 54 participating dermatology hospitalists reached consensus on all 49 statements (30 appropriate, 3 inappropriate, 16 uncertain). In round 2, they agreed on another 15 statements (8 appropriate, 7 uncertain). There was consistent agreement on the need for a skin-specific instrument; on the most-often affected skin sites (head and neck, chest, upper back, ocular mucosa, oral mucosa); and that blanching erythema, dusky erythema, targetoid erythema, vesicles/bullae, desquamation, and erosions comprise the morphologic traits of EN and can be consistently differentiated. Conclusions and Relevance This consensus exercise confirmed the need for an EN skin-directed scoring system, nomenclature, and differentiation of specific morphologic traits, and identified the sites most affected. It also established a baseline consensus for a standardized EN instrument with consistent terminology.

AbstractObjectiveThe Longitudinal Early‐Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early‐onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data‐collection mid‐point.MethodsData from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid‐positive EOAD [n = 212], and amyloid‐negative early‐onset non‐Alzheimer's disease [EOnonAD; n = 70]).ResultsCognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures.ConclusionsWe present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant.HIGHLIGHTS Findings represent the most comprehensive baseline characterization of sporadic early‐onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.

Abstract Introduction The transgender population has long been marginalized by society. Societal stigmata, fear to seek care, and dearth of provider knowledge regarding transgender health issues has caused disparities to widen. Objective The purpose of this case study is to call to attention the often-overlooked aspect of pediatric transgender care: the importance of fertility preservation prior to instituting gender-affirming therapy. Methods Twenty-one genetically XY females, followed by their multidisciplinary transgender care teams, were interested in starting hormone therapy due to impending onset and/or progression of puberty. Fortunately for these patients, their physicians were aware of fertility struggles after undergoing hormone therapy. Results Sperm cryopreservation via open gonadal biopsy, testicular tissue cryopreservation (TTC), and semen sample (when age/maturity-appropriate) were discussed. Though requiring surgery, biopsy/TTC relieves patients of the psychological impact of semen sample production. With IRB approval, 20 patients (median age 12 years, range 10-16 years) underwent TTC (Figure 1). One patient (age 16 years) opted for semen sample. All patients had success with spermatogonial stem cells cryopreserved for future patient use. Conclusions Gender affirming procedures and hormone therapy affect the long-term reproductive potential of transgender individuals. While cost concerns and insurance coverage regarding oncofertility is a prominent area of discussion, the transgender community is often excluded. With more individuals beginning medical and surgical therapy at a younger age, fertility preservation discussions are essential but often overlooked, depriving these individuals the joy of becoming a biological parent. As health care providers, addressing psychological, emotional, physical, and spiritual needs of patients is crucial, and fertility is a key aspect of this care. TTC can be safely done in pediatric populations, though research is necessary to expand beyond current experimental stage of tissue-development. Disclosure No

OBJECTIVE Clear diagnostic delineation is necessary for the development of a strong evidence base in lumbar spinal surgery. Experience with existing national databases suggests that International Classification of Diseases, Tenth Edition (ICD-10) coding is insufficient to support that need. The purpose of this study was to assess agreement between surgeon-specified diagnostic indication and hospital-reported ICD-10 codes for lumbar spine surgery. METHODS Data collection for the American Spine Registry (ASR) includes an option to denote the surgeon’s specific diagnostic indication for each procedure. For cases treated between January 2020 and March 2022, surgeon-delineated diagnosis was compared with the ICD-10 diagnosis generated by standard ASR electronic medical record data extraction. For decompression-only cases, the primary analysis focused on the etiology of neural compression as determined by the surgeon versus that determined on the basis of the related ICD-10 codes extracted from the ASR database. For lumbar fusion cases, the primary analysis compared structural pathology, which may have required fusion, as determined by the surgeon versus that determined on the basis of the extracted ICD-10 codes. This allowed for identification of agreement between surgeon delineation and extracted ICD-10 codes. RESULTS In 5926 decompression-only cases, agreement between the surgeon and ASR ICD-10 codes was 89% for spinal stenosis and 78% for lumbar disc herniation and/or radiculopathy. Both the surgeon and database indicated no structural pathology (i.e., none) suggesting the need for fusion in 88% of cases. In 5663 lumbar fusion cases, agreement was 76% for spondylolisthesis but poor for other diagnostic indications. CONCLUSIONS Agreement between surgeon-specified diagnostic indication and hospital-reported ICD-10 codes was best for patients who underwent decompression only. In the fusion cases, agreement with ICD-10 codes was best in the spondylolisthesis group (76%). In cases other than spondylolisthesis, agreement was poor due to multiple diagnoses or lack of an ICD-10 code that reflected the pathology. This study suggested that standard ICD-10 codes may be inadequate to clearly define the indications for decompression or fusion in patients with lumbar degenerative disease.

ImportanceNational Hockey League (NHL) players are exposed to frequent head trauma. The long-term consequences of repetitive brain injury, especially for players who frequently engage in fighting, remains unknown.ObjectiveTo investigate the mortality rates and causes of death among NHL enforcers with more career fights and penalty minutes as compared with matched controls.Design, Setting, and ParticipantsThis matched cohort study examined 6039 NHL players who participated in at least 1 game in the seasons between October 11, 1967, and April 29, 2022, using official NHL data. Cohorts designated as enforcer-fighter (E-F) and enforcer-penalties (E-P) were selected. The E-F cohort consisted of players who participated in 50 or more career fights (n = 331). The E-P cohort included players with 3 or more penalty minutes per game (n = 183). Control-matched NHL players were identified for each E-F player (control-fighter [C-F]) (n = 331) and each E-P player (control-penalties [C-P]) (n = 183).ExposuresFighting and penalty minutes were both used as proxies for head trauma exposure. Players with significantly increased exposure to fighting and penalties (E-F and E-P cohorts) were compared with NHL players with less frequent exposure to head trauma (C-F and C-P cohorts).Main Outcomes and MeasuresMortality rates and age at death of the enforcer and control cohorts, and their causes of death using data obtained from publicly available sources such as online and national news sources, including NHL.com.ResultsAmong the 6039 NHL players identified (mean [SD] age, 47.1 [15.2] years), the mean (SD) number of fights was 9.7 (24.5). The mortality rates of E-F and C-F players (13 [3.9%] vs 14 [4.2%], respectively; P = .84) or E-P and C-P players (13 [7.1.%] vs 10 [5.5%]; P = .34) were not significantly different. The mean (SD) age at death was 10 years younger for E-F players (47.5 [13.8] years) and E-P players (45.2 [10.5] years) compared with C-F players (57.5 [7.1] years) and C-P players (55.2 [8.4] years). There was a difference in causes of death between the control and enforcer players (2 neurodegenerative disorders, 2 drug overdoses, 3 suicides, and 4 vehicular crashes among enforcers vs 1 motor vehicle crash among controls; P = .03), with enforcers dying at higher rates of overdose (2 of 21 [9.5%] vs 0 of 24) and suicide (3 of 21 [14.3%] vs 0 of 24) (P = .02).Conclusions and RelevanceThe findings of this matched cohort study indicate that there is no difference in overall mortality rates between NHL enforcers and controls. However, being an enforcer was associated with dying approximately 10 years earlier and more frequently of suicide and drug overdose.

OBJECTIVE The American Spine Registry (ASR) is a collaborative effort between the American Academy of Orthopaedic Surgeons and the American Association of Neurological Surgeons. The goal of this study was to evaluate how representative the ASR is of the national practice with spinal procedures, as recorded in the National Inpatient Sample (NIS). METHODS The authors queried the NIS and the ASR for cervical and lumbar arthrodesis cases performed during 2017–2019. International Classification of Diseases, 10th Revision and Current Procedural Terminology codes were used to identify patients undergoing cervical and lumbar procedures. The two groups were compared for the overall proportion of cervical and lumbar procedures, age distribution, sex, surgical approach features, race, and hospital volume. Outcomes available in the ASR, such as patient-reported outcomes and reoperations, were not analyzed due to nonavailability in the NIS. The representativeness of the ASR compared to the NIS was assessed via Cohen’s d effect sizes, and absolute standardized mean differences (SMDs) of < 0.2 were considered trivial, whereas > 0.5 were considered moderately large. RESULTS A total of 24,800 arthrodesis procedures were identified in the ASR for the period between January 1, 2017, and December 31, 2019. During the same time period, 1,305,360 cases were recorded in the NIS. Cervical fusions comprised 35.9% of the ASR cohort (8911 cases) and 36.0% of the NIS cohort (469,287 cases). The two databases presented trivial differences in terms of patient age and sex for all years of interest across both cervical and lumbar arthrodeses (SMD < 0.2). Trivial differences were also noted in the distribution of open versus percutaneous procedures of the cervical and lumbar spine (SMD < 0.2). Among lumbar cases, anterior approaches were more common in the ASR than in the NIS (32.1% vs 22.3%, SMD = 0.22), but the discrepancy among cervical cases in the two databases was trivial (SMD = 0.03). Small differences were illustrated in terms of race, with SMDs < 0.5, and a more significant discrepancy was identified in the geographic distribution of participating sites (SMDs of 0.7 and 0.74 for cervical and lumbar cases, respectively). For both of these measures, SMDs in 2019 were smaller than those in 2018 and 2017. CONCLUSIONS The ASR and NIS databases presented a very high similarity in proportions of cervical and lumbar spine surgeries, as well as similar distributions of age and sex, and distribution of open versus endoscopic approach. Slight discrepancies in anterior versus posterior approach among lumbar cases and patient race, and more significant discrepancies in geographic representation were also identified, yet decreasing trends in differences suggested the improving representativeness of the ASR over the course of time and its progressive growth. These conclusions are important to underline the external validity of quality investigations and research conclusions to be drawn from analyses in which the ASR is used.

Introduction While neurovascular surgeries have largely been performed by neurosurgeons, the advent of endovascular procedures has produced increasing involvement of other specialists in this arena (i.e. neurologists and radiologists).This study aims to analyzethe involvement of different specialties within theneuroendovascular workforce by characterizingthem by their primary specialty. Methods The Medicare Provider Utilization Database was queried from 2013 to 2019 for all primary Current Procedural Terminology (CPT) codes identified by the American Medical Association as pertaining to endovascular procedures of the nervous system (61623, 61624, 61630, 61635, 61626, 61645, and 61650). We counted the number of unique providers in respective fields (neurology, neurosurgery, and radiology) who performed these procedures. Statistical analyses, including data aggregation, exploratory analysis, and propensity adjustment, were performed using R, version 4.0.1 (The R Foundation, Vienna, Austria). The two‐sided Mann‐Kendall trend test, a non‐parametric statistical test that assesses for monotonic trends in either an upward or downward trend, was utilized to assess for trends over time. Within each year analyzed, a Chi‐squared test for trend in proportions was used. A significance level of 0.05 was used. Results In 2013, neurosurgeons comprised 45% of the workforce performing these procedures, neurologists were 9%, and radiologists were 47%. By 2019, neurosurgeons decreased to 34.5% of the workforce, while neurologists increased to 21.5%, and radiologists decreased slightly to 44%. Neurologists were the only field in which the proportional shift in providers was noted to have a significant change in trajectory (p:0.04), an upward trajectory. Overall proportional differences between respective specialists were statistically significant each year (p< 0.01). Conclusions Neurologists are increasingly performing endovascular procedures. Increased communication and coordination between specialties can improve disparities in care to ensure adequate access to neurovascular care across the US.