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Multi-Disciplinary Care Model for Transition and Re-Transition after Gene Therapy in Sickle Cell Disease
Gu, Lidan , Yund, Brianna, Claar, Melissa Kay, Greenwood, Katie L, Mallory, Samantha, Blaylark, Rae, Thompson, Caitlyn, Ripken, Erica, Watson, Andrea , Milanovich, Samuel, Gupta, Ashish O. , Lilla, Stephanie A. Fritch, Kao, Roy L. , Ferdjallah, Asmaa , Boucher, Alexander A.

Blood | December 6, 2024 | Volume: 144 | Issue: Supplement 1 | Pages: 5004-5004

10.1182/blood-2024-210506 Get It

Background: Hematopoietic stem cell transplant (HSCT) based gene therapies (GT) have successfully demonstrated significant reduction in vasocclusive crises (VOCs) associated with sickle cell disease (SCD). The efficacy and safety of these products is well established across multiple clinical trials (Kanter et al. NEJM 2022, Frangoul et al. NEJM 2024). This led to the Food and Drug Administration (FDA) approval of the lentiviral-based gene addition product (lovotibeglogene autotemcel) and CRISPR-Cas9 based gene editing product (exagamglogene autotemcel) for patients with SCD above 12 years of age. As these therapies have a different logistical process compared to a standard allogeneic HSCT, there is a need to develop a collaborative transition of care plan for these patients and families prior to and long after completion of transformative therapies. Methods: Upper Midwest Sickle Cell Curative Therapies Consortium is a collaborative model including multiple stakeholders between 7 centers across the upper Midwest United States, the regional community-based organization (CBO) and National Marrow Donors Program (NMDP). The structure and workflow for this model was presented previously (Blaylark et al. ASH 2023). With the advent of commercial GTs, we developed a multi-specialty care model in collaboration with community stakeholders to address diverse patient and logistical needs for smoother transition to and from these therapies. Discussion: The initial transition is a period of potential gaps in medical care and often high anxiety for patients and families. Thus, when patients and families are considering GT, our care model engages a multidisciplinary team. As part of the comprehensive evaluation prior to gene therapy, an initial shared collaborative checklist includes an extensive medical history, assessment of treatment plan, an individualized pain plan and adherence, transfusion planning (simple or exchange) with setting of target hemoglobin and hemoglobin S% targets, and coordination of multi-specialty consults including apheresis, fertility preservation, child life, and social work. Additionally, pain, psychology, and integrative medicine specialists address not only ongoing concerns, but also help develop a plan for future transition back to the primary site of SCD care (“re-transition”) after GT. Patients undergo neuropsychological evaluations to establish baseline functioning and the role of chronic pain and fatigue, as GT can significantly impact long term cognitive functioning, emotional coping with transitions, and overall daily functioning. When appropriate and available, warm handoffs are encouraged between centers within each of these specialties. Our team also reviews available resources for education and ongoing support through the process and after from national and regional CBOs. Similarly, the post-GT transition is also a period of potential medical care gaps and high anticipated anxiety and concern, as patients go through significant unfamiliar adverse effects followed by the potential for persistent freedom from VOCs. In the post-GT transition, ongoing psychology, integrative medicine, and pain team support; peer mentoring; and support groups are critical for a smooth re-transition to post-GT care and further successful re-transition back into the community. Using this interdisciplinary approach across GT clinical trials, we successfully weaned opioids in 83% of patients (5/6) by day 60 post-GT infusion and successful re-transition of these patients, further highlighting the role of interdisciplinary care. Our team's collaborative approach to SCD care with sickle cell specialists, transplant team and other care providers and CBO continues into the long term follow up period, including ongoing supportive services for both patients and their families. Conclusion: As newer therapies are developed and approved for transformative SCD care, development of a transitional model with early engagement of an interdisciplinary team is critical for empowering sickle cell warriors and for their successful transition back into the community.
Preclinical Evaluation of Stx-0712, a CCR2 Cytotoxicity Targeting Chimera (CCR2-CyTAC) for the Treatment of Chronic Myelomonocytic Leukemia
Turunen, Brandon J. , Leach, Craig A., Smith, Matthew, Finke, Christy M. , Mangaonkar, Abhishek A. , Al‐Kali, Aref , Kusne, Yael , Foran, James M. , Margaert, Aisha, Baptista, Michelle, Wiltzius, Stephanie M., Patnaik, Mrinal M. , Lasho, Terra L. , Badar, Talha , Baptista, Michelle

Blood | December 6, 2024 | Volume: 144 | Issue: Supplement 1 | Pages: 2771-2771

10.1182/blood-2024-209024 Get It

Introduction: Chronic myelomonocytic leukemia (CMML) is a myeloid stem cell neoplasm with few effective therapies and poor prognosis. This disease is characterized by an expansion of malignant monocytes which express high and homogeneous levels of the homing chemokine receptor CCR2. We have developed a CCR2 targeting Cytotoxicity Targeting Chimera (CCR2-CyTAC, STX-0712), which potently binds CCR2 on cells, and when combined with the CyTAC platform antibody, eliminates target cells via enhanced effector mediated killing. We present here the characterization of CCR2 expression in CMML patient samples, ex vivo depletion of CMML cells via treatment with STX-0712, and the dose dependent depletion of MO1 monocytes (classical monocytes) in non-human primates, supporting CMML as a promising indication for STX-0712. Methods: IRB approval was obtained from Mayo Clinic for patient sample use. For CCR2 characterization and depletion experiments, we used bone marrow biopsy specimens and peripheral blood mononuclear cells (PBMCs) obtained from CMML patients and controls from healthy donors. CCR2 expression and monocyte depletion were evaluated via flow cytometry, as previously described. In vivo pharmacokinetic (PK) and pharmacodynamic (PD) studies were conducted in cynomolgus monkeys. Results: First, we evaluated CCR2 expression in peripheral blood and bone marrow in CMML samples by flow cytometry. In 6/6 (100%) peripheral blood samples CCR2 was highly expressed on >98% of the monocytes. Also, in 3/3 (100%) bone marrow samples, CCR2 was expressed on a subset of CD34+ progenitors, while low/no expression was observed in healthy controls. This progenitor subpopulation had characteristics of the inflammatory granulocyte-macrophage progenitor (GMP)-like cells. Next, STX-0712 was added to freshly isolated PBMCs from CMML donors and CCR2+ monocyte depletion, mediated by endogenous Fc gamma receptor 3a positive (FcγRIIIa) effector cells, was assessed. In 5/5 (100%) CMML patient samples, the drug selectively induced depletion of CD14+, CCR2+ cells with an average potency of 3nM and 66-91% target cell killing vs no drug control. Finally, we evaluated the effects of STX-0712 in cynomolgus monkeys to evaluate PK and PD effects on CCR2 MO1 monocytes in vivo. STX-0712 demonstrated PK supportive of dosing in man. In 9/9 (100%) animals, STX-0712 effectively depleted >95% of CCR2+ monocytes which returned after drug levels dropped below ~10ng/mL. All doses were well tolerated and the findings of comprehensive immunophenotyping were to be as expected, predictable and mechanism directed. Conclusion: These results demonstrate high and homogenous CCR2 expression on malignant monocytes, ex vivo human target engagement and pharmacodynamics, and in vivo depletion of CCR2 MO1 monocytes in a potent and dose dependent manner. Based on this data we plan a First in Human, phase 1 clinical trial for patients with relapsed/refractory CMML.
Efficacy and Safety of Brexucabtagene Autoleucel for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in Patients Aged 60 and Above
Jeyakumar, Nikeshan , Miller, Katharine, Zhang, Amy , Sutherland, Katherine C. , Boccucci, Jacob , Ulrickson, Matthew L. , Vasu, Sumithira, Langston, Amelia , Kopmar, Noam E. , Tsai, Stephanie B., O’Connor, Timothy E. , Park, Jae H. , Valtis, Yannis K. , Solh, Melhem , Dekker, Simone E. , Malik, Shahbaz A. , Shaughnessy, Paul , Mountjoy, Luke , Hoeg, Rasmus T. , Oliai, Caspian , Gupta, Vishal , Koura, Divya, Kumaran, Muthu V., Schwartz, Marc S. , Tracy, Sean , O'Dwyer, Kristen M., Moore, Jozal , Bobillo, María Silvina Odstrcil , Frey, Noelle, Connor, Matthew P. , Ladha, Abdullah , Yaghmour, George , Gatell, Vivian Irrizary, Pullarkat, Vinod , Merchant, Akil, Muffly, Lori , Muffly, Lori , Muhsen, Ibrahim N. , Advani, Anjali S. , Roloff, Gregory W. , Grunwald, Michael R. , Kota, Vamsi , Sasine, Joshua , Aldoss, Ibrahim , Othman, Tamer , Vasu, Sumithira , Reshef, Ran , Luskin, Marlise R , Chen, Evan , Lin, Chenyu , Cassaday, Ryan D. , Tsai, Stephanie B., Hilal, Talal , Faramand, Rawan , Bezerra, Evandro D. , Leonard, Jessica T , Majhail, Navneet S. , Battiwalla, Minoo , Mathews, John, Oliai, Caspian H , Dykes, Kaitlyn C. , Logan, Aaron C , Stock, Wendy , Schwartz, Marc, Bachanová, Veronika , O'Dwyer, Kristin , Lee, Catherine J , Frey, Noelle, Jamy, Omer , Daunov, Michael , Jackson, Clayton, Gatell, Vivian Irizarry , Oluwole, Olalekan O. , Dholaria, Bhagirathbhai , Shah, Bijal , Hill, LaQuisa C.

Blood | December 6, 2024 | Volume: 144 | Issue: Supplement 1 | Pages: 523-523

10.1182/blood-2024-210682 Get It

Introduction: Brexucabtagene Autoleucel (brexu-cel) is the first CD19-targeting chimeric antigen receptor (CD19.CAR) T-cell therapy approved for the treatment of relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in adult (≥18 yo) patients (pts) based on results from the ZUMA-3 trial. However, data on the safety and efficacy of CAR-T cells in older pts (≥60 yo) remains limited, with only 8 pts >65 yo enrolled in the ZUMA-3 trial. We evaluated the treatment characteristics and outcomes with use of brexu-cel amongst patients ≥60 yo in the Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database. Methodology: ROCCA is a consortium of over 30 U.S.-based institutions with a database of adult pts with B-ALL who received brexu-cel as standard of care therapy. We identified pts ≥60 yo and further stratified them into two cohorts: 60-69 yo and ≥70 yo. Outcomes of interest included OS, PFS, ORR, and toxicities (CRS and ICANS). Both OS and PFS were calculated from the day of brexu-cel infusion. Response assessment occurred on day +28, and MRD evaluation was per institutional practices. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy criteria. Results: Of 280 brexu-cel recipients in the ROCCA database, 73 (26%) were ≥60 yo, of which 58 (79%) were between 60-69 yo and 15 (21%) were ≥70 yo. Among pts ≥60 yo, the median age at infusion was 65 (range 60-81). Pts were heavily pretreated with a median of 3 prior lines of therapy (range 2-9). Prior therapies included: allogeneic HSCT (38%), inotuzumab ozogamicin (41%), and blinatumomab (62%). Forty pts (55%) had Ph-negative B-ALL, 24 (33%) had Ph+ B-ALL and 9 (12%) had Ph-like B-ALL. When grouped by HCT-CI equal to 0, 1-2 or ≥3, a higher proportion of pts ≥60 yo had HCT-CI ≥3 (19% vs. 7% in <60 yo; p=0.004). Pre-apheresis, 33 pts (45%) had active disease (>5% marrow blasts or extramedullary disease), 34 (47%) were in CR (of whom 14 were MRD-negative) and 6 had unknown disease status. Following brexu-cel, 43 (59%) achieved MRD-negative CR, 20 (27%) had MRD + or CR with unknown MRD status, 6 (8%) had refractory disease and 5 had no disease evaluation available. The ORR was similar between pts 60-69 and ≥70 yo (MRD-negative CR rate: 58% vs 61%, r/r to brexu-cel: 9% vs 6%) and was comparable to pts <60 yo (MRD-negative CR 66%; r/r disease of 9%). The rate of all grade ICANS was higher in pts ≥70 (77%) than in pts 60-69 (47%) or pts <60 (49%), with grade 1-2 ICANS occurring at a significantly higher rate in pts ≥70 (44% vs. 20% in 60-69 and 20% in <60, p=0.049). Grade 3-4 ICANS were similar between the groups: 33%, 27% and 29% in the ≥70, 60-69, and <60 groups, respectively. Conversely, rates of CRS were similar across age groups (80-84%). There was no statistically significant difference in the rate of grade 3-4 CRS which was 17% in pts ≥70, 4% in pts 60-69, and 11% in pts <60 yo. With a median follow-up of 332 days (range 8-936 days) from infusion, pts ≥60 yo had a median PFS of 395 days compared to 547 days in pts <60 yo. Median PFS was lower in the ³70 yo (231 days) compared to 677 in the 60-69 yo cohort. No statistically significant difference was found between the <60 and ≥60groups in 6- and 12-month PFS rates (6 months PFS: 66% vs 64%, p=0.77 and 12 months PFS: 57% vs 57%, p=1.00). When pts ≥60 yo were stratified by age, pts ≥70 yo had similar 6-month PFS compared to other age groups but significantly lower 12-month PFS (38%; vs. 64% in pts 60-69and 57% in pts <60, p=0.001). Median OS was not reached in any of the age groups, and there was no statistically significant difference in 6-month OS (72% in ≥ 70 vs. 82% in the 60-69 vs. 82% in <60, p=0.14) or 12-months OS (61% in ≥ 70 vs. 69% in 60-69 vs. 73% in <60, p=0.18). Conclusion: This is the largest study to date of older B-ALL pts receiving CAR-T cells. We observed that older pts, particularly those aged 60-69, have similar outcomes to younger pts. However, pts ≥70 yo had lower median and 12-month PFS when compared to younger patients. Additionally, pts ≥70 yo had higher rates of grades 1-2 ICANS. An important limitation of this analysis is the potential selection bias among clinicians when selecting older patients for this treatment. Longer follow-up, including inclusion of additional pts ≥70 yo is needed to confirm these results, and further studies are needed to identify the optimal approach for use of CAR T-cell therapy in patients in this age group.
Ivosidenib in Patients with Mutant Isocitrate Dehydrogenase 1 (mIDH1) Relapsed/Refractory Myelodysplastic Syndromes: Update of the Phase 1 Substudy per the International Working Group 2023 Response Criteria
Fathi, Amir T. , Garcia‐Manero, Guillermo , Watts, Justin M. , Prince, Gabrielle T., Baratam, Praneeth , Stein, Anthony S. , Foran, James M. , Arellano, Martha , Sallman, David A. , Kapsalis, Stephanie M., Patel, Prapti A. , Madanat, Yazan F. , Roboz, Gail J. , Botton, Stéphane de , Zhang, Yuanye (Vickie), DiNardo, Courtney D.

Blood | December 5, 2024 | Volume: 144 | Issue: Supplement 1 | Pages: 1841-1841

10.1182/blood-2024-204862 Get It

Introduction Patients (pts) with relapsed/refractory (R/R) myelodysplastic syndromes (MDS) have a poor prognosis and, until recently, lacked therapeutic options. Ivosidenib (IVO) is an oral, targeted, small-molecule inhibitor of mIDH1. In October 2023, IVO was granted FDA approval for the treatment of adult pts with mIDH1 R/R MDS on the basis of results from the pivotal AG120-C-001 MDS substudy (NCT02074839); IVO showed an acceptable safety profile and induced durable remissions, with a high rate (38.9%) of complete remissions (CR) per International Working Group (IWG) 2006 criteria (DiNardo et al. Blood Adv 2024; bloodadvances.2023012302.). Response criteria evolve to better reflect clinical benefit in specific pt populations and reduce interobserver variability. The updated IWG 2023 criteria for higher-risk MDS lowered the hemoglobin threshold for CR, added response categories for pts with <5% blasts or limited count recovery, and eliminated the marrow CR (mCR) category. Herein we analyze responses, transfusion independence (TI), and survival outcomes of pts treated with IVO according to IWG 2023 criteria. In addition, responses assessed per IWG 2023 and IWG 2006 criteria are compared. Methods Pts with mIDH1 R/R MDS who had received prior SOC therapy were eligible. Oral IVO 500 mg was administered daily on days 1-28 of 28-day cycles. Responses were assessed per IWG 2023 criteria, and a composite CR (CRc) category was included in the analysis, which comprises all CR categories: CR + CR equivalent (CRe) + CR with limited count recovery (CRL) + CR with partial hematologic recovery (CRh). Overall response rate (ORR) was defined as CR + mCR + partial remission (PR) per IWG 2006 criteria, and as CRc + PR + hematologic improvement (HI) per IWG 2023 criteria. For TI analysis, non-CRc was defined as HI + PR + no response (NR)/not evaluable + progressive disease. TI was defined as requiring no transfusion for ≥56 days. Results In total, 19 pts were enrolled (median age: 73 yr; prior hypomethylating therapy: 78.9%) and data from 18 efficacy-evaluable pts were analyzed. CR + PR rate (primary endpoint) per IWG 2006 was 38.9%, with all 7 (38.9%) responders having CR. CRc + PR rate per IWG 2023 was 66.7% (n=12), with all responders having CRc, including 5 (27.8%) pts with CR, 3 (16.7%) with CRe, and 4 (22.2%) with CRL (CR unilineage [CRLuni], n=2 [11.1%]; CR bilineage [CRLbi], n=2 [11.1%]); no pt had CRh or PR. ORR was 83.3% per IWG 2006, with 7 (38.9%) pts having CR and 8 (44.4%) mCR; 4 (22.2%) pts with mCR had HI. Per IWG 2023 criteria, the ORR was 72.2%, with 12 (66.7%) pts having CRc and 1 (5.6%) HI with neutrophil response. The 8 mCR per IWG 2006 criteria were reclassified as 1 CR, 4 CRL (2 CRLuni and 2 CRLbi), 1 HI, and 2 NR per IWG 2023. Median time to CRc was 1.58 mo. Median duration of CRc was not reached and Kaplan-Meier (KM) estimates at 3, 6, and 12 mo were 90.9%, 81.8%, and 68.2%, respectively. Five (CRc group n=4; non-CRc group n=1) of 7 (71.4%) and 3 (CRc, n=1; non-CRc, n=2) of 4 pts requiring red blood cell (RBC) and platelet transfusion at baseline, respectively, had TI. Median time to any (RBC/platelet) TI was 2.64 and 2.43 mo for pts with CRc and non-CRc, respectively. Moreover, 10 of 12 (83.3%) pts with CRc and 3 of 6 (50%) with non-CRc had or maintained TI during the study. Median duration of TI was not reached and KM estimates at 3 and 6 mo were 90.0% and 65.6%, respectively, for pts with CRc and 100% and 66.7% for non-CRc. Median event-free survival (EFS) was not reached for pts with CRc (n=12) or NR (n=5), and KM estimates at 1 yr were 68.2% and 53.3%, respectively. Median overall survival (OS) was not reached for pts with CRc and was 16.5 mo for pts with NR. For pts with CRc, OS KM estimates at 1, 3, and 5 yr were 90.9%, 51.1%, and 51.1%, respectively. For pts with NR, OS KM estimates were 75% at 1 yr and not estimable at 3 and 5 yr. For the pt with HI, the EFS estimate at 1 yr was 100% and OS estimates were 100% at 1, 3, and 5 yr. Conclusions IVO resulted in a high ORR (72.2%) according to IWG 2023 criteria, including a 66.7% CRc rate, despite the removal of the mCR category. Of 8 mCR per IWG 2006 criteria, 5 (62.5%) were reclassified as CRc per IWG 2023 criteria. By eliminating mCR and assessing response in a high-risk population with <5% blasts, IWG 2023 criteria accurately capture the clinical benefit of IVO in R/R MDS. While comparison of survival outcomes between IWG 2006 and IWG 2023 is limited by the small sample size, a similar trend with response-dependent EFS and OS outcomes was observed.
Rationale and Logistics of Continuous Infusion Cephalosporin Antibiotics
Blunier, Abbie L. , Crocker, R. Jake , May, Stephanie Shealy , Powers, Caroline , Bookstaver, P. Brandon , May, Stephanie S , Bookstaver, P Brandon , Foster, Rachel

Pharmacy | December 5, 2024 | Volume: 12 | Issue: 6 | Pages: 185

10.3390/pharmacy12060185 | PMID 39728850 Get It

Cephalosporins have traditionally been administered as an intermittent infusion. With the knowledge that cephalosporins demonstrate a time-dependent pharmacodynamic profile, administration via continuous infusion may provide more effective antibiotic exposure for successful therapy. Proposed benefits of administration via continuous infusion include less IV manipulation, decreased potential for antibiotic resistance, and potential cost savings. The objective of this review was to provide a detailed assessment of available evidence for the use of continuous infusion cephalosporins and practical dosing and administration recommendations. Studies were gathered and assessed for inclusion via a literature search of PubMed and Ovid MEDLINE using mesh terms [“continuous infusion” and “cephalosporin”], “intermittent infusion”, [“intermittent versus continuous” and “cephalosporin”], “continuous infusion cephalosporin”, as well as specific drug names. References from included studies were also evaluated for inclusion. Data which compared the two administration methods (continuous infusion vs. intermittent infusion) were evaluated. Thirty-five studies were analyzed among several cephalosporins with variable delivery. Dosing regimens utilized in the selected studies were assessed with known compatibility and stability data and further summarized.
Disease Severity Staging System for NOTCH3 -Associated Small Vessel Disease, Including CADASIL
Rutten, Julie W. , Cerfontaine, Minne N. , Hack, Remco J. , Jolly, Amy A. , Guey, Stéphanie , Hsu, Shao‐Lun , Yuan, Yun , Neilson, S. , Poggesi, Anna, Shourav, Md Manjurul Islam , Ishiyama, Hiroyuki , Mayoral, Ana Domínguez, Nogueira, Renata , Muiño, Elena , Santo, Gustavo, Sukhonpanich, Nontapat , Park, Ashley , Lee, Jung Seok , Rodríguez-Girondo, Mar , Vonk, Sebastiaan J. J., Börjesson‐Hanson, Anne, Pantoni, Leonardo , Montanaro, Vinícus V. A., Kalaria, Raj N. , Pescini, Francesca , Choi, Jay Chol , Chen, Ling , Kim, Hyunjin , Markus, Hugh , Lee, Yi‐Chung , Oberstein, Saskia A.J. Lesnik , Guey, Stéphanie , Neilson, Sam J , Shourav, Md Manjurul Islam , Lee, Yi-Chung , Lesnik Oberstein, Saskia A J , Rutten, Julie W , Gravesteijn, Gido , Liao, Yi‐Chu , Park, Jae Young , Kopczak, Anna , Rifino, Nicola , Poggesi, Anna , Saitô, Satoshi , Andersen, Pia, Stefano, Nicola De , Santo, Gustavo, Mele, Francesco , Brodtmann, Amy G. , Fernández‐Cadenas, Israel , Silva, Ana Rita , Montanaro, Vinícius Viana Abreu , Lopergolo, Diego , Ihara, Masafumi , Meschia, James F. , Muir, Keith W. , Bersano, Anna , Duering, Marco , Chabriat, Hugues

JAMA Neurology | November 29, 2024 | Volume: 82 | Issue: 1 | Pages: 49

10.1001/jamaneurol.2024.4487 | PMID 39610302 Get It

Importance Typical cysteine-altering NOTCH3 ( NOTCH3 cys ) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3 -SVD severity spectrum is needed and currently lacking. Objective To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3 -SVD severity spectrum. Design, Setting, and Participants A cohort study was performed in which the NOTCH3 -SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3 cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3 cys -positive cases from families with CADASIL; the validation set included 1713 NOTCH3 cys -positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3 cys -positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024. Main Outcomes and Measures Percentage of cases following the sequence of events of the NOTCH3 -SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level. Results The NOTCH3 -SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3 -SVD staging system. The NOTCH3 -SVD stages were associated with neuroimaging outcomes in the NOTCH3 cys -positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3 -SVD staging system captured disease progression and was associated with 18-year survival. Conclusions and Relevance The NOTCH3 -SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3 cys variant to patients with end-stage disease. The NOTCH3 -SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.
Coccidioidomycosis Transmission Through Solid Organ Transplantation (2013–2022): A Report of the Organ Procurement and Transplantation Network ad hoc Disease Transmission Advisory Committee
Lee, Dong Heun , Fisher, Cynthia E. , Hughart, Anna L., Toda, Mitsuru , Williams, Samantha , Berry, Gerald J. , Graves, Riki, Handarova, Dzhuliyana, Kittleson, M. , Levi, Marilyn E. , Livelli, Taylor, Marboe, Charles C. , Annamabhotla, Pallavi, Miller, Rachel A. , Sellers, Marty T. , Taimur, Sarah , Te, Helen S. , Danziger‐Isakov, Lara , Abidi, Maheen Z , Fisher, Cynthia , Berry, Gerald J , Taimur, Sarah , Te, Helen S , Trindade, Anil J , Pouch, Stephanie M , Danziger-Isakov, Lara , Abidi, Maheen Z. , Ho, Chak‐Sum , Miller, Rachel A., Sharma, Tanvi S. , Wood, R. Patrick, Zaffiri, Lorenzo , Pouch, Stephanie M.

Transplant Infectious Disease | November 28, 2024 | Volume: 27 | Issue: 1 | Pages: No page available

10.1111/tid.14406 | PMID 39603983 Get It

ABSTRACTBackgroundCoccidioidomycosis is a fungal infection that poses a serious risk when transmitted through organ transplantation. We analyzed cases reported to the Organ Procurement and Transplantation Network ad hoc Disease Transmission Advisory Committee from 2013 to 2022.MethodsDonors and/or recipients who had positive Coccidioides immitis/posadasii serology, pathology, and/or culture were included in this study. Cases adjudicated as ‘proven’ or ‘probable’ were analyzed for donor infection risk factors, the timing of infection, transmission by organ type, clinical manifestations, and recipient outcomes. Patient and facility identifiers were removed prior to review.ResultsDuring this time period, 73 potential instances of Coccidioides donor disease transmission events were reported. Among them, infection was transmitted from seven deceased donors to eight recipients. All seven deceased donors had prior infection or exposure to regions where coccidioidomycosis is endemic. Of 20 individuals receiving organs from these donors, eight developed infection, resulting in a 40% transmission rate. The median time to diagnosis post‐transplant was 39 days. Disseminated disease occurred in six recipients, five of whom died from the infection. Notably, none of the recipients who received prophylactic antifungal treatment died from the infection.ConclusionDespite its rarity, donor‐derived Coccidioides infection is a serious concern, particularly due to the high mortality rate in the early post‐transplant period. To mitigate these risks, a thorough assessment of donor exposure history, coupled with donor serology and bronchoalveolar lavage cultures, can effectively guide post‐transplant antifungal prophylaxis. Prompt reporting is crucial to prevent Coccidioides infections among other recipients. image
A Simple Clinical Predictive Model for Arthroscopic Mobility of Osteochondritis Dissecans Lesions of the Knee
Milewski, Matthew D., Milewski, Matthew D., Miller, Patricia E., Gossman, Emma C. , Coene, Ryan P. , Tompkins, Marc , Anderson, Christian N. , Bauer, Kathryn, Busch, Michael T., Carey, James L. , Ellermann, Jutta , Ellis, Henry B. , Erickson, John , Ganley, Theodore J. , Heyworth, Benton E. , Latz, Kevin, Lyon, Roger, Mayer, Stephanie W. , Milewski, Matthew D. , Milewski, Matthew D., Miller, Patricia E., Nepple, Jeffrey J. , Nguyen, Jie C. , Nissen, Carl W. , Paterno, Mark V. , Pennock, Andrew T. , Perkins, Crystal A. , Polousky, John D. , Saluan, Paul, Shea, Kevin G. , Wall, Eric J. , Willimon, Clifton, Wilson, Philip L., Wright, Rick W. , Zbojniewicz, Andy, Myer, Gregory D , Milewski, Matthew D., Milewski, Matthew D., Miller, Patricia E., Carsen, Sasha , Chambers, Henry G. , Edmonds, Eric W. , Fabricant, Peter D , Green, Daniel W , Hui, James Hoi Po , Kocher, Mininder Singh , Krych, Aaron J. , Milewski, Matthew D., Miller, Patricia E., Nelson, Bradley J. , Pace, J Lee , Weiss, Jennifer M., Wilson, Philip L. , Myer, Gregory D.

The American Journal of Sports Medicine | November 25, 2024 | Volume: 52 | Issue: 14 | Pages: 3543-3550

10.1177/03635465241296133 | PMID 39584729 Get It

Background: Osteochondritis dissecans (OCD) of the knee is a focal idiopathic alteration of subchondral bone and/or its precursor with risk for instability and disruption of adjacent cartilage. Treatment options focused on preventing premature osteoarthritis vary depending on multiple patient and lesion characteristics, including lesion mobility. Purpose: To differentiate lesion mobility before arthroscopy using a multivariable model that includes patient demographic characteristics and physical examination findings. Study Design: Cohort study (Diagnosis); Level of evidence, 2. Methods: Demographic, preoperative physical examination, and radiographic data were collected from a multicenter national prospective cohort of patients with OCD of the knee. Inclusion criteria included patients <19 years of age and patients with arthroscopically confirmed mobility status based on the Research on Osteochondritis Dissecans of the Knee arthroscopy classification. Multivariable logistic regression analysis using stepwise model selection was used to determine factors associated with the likelihood of a mobile versus an immobile lesion. A 75% partition of the data was used for model training, and 25% was used as a validation cohort. Quantitative model fit statistics were computed using the holdout data, including sensitivity, specificity, and the area under the receiver operating characteristic curve (AUC), along with the corresponding 95% CI. Results: A total of 407 patients in the prospective cohort met inclusion criteria, and 62% were male. The mean ± SD age was 13.7 ± 2.2 years, height 161.8 ± 5.3 cm, and weight 59.2 ± 42.2 kg. Arthroscopic evaluation yielded 235 immobile and 172 mobile lesions. Multivariable analysis determined that the best model to predict lesion mobility included chronologic age ≥14 years ( P < .001), effusion on physical examination ( P < .001), and any loss of range of motion on physical examination ( P = .07), while controlling for male sex ( P = .38) and weight >54.4 kg ( P = .12). In the 25% holdout validation sample (n = 102), a sensitivity of 83%, a specificity of 82%, and an AUC of 0.89 (95% CI, 0.82-0.95) were achieved with these predictive factors. Conclusion: Age, effusion, and loss of motion can predict knee OCD lesion mobility at the time of arthroscopy. Education about lesion mobility can help with surgical planning and patient and family counseling.
Abstract 4147355: Tracking Mood Phenotypes in TIA and Ischemic Stroke Patients Using Smartphone Sensors: Preliminary Results from a Real-World Data Pilot Study
Dumitrascu, Oana M. , Ganjizadeh, Ali , Hagen, Clint , Harahsheh, Ehab , Zawada, Stephanie , Demaerschalk, Bart M. , Erickson, Bradley J.

Circulation | November 14, 2024 | Volume: 150 | Issue: Suppl_1 | Pages: No page available

10.1161/circ.150.suppl_1.4147355 Get It

Background: Although no tests are currently available to predict post-stroke depression (PSD), a risk factor for diminished quality of life and stroke-related death, emerging evidence suggests that ischemic stroke (IS) may induce behavioral changes by damaging connections throughout the brain rather than via localized injury. Hypothesis: We sought to determine if active (surveys) and passive (accelerometer, GPS, and other sensors) smartphone data could quantify exploratory behavioral proxies of PSD. Methods: Thirty-four adults with a recent IS (n = 12) or transient ischemic attack (TIA) (n = 22) diagnosis were followed for 3 months. Participants used the Beiwe app to complete a weekly Patient Health Questionnaire-8 (PHQ-8) survey and were evaluated every 30 days with the Montgomery-Asberg Depression Rating Scale (MADRS). Results: Preliminary analysis of app survey compliance was adequate (86%), and the quantity of data collected was greater for Android than iOS phones. PHQ-8 indicated depression (moderate or severe) in 20% of participants. MADRS highly correlated with the most recent PHQ-8 ( r = 0.92, 95% CI (0.19, 0.99), P = 0.028). Several exploratory passive physical activity and social measures showed statistically significant change over time and/or associations with PHQ-8 and MADRS. Conclusion: Low-burden smartphone data holds promise for developing novel IS and TIA outcome measures as well as identifying patients most at risk of PSD.
Short-term Surgical Outcomes of Papillary Craniopharyngiomas: A Multicenter Study
Catalino, Michael P. , Pham, D. T. , Pacione, Donato , Suryadevara, Carter M. , Silverstein, Julie , Gardner, Paul A. , Fernandez‐Miranda, Juan C. , Benjamin, Carolina , Kshettry, Varun R. , Zada, Gabriel , Zwagerman, Nathan T. , Cheok, Stephanie , Wu, Kyle C., Little, Andrew S. , Pham, Duy, Rennert, Robert C , Couldwell, William T. , Kim, Won Bae , Kim, Albert , Chicoine, Michael , Barkhoudarian, Garni , Gompel, Jamie J. Van , Palit, Sandhya R. , Prevedello, Daniel M. , Mamelak, Adam N. , Pacult, Mark A. , Karsy, Michael

No container title available | November 13, 2024 | Volume: No volume available | Issue: No issue available | Pages: No page available

10.21203/rs.3.rs-5245655/v1 Get It

Abstract Purpose: Craniopharyngiomas are rare parasellar tumors, and papillary craniopharyngiomas (PCP) represent 8-20% of cases. We assessed surgical outcomes of these very rare tumors among patients treated in the last decade. Methods: Retrospective data from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) were used to evaluate patients with PCP treated between 2011 and 2023 at 14 US-based academic skull base centers. Demographic, imaging, surgical, and outcome variables were analyzed. Results: Ninety-nine patients with PCP were included. Mean age was 51.8±14.7 and 57.6% were male. Most tumors showed mixed cystic/solid components (67.5%), were trans-infundibular (50.0%), and were treated endoscopically (74.5%), with 51.1% demonstrating gross total resection (GTR). Pituitary stalk was preserved in 51.9%. Permanent arginine vasopressin deficiency was seen in 68.8% and was associated with pituitary stalk sacrifice (p=0.02). Cerebrospinal fluid leak was the most common nonendocrine postsurgical, 30-day complication (9.1%), reason for return to the operating room (3.1%), and reason for 90-day readmission (8.1%). Return to the operating room was associated with discharge to a skilled nursing or rehabilitation facility (p=0.0001). Most patients (63.9%) received no adjuvant therapy; GTR was associated with decreased radiotherapy use (p=0.0001). BRAFV600E mutation was detected in 64/69 tumors tested, although only 1 patient was treated with a BRAF inhibitor. Conclusion: To our knowledge, the RAPID consortium enabled the largest real-world clinical information dataset for PCP. Our data can be used as a benchmark for short-term surgical outcomes. Longer-term follow-up studies are needed to understand how to optimize outcomes from each treatment modality.