Citations

Abstract Multiple clinical trials have assessed de-escalation strategies from combined modality therapy (CMT) to chemotherapy-alone for the treatment of early-stage classical Hodgkin lymphoma (cHL), confirming similar outcomes. The application of these data to the real-world is limited, however. We conducted a retrospective, multicenter cohort study comparing CMT vs chemotherapy-alone in patients with early-stage cHL (stage IA-IIB) treated between January 2010 and December 2020. Positron emission tomography (PET) scans after chemotherapy cycle 2 (PET2) were independently reviewed by a nuclear radiologist (Deauville score ≥4, positive; ≤3, negative). Patient outcomes were compared by using an intention-to-treat analysis. Among 125 patients (CMT, n = 63; chemotherapy-alone, n = 62) with a median follow-up of 59.8 months (95% CI, 48.6-71.0), no differences in overall survival were observed (5-year overall survival, CMT 98.0% vs chemotherapy-alone 95.1%; log-rank test, P = .38). However, there was reduced progression-free survival (PFS) with chemotherapy-alone among all patients (2-year PFS, CMT 95.1% vs chemotherapy-alone 75.3%; log-rank test, P = .005) and in those with bulky (n = 43; log-rank test, P < .001), unfavorable (n = 81; log-rank test, P = .002), or PET2-positive (n = 15; log-rank test, P = .02) disease. No significant differences in PFS were seen for patients with non-bulky (log-rank test, P = .35), favorable (log-rank test, P = .62), or PET2-negative (log-rank test, P = .19) disease. Based on our real-world experience, CMT seems beneficial for patients with early-stage cHL, especially those with PET2-positive and unfavorable disease. Chemotherapy-alone regimens can lead to comparable outcomes for patients with favorable, non-bulky, or PET2-negative disease. We conclude that although results seen in clinical trials are replicated in certain patient subgroups, other subgroups not fitting trial criteria do poorly when radiotherapy is excluded.

Objective: Trauma-induced coagulopathy (TIC) is provoked by multiple mechanisms and is perceived to be one driver of massive transfusions (MT). Single laboratory values using prothrombin time (INR) or thrombelastography (TEG) are used to clinically define this complex process. We used a proteomics approach to test whether current definitions of TIC (INR, TEG, or clinical judgment) are sufficient to capture the majority of protein changes associated with MT. Methods: Eight level I trauma centers contributed blood samples from patients available early after injury. TIC was defined as INR >1.5 (INR-TIC), TEG maximum amplitude <50 mm (TEG-TIC), or clinical judgment (Clin-TIC) by the trauma surgeon. MT was defined as >10 units of red blood cells in 24 hours or >4 units RBC/hour during the first 4 hours. SomaLogic proteomic analysis of 1305 proteins was performed. Pathways associated with proteins dysregulated in patients with each TIC definition and MT were identified. Results: Patients (n = 211) had a mean injury severity score of 24, with a MT and mortality rate of 22% and 12%, respectively. We identified 578 SOMAscan analytes dysregulated among MT patients, of which INR-TIC, TEG-TIC, and Clin-TIC patients showed dysregulation only in 25%, 3%, and 4% of these, respectively. TIC definitions jointly failed to show changes in 73% of the protein levels associated with MT, and failed to identify 26% of patients that received a massive transfusion. INR-TIC and TEG-TIC patients showed dysregulation of proteins significantly associated with complement activity. Proteins dysregulated in Clin-TIC or massive transfusion patients were not significantly associated with any pathway. Conclusion: These data indicate there are unexplored opportunities to identify patients at risk for massive bleeding. Only a small subset of proteins that are dysregulated in patients receiving MT are statistically significantly dysregulated among patients whose TIC is defined based solely on laboratory measurements or clinical assessment.

AbstractIntroductionAs knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD.MethodsFrequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers.ResultsAD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1%. Cross‐sectionally, mutation carriers with AD neurological examination findings showed a more than two‐fold faster cognitive decline and had greater parieto‐temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time.DiscussionADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs.

Abstract Background Despite aggressive upfront treatment in glioblastoma (GBM), recurrence remains inevitable for most patients. Accumulating evidence has identified hypermutation induced by temozolomide (TMZ) as an emerging subtype of recurrent GBM. However, its biological and therapeutic significance has yet to be described. Methods We combined GBM patient and derive GBM stem cells (GSCs) from tumors following TMZ to explore response of hypermutant and non-hypermutant emergent phenotypes and explore the immune relevance of hypermutant and non-hypermutant states in vivo. Results Hypermutation emerges as one of two possible mutational subtypes following TMZ treatment in vivo and demonstrates distinct phenotypic features compared to non-hypermutant recurrent GBM. Hypermutant tumors elicited robust immune rejection in subcutaneous contexts which was accompanied by increased immune cell infiltration. In contrast, immune rejection of hypermutant tumors were stunted in orthotopic settings where we observe limited immune infiltration. Use of anti-PD-1 immunotherapy showed that immunosuppression in orthotopic contexts was independent from the PD-1/PD-L1 axis. Finally, we demonstrate that mutational burden can be estimated from DNA contained in extracellular vesicles (EVs). Conclusion Hypermutation post-TMZ are phenotypically distinct from non-hypermutant GBM and requires personalization for appropriate treatment. The brain microenvironment may be immunosuppressive and exploration of the mechanisms behind this may be key to improving immunotherapy response in this subtype of recurrent GBM.

Background: Type I tibial spine fractures are non-displaced or minimally displaced (≤ 2mm displacement) fractures of the tibial eminence and ACL insertion traditionally managed nonoperatively with immobilization. Hypothesis/Purpose: We hypothesized that type I fractures do not carry significant risk of associated injuries and therefore do not require additional interventions aside from immobilization. Methods: We reviewed 52 patients classified by their treating institution with type I tibial spine fractures presenting between January 1, 2000 and January 31, 2019 at 10 institutions. Patients of age ≤ 18 years with pre-treatment plain radiographs and at least one year of follow-up were included. Data was collected on patient demographics, injury mechanism, treatment details, presence of concomitant injuries, range of motion (ROM) at final follow-up, treatment complications, and any return to the operating room for the injured knee. Pre-treatment imaging was reviewed by four authors to assess agreement of classification among the treating institutions. Patients were subclassified into two groups to ensure outcomes represented classic type I fracture patterns. Any patient with universal agreement among the four authors that the fracture did not appear consistent with a type I classification were assigned to Type 1+ Group (T1+). All other patients were assigned to the True Type I Group (TT1). We evaluated concomitant injury, need for operative intervention, and treatment outcomes overall and for each group independently. Results: 48 patients met inclusion criteria. 40/48 were TT1 fractures, while 8/48 were T1+ fractures, indicating less than universal agreement among sports specialists in classification of these fractures. Among TT1 patients, 7 of 40 (18.4%) underwent surgical treatment, though this represented 35.7% (5/14) of those who had undergone pretreatment advanced imaging. In the T1+ group, 6 of 8 (75%) underwent surgical treatment, 50% of whom (3/6) had pretreatment advanced imaging. Overall, twelve of 48 patients (25%) had concomitant injuries, nine TT1 patients and three T1+ patients (p=0.77), with 7 concomitant injuries requiring additional surgical management. Conclusions: Classification of type I fractures can be challenging. Nonetheless, a substantial percentage of patients with these fractures (>20%) were found to have concomitant injuries by advanced pretreatment imaging, with surgical management indicated in 58.3% of these patients. Contrary to traditional thought, type I tibial spine fractures do carry a risk of associated injuries. Simple cast immobilization may not be the ideal treatment in all cases. Advanced imaging would be beneficial for those whose plan of care may initially be non-operative treatment.

Background: When operative treatment is indicated, tibial spine fractures can be successfully managed with open or arthroscopic reduction and internal fixation. Hypothesis/Purpose: We hypothesized both approaches can lead to satisfactory outcomes for fracture healing, but that open treatment without preoperative advanced imaging can potentially lead to missed concomitant injuries. Methods: We performed an Institutional Review Board (IRB)-approved retrospective cohort study of pediatric tibial spine fractures presenting between January 1, 2000 and January 31, 2019 at 10 institutions. Patients were categorized into two cohorts based on treatment: arthroscopic reduction and internal fixation (ARIF) and open reduction and internal fixation (ORIF). Surgical outcomes, the incidence of concomitant injuries, and surgeon demographics were compared between groups. Results: There were 477 patients with tibial spine fractures who met inclusion criteria, 420 of whom (88.1%) were treated with ARIF, while 57 (11.9%) were treated with ORIF. Patients treated with ARIF were more likely to have an identified concomitant injury (41.4%) compared to those treated with ORIF (24.6%, p=0.021). Patients treated with ARIF were also more likely to have pre-treatment MRI (41.7% vs. 22.8%, p =0.010). Most concomitant injuries (74.5%) required surgical intervention. The most common treatment complications included arthrofibrosis (6.9% in ARIF patients, 7.0% in ORIF patients, p=1.00) and subsequent ACL injury (2.1% in ARIF patients and 3.5% in ORIF, p=0.86). The rate of complications, return to the operating room, and failure to return to full range of motion were similar between groups. Twenty surgeons with sports subspecialty training completed 85.0% of ARIF cases; the remaining 15.0% were performed by 12 surgeons without additional sports training. The majority (56.1%) of ORIF cases were completed by 14 surgeons without sports subspecialty training. Conclusion: This is the largest study comparing ARIF to ORIF in pediatric tibial spine fractures. This study demonstrated no difference in outcomes or nonunion following ARIF or ORIF for pediatric tibial spine fractures. There were significantly higher rates of concomitant injuries in patients treated with ARIF, however, these patients also had a higher rate of pre-treatment MRI. The majority of these concomitant injuries (74.5%) required surgical intervention. Pre-treatment MRI should be considered in the workup of tibial spine fractures to increase identification of concomitant injury. Concomitant injuries may be missed in tibial spine fractures treated with an open approach, especially in cases where preoperative advanced imaging is not obtained. Surgeon preference and training may impact treatment approach and identification and treatment of concomitant injury.

ABSTRACT Despite advances in early revascularization, percutaneous hemodynamic support platforms, and systems of care, cardiogenic shock (CS) remains associated with a mortality rate higher than 50%. Several risk stratification models have been derived since the 1990 s to identify patients at high risk of adverse outcomes. Still, limited information is available on the differences between scoring systems and their relative applicability to both acute myocardial infarction and advanced decompensated heart failure CS. Thus, we reviewed the similarities, differences, and limitations of published CS risk prediction models and herein discuss their suitability to the contemporary management of CS care.

AbstractThe extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of ‘sporadic’ late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease.We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer’s Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset.Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants.These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct.