Washington University Physicians

Abstract Background Chronic lung allograft dysfunction (CLAD) is the leading cause of death beyond the first year after lung transplantation. Several treatments have been used to prevent the progression or reverse the effects of CLAD. Cytolytic therapy with rabbit antithymocyte globulin (rATG) has previously shown to be a potential option. However, the effect on patients with restrictive allograft syndrome (RAS) versus bronchiolitis obliterans syndrome (BOS) and the effect of cumulative dosing are unknown. Methods The charts of lung transplant patients treated with rATG at Barnes‐Jewish Hospital from 2009 to 2016 were retrospectively reviewed. The primary outcome was response to rATG; patients were deemed responders if their FEV 1 improved in the 6 months after rATG treatment. Safety endpoints included incidence of serum sickness, cytokine release syndrome, malignancy, and infectious complications. Results 108 patients were included in this study; 43 (40%) patients were responders who experienced an increase in FEV 1 after rATG therapy. No predictors of response to rATG therapy were identified. Serum sickness occurred in 22% of patients, 15% experienced cytokine release syndrome, and 19% developed an infection after therapy. Conclusion 40% of patients with CLAD have an improvement in lung function after treatment with rATG although the improvement was typically minimal.

OBJECTIVES: This study aimed to assist practitioners in performing an accurate assessment of the external and internal pelvic musculoskeletal (MSK) systems to improve appropriate diagnosis and referral of patients with pelvic floor disorders or pelvic pain and to improve understanding of physical therapy (PT) treatment principles, thereby improving communication between practitioners and encouraging a multidisciplinary approach. METHODS: A referenced review of the anatomy of the pelvic floor muscles, pelvis, and surrounding structures, followed by a detailed assessment of anatomy, posture, and gait, is presented. A thorough description of PT assessment and treatment is included with clinical relevance. RESULTS: When proper assessments are routinely performed, MSK conditions can be recognized, allowing for prompt and appropriate referrals to PT. Assessment and treatment by qualified physical therapists are integral to pelvic health care. After efficient medical assessment, MSK dysfunction can be addressed expeditiously, thereby avoiding further decline. Left unaddressed, pelvic dysfunction may become chronic. CONCLUSIONS: We propose a guide for MSK assessment of the pelvis and associated structures that can be used for both clinical and research purposes. This guide is designed for health care providers caring for women with pelvic floor disorders, including physicians, advanced practice providers, and nurses. This guide serves to improve communication among multidisciplinary practitioners to refine MSK assessment and treatment approaches and thereby advance clinical care and research.

Importance: Ocular surface events are a class effect of microtubule-inhibitor payload-containing antibody-drug conjugates (ADCs); the mechanism underlying these events has not been fully elucidated. Objective: To characterize corneal epithelial changes in patients with relapsed or refractory multiple myeloma (RRMM) treated with belantamab mafodotin, a maleimidocaproyl monomethyl auristatin-F (MMAF)-containing ADC. Design, Setting, and Participants: This multicenter, phase 3b case series study was conducted in the US from March 26, 2020, to November 21, 2022, among adults with RRMM. Data were analyzed from May 2021 to May 2023. Exposure: Prior or ongoing treatment with belantamab mafodotin. Main Outcomes and Measures: The primary end point included pathologic characteristics and composition of corneal epithelial changes obtained by impression cytology (IC) or superficial keratectomy (SK) in patients treated with belantamab mafodotin. Tear film and blood were collected to determine belantamab mafodotin concentrations in patients at the time of sampling. Results: Of 16 patients screened, 9 were included in this study, with 6 evaluable corneal samples obtained from 6 patients either by IC (n = 4) or SK (n = 2). Of 9 patients included, median (range) patient age was 67.0 (57.0-81.0) years for those with samples obtained by IC and 68.0 (65.0-81.0) years for those with samples obtained by SK. Six patients (67%) were female. All samples demonstrated epithelial cells with eosinophilic intracytoplasmic inclusions, basophilic granular cytoplasm, or both. Five samples were positive for apoptosis, and 3 samples showed evidence of inflammation. All patients experienced complete IC or SK wound healing. ADC was detected in the tear fluid of 5 of 7 patients with tear fluid sampling, while ADC was quantifiable in 3 of 4 patients with blood samples. Conclusions and Relevance: In this case series study, intracytoplasmic inclusions were observed by histopathology in the corneal epithelium of patients exposed to belantamab mafodotin, and the pattern of corneal changes suggests limbal vessels may be a primary pathway enabling ADC to reach the cornea. Although limited to 6 samples, this study helps us better understand corneal changes associated with certain ADCs. Trial Registration: ClinicalTrials.gov Identifier: NCT04549363.

Abstract Ruxolitinib (RUX) is an oral selective Janus-associated kinase 1 (JAK1) and JAK2 inhibitor that is approved by the FDA for the treatment of patients with myeloproliferative neoplasms. JAKs transmit the signaling of ligand binding to inflammatory cytokine receptors into intracellular responses, and inhibition of JAK is effective in the treatment of autoimmune disorders. In MHC-mismatched mouse transplant models, pharmacologic inhibition of IFNγR signaling with RUX reduced graft-versus-host disease (GVHD) and improved survival (Choi et al Blood 2012); and preliminary reports have shown that 13/14 patients with steroid-refractory acute (10) and chronic (4) GVHD responded to RUX therapy. (Sporell et al Blood 2014). Between 09/2014 and 7/2015, 16 patients (12M/4F), with hematological malignancies and recipients of unrelated donor (14), matched sibling (2) blood (15) or marrow (1) transplant developed quiescent (12) or de novo (4) severe (NIH criteria) steroid-dependent cGVHD and received RUX as 2nd (4), 3d (7) 4th (4) or 5th (1) line salvage. 12 had prior grades 1 (3) 2 (6) 3(2) or 4 (1) acute GVHD that affected the skin (12) and gastrointestinal system (GI, 5). Median time of onset of cGVHD was d+130 (range, 90-299), and affected skin (16) eyes (12), mouth (10), GI (8), lungs (4), liver (3) and the musculoskeletal system (3). cGVHD was steroid dependent with recurrences of cGVHD symptoms with steroid tapers that were attempted a median of 4 times(range, 2-10). Median duration of continuous exposure to steroids for cGVHD was 24 months (range, 6-53). RUX was administered at the dose of 5 mg BID. Median weight was 82 kg (range, 56-158). RUX dose was increased to 15 mg/d (4) or 20 mg/d (3) due to physician preference (4), patient weight (1), or flare of cGVHD after initial response due to discontinuation of immunosuppression (1) or temporary perioperative hold of RUX (1). Median duration of RUX therapy was 6 months (range 1-14). All patients were evaluable for response. Complete resolution of clinical manifestations of cGVHD was observed in the following organs: lungs (dyspnea/O2 dependence), mouth (oral ulcerations), skin (non-sclerodermatous erythema), liver (sGOT, sGPT, alkaline phosphatase), musculoskeletal and GI (dysphagia, diarrhea). Subjective improvement was reported in sclerodermatous and ocular cGVHD. Responses were observed early after initiation of RUX (median 14 days). Prednisone was successfully reduced to physiologic doses (n=2) or discontinued (n=10) in 12 (75%), and taper is currently in progress for the 4 patients who started RUX in the past 8 weeks. Median time from initiation of RUX to prednisone discontinuation was 72 days (range, 31-120). With a median follow-up of 4 months (range, 1-12) from prednisone discontinuation/reduction to physiologic doses, 2 patients experienced a transient flare of cGVHD symptoms associated with discontinuation of immunosuppression (1) and temporary hold of RUX. None of the other patients required a restart of prednisone or increased immunosuppression. We conclude that RUX is an effective steroid-sparing agent in steroid-dependent severe cGVHD. Validation of these results in prospective trials is needed. Disclosures Jillella: Seattle Genetics, Inc.: Research Funding.

Children with B-precursor acute lymphoblastic leukemia and B-cell lymphoma, particularly those with relapsed or refractory disease, are increasingly enrolled on phase II and phase III clinical trials studying immunotherapies. These therapeutic agents may be associated with a high risk of cytokine release syndrome (CRS), and nurses lack standardized guidelines for monitoring and managing patients with CRS. Six studies and one clinical practice guideline were included in this systematic review that examined the evidence of CRS following administration of chimeric antigen receptor T-cell therapy or the bi-specific T-cell engager antibody, blinatumomab. Six nursing practice recommendations (five strong, one weak) were developed based on low or very low-quality evidence: three reflect preinfusion monitoring, one focuses on monitoring during and postinfusion, and three pertain to the nurse's role in CRS management.

Background: Camp Oasis is an annual week-long camp serving children with inflammatory bowel disease (IBD) and hosted by the Crohn's and Colitis Foundation. Youth with IBD are at increased risk for mental health challenges, with Camp Oasis potentially mitigating these risks. The aim of this study is to measure change in and predictors of social-emotional well-being and protective factors of self-worth as a result of attending Camp Oasis. Methods: -tests compared change in participants' and caregivers' perceptions before and after camp; path analyses examined the key predictors of social-emotional well-being. Results: A total of 6011 online surveys were analyzed. Participants and caregivers reported consistently positive perceptions of participants' experiences during and after camp. Significant improvements in confidence, independence, activity, comfort around others, being more open about disease, and taking medication as expected were observed. Being new to Camp Oasis was one of the strongest predictors of both disease-related self-efficacy and social connections after camp. Conclusions: The uniformly high rates of participants' perceptions during camp suggest camp is a life-changing experience for youth with IBD, reduces disease-related stigma, and enhances confidence and social skills. Participants' positive experiences appear to foster notable benefits after camp in terms of openness, their sense of belonging, connections, and confidence.

STUDY OBJECTIVE: The purpose of this study was to comprehensively evaluate the long-term adverse effects of proton pump inhibitors (PPIs) compared with histamine-2 receptor antagonists (H2RAs) in kidney transplant recipients. METHODS: This retrospective cohort compared 582 patients treated with PPI with 705 patients treated with H2RA and evaluated adverse effects throughout their course of acid suppressant therapy to a maximum of nine years posttransplant. The primary outcome of interest was renal function at 1 year posttransplant; secondary outcomes included renal function at 30 days, 3, 5, and 9 years posttransplant as well as rejection, electrolyte and laboratory abnormalities, osteoporosis, pneumonia, and Clostridium difficile infections. RESULTS: Renal function did not significantly differ at any timepoint posttransplant. Rejection rates and Clostridium difficile infections were similar between groups; osteoporosis and pneumonia rates were numerically higher in the PPI treated arm but did not reach statistical significance. Proton pump inhibitor (PPI) treated patients were more likely to experience hypomagnesemia requiring supplementation. High dose PPI treated patients had significantly higher rates of pneumonia and osteoporosis compared with H2RA treated patients. Patients were maintained on PPI therapy for an average of 5 years and H2RA therapy for 3 years posttransplant, the majority without a clear indication for therapy. CONCLUSIONS: There was no difference in renal function, rejection, or graft loss between PPI and H2RA treated patients. The majority of patients were maintained on PPI therapy for several years posttransplant without a clear indication; critical evaluation of ongoing need for acid suppressant therapy in the posttransplant course should be an area of future focus.

This position statement was approved by the NAEMSP Board of Directors on 8/24/21.

Since the publication of the last Cellular Therapy and Stem Cell Transplant blueprint in 2013, Children’s Oncology Group cellular therapy-based trials for advanced the field and created new standards of care across a wide spectrum of pediatric cancer diagnoses. Key findings include that tandem autologous transplant improved survival for patients with neuroblastoma and atypical teratoid/rhabdoid brain tumors, one umbilical cord blood (UCB) donor was safer than two UCB donors, killer immunoglobulin receptor (KIR) mismatched donors did not improve survival for pediatric acute myeloid leukemia when in vivo T cell depletion is used and the depth of remission as measured by next-generation sequencing based minimal residual disease assessment pre-transplant was the best predictor of relapse for acute lymphoblastic leukemia. Plans for the next decade include optimizing donor selection for transplants for acute leukemia/myelodysplastic syndrome, using novel engineered cellular therapies to target a wide array of malignancies, and developing better treatments for cellular therapy toxicities such as viral infections and graft-vs-host disease.

Lead (Pb) and cadmium (Cd) are metals that occur naturally in the environment and are present in biomass fuels, such as wood. When these fuels are burned, they can release Pb and Cd into the air, leading to exposure through inhalation. Studies of exposure to metals and health outcomes suggest harmful impacts, including cardiovascular diseases. We assessed baseline associations between Pb and Cd concentrations in dried blood spots with systolic and diastolic blood pressure (SBP, DBP) among women in the Household Air Pollution Intervention Network (HAPIN) trial. We analyzed data from three of the four HAPIN randomized controlled trial sites (Guatemala, Peru, and Rwanda), focusing on women aged 40 to 79 years living in households reliant on biomass cooking. Dried blood spots were collected, processed, and analyzed for Pb and Cd exposure; SBP and DBP were measured following international guidelines. Demographic, socioeconomic, and dietary variables were collected via standardized questionnaires administered by local field staff. Statistical analyses included multivariable linear regression to examine associations between Pb and Cd, separately, and BP, adjusting for covariates informed by a Directed Acyclic Graph. Additional analyses assessed effect modification by age and research site. There was regional variation in BP levels among women, with median SBP and DBP values higher in Rwanda (116.3 mmHg, 73.0 mmHg) and Guatemala (113.3 mmHg, 68.3 mmHg) compared to Peru (106.0 mmHg, 63.3 mmHg). Pb exposure showed positive associations with both SBP and DBP. For each log-unit increase in Pb concentration, we observed increases of 2.36 mmHg SBP (95% CI 0.51, 4.20) and 1.42 mmHg DBP (95% CI 0.16, 2.67). Cd was not associated with SBP or DBP in this analysis. Pb exposure may be an important risk factor for increased SBP and DBP, markers of cardiovascular disease risk.

Data and code necessary to reproduce figures and tables in the paper.

Dataset #1 of 4

Data and code necessary to reproduce figures and tables in the paper.

HISTORY OF CASE: 38-year-old female with no significant medical history who presented for evaluation of left upper extremity numbness and weakness 49 days after a motor vehicle collision. Patient reports difficulty lifting her arms overhead and weakness in her grasp and fine motor activities. PHYSICAL EXAM: In no acute distress. Well-developed and well nourished. 4/5 left first dorsal interosseous, abductor digiti minimi, abductor pollicis brevis, and extensor indicis proprius. 5/5 left shoulder abduction, elbow flexion, elbow extension, and wrist extension. Pain in dorsal aspect of forearm with numbness and pain over the dorsum of the thumb, 2nd, and 3rd fingers. Hoffman’s negative. Soft tissue swelling with the ulnar aspect of the distal forearm, no warmth, rash, or erythema. Tenderness to palpation over the left supinator and medial epicondyle. Spurling's negative, only reproduced neck pain. Tinel’s negative at the left wrist and elbow. DIFFERENTIAL DIAGNOSIS: 1. Cervical Radiculopathy2. Carpal Tunnel Syndrome3. Cubital Tunnel Syndrome4. Brachial Plexopathy TESTS AND RESULTS: Magnetic resonance imaging of the cervical spine:-mild flattening of the ventral cord at left C5-C6 and right C6-C7Electrodiagnostic testing:-No evidence of left median, ulnar neuropathy, or cervical radiculopathyUltrasound:-No evidence of median or ulnar neuropathy-6 mm (millimeters) x 4 mm x 12 mm ganglion cyst against the radial nerve just proximal to it giving off the branch of the posterior interosseous nerve-No increased power Doppler or color Doppler flow in the ganglion cyst FINAL/WORKING DIAGNOSIS: 1. Left dorsal forearm pain consistent with radial neuritis in the setting of a space-occupying ganglion cyst of the elbow2. Progressive left-hand weakness in a predominantly ulnar/C8-T1 distribution TREATMENT AND OUTCOMES: Follow-up for ganglion cyst aspiration and injection with corticosteroid after delivery of child.

Understanding the molecular landscape of papillary thyroid carcinoma (PTC), the most common thyroid cancer in children, creates additional therapeutic approaches. RET gene rearrangements are observed in pediatric PTC and selective inhibition of RET is now possible with specific tyrosine kinase inhibitors designed to target diverse RET -activating mutations. We present a 13-year-old female with radioactive iodine-refractory metastatic PTC, found to harbor a NCOA4-RET fusion, who responded to treatment with selpercatinib with elimination of supplemental oxygen need, marked reduction in pulmonary nodules and mediastinal lymphadenopathy, and substantial improvement in thyroglobulin levels. Response was maintained despite 2 dose reductions for possibly-related weight gain.

HISTORY: 70-year-old male with past surgical history significant for Grade 1 open right comminuted intra-articular distal humerus fracture and traumatic laceration of the right triceps tendon status-post open reduction internal fixation (ORIF) of right distal humerus, transposition of the right ulnar nerve, and primary repair of the triceps tendon laceration 3 years ago, who presented with persistent paresthesias in the medial forearm and hand into the 4th and 5th digits and pain the posterior lateral aspect of his elbow since time of surgery. PHYSICAL EXAMINATION: Examination of the right elbow demonstrates well-healed posterior surgical incision. Tenderness to palpation over the olecranon, medial epicondyle, and lateral epicondyle. Passive and active range of motion testing demonstrates 10 degrees short of elbow extension, 130 degrees of flexion, 80 degrees of pronation, and 70 degrees of supination. Strength testing demonstrates 5-/5 right elbow extension, 4/5 first dorsal interosseous, and 5/5 pronation, supination, and wrist extension/flexion. Positive Tinel's anterior to the cubital tunnel. Decreased sensation in the ulnar nerve distribution. DIFFERENTIAL DIAGNOSIS: 1. Ulnar neuropathy2. Cubital tunnel syndrome3. Carpal tunnel syndrome4. Cervical radiculopathy5. Hardware failure TEST AND RESULTS: Electrodiagnostic testing:- Ulnar neuropathy at the elbow that appears electrically moderate in severity- No evidence of cervical radiculopathySonographic evaluation:- Ulnar nerve sits posterior to the medial epicondyle, abut against the medial fixation plate, and partially sublux on flexion FINAL WORKING DIAGNOSIS: 1. Right ulnar neuropathy secondary to hardware malpositioning, failed ulnar nerve transposition, and ulnar nerve subluxation over the medial fixation plate. TREATMENT AND OUTCOMES: Patient to follow-up with orthopaedic surgery for removal of hardware and transposition of the ulnar nerve.

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