Impact of tumor microenvironment on efficacy of anti-CD19 CAR T cell therapy or chemotherapy and transplant in large B cell lymphoma.

The phase 3 ZUMA-7 trial in second-line large B cell lymphoma demonstrated superiority of anti-CD19 CAR T cell therapy (axicabtagene ciloleucel (axi-cel)) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation) ( NCT03391466 ). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B cell gene expression signature (GES) and CD19 expression associated significantly with improved event-free survival for axi-cel (P = 0.0002 for B cell GES; P = 0.0165 for CD19 expression) but not SOC (P = 0.9374 for B cell GES; P = 0.5526 for CD19 expression). Axi-cel showed superior event-free survival over SOC irrespective of B cell GES and CD19 expression (P = 8.56 × 10-9 for B cell GES high; P = 0.0019 for B cell GES low; P = 3.85 × 10-9 for CD19 gene high; P = 0.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune-suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase and cell-of-origin impacted SOC more than axi-cel outcomes. T cell activation and B cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.

Product Attributes of CAR T-cell Therapy Differentially Associate with Efficacy and Toxicity in Second-line Large B-cell Lymphoma (ZUMA-7).

Treatment resistance and toxicities remain a risk following chimeric antigen receptor (CAR) T-cell therapy. Herein, we report pharmacokinetics, pharmacodynamics, and product and apheresis attributes associated with outcomes among patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) in ZUMA-7. Axi-cel peak expansion associated with clinical response and toxicity, but not response durability. In apheresis material and final product, a naive T-cell phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved response durability, event-free survival, progression-free survival, and a lower number of prior therapies. This phenotype was not associated with high-grade cytokine release syndrome (CRS) or neurologic events. Higher baseline and postinfusion levels of serum inflammatory markers associated with differentiated/effector products, reduced efficacy, and increased CRS and neurologic events, thus suggesting targets for intervention. These data support better outcomes with earlier CAR T-cell intervention and may improve patient care by informing on predictive biomarkers and development of next-generation products. SIGNIFICANCE: In ZUMA-7, the largest randomized CAR T-cell trial in LBCL, a naive T-cell product phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved efficacy, decreased toxicity, and a lower number of prior therapies, supporting earlier intervention with CAR T-cell therapy. In addition, targets for improvement of therapeutic index are proposed. This article is featured in Selected Articles from This Issue, p. 4.

Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma.

Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2 weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell subsets were validated in three independent LBCL datasets. In the ZUMA-1 trial samples, clinical response and overall survival were associated with pre-treatment immune contexture as characterized by Immunoscore and Immunosign 21. Circulating CAR T cell levels were associated with post-treatment TME T cell exhaustion. TME enriched for chemokines (CCL5 and CCL22), γ-chain receptor cytokines (IL-15, IL-7 and IL-21) and interferon-regulated molecules were associated with T cell infiltration and markers of activity. Finally, high density of regulatory T cells in pre-treatment TME associated with reduced axi-cel-related neurologic toxicity. These findings advance the understanding of LBCL TME characteristics associated with clinical responses to anti-CD19 CAR T cell therapy and could foster biomarker development and treatment optimization for patients with LBCL.

Outcome of carpal tunnel decompression with pre-surgical diagnosis determined on general practitioner assessment and nerve conduction study.

BACKGROUND: Accurate diagnosis of carpal tunnel syndrome is key to successful treatment. At our center a treatment pathway was recently established for patients with carpal tunnel syndrome. Within this pathway patients are assessed by their community practitioner. Patients who fail to improve with conservative treatment and have a positive nerve conduction study are put forward for surgery without a specialist assessment. Recent literature has shown nerve conduction study may produce a high rate of false-positive results when used to diagnose carpal tunnel syndrome. The aim of this study was to retrospectively review outcomes of carpal tunnel decompression surgery in patients whose diagnoses was based on a community practitioner assessment and positive nerve conduction study. METHODS: All patients who had carpal tunnel release surgery between August 1, 2017 and August 31, 2018 at our center were screened for eligibility. Data from hospital records and a standardized telephone questionnaire was used to assess surgical outcome. RESULTS: The final study population included 128 operated hands. The mean follow up time after surgery was 9.6 months. We found 79% of patients reported significant improvement of their symptoms following carpal tunnel release. The overall complication rate was 2.3%. CONCLUSION: This study has demonstrated good outcomes from carpal tunnel decompressive surgery are possible in a cohort of patients whose diagnosis was made on the basis of a positive nerve conduction study and community practitioner assessment.

Fixation of the Fractured Lunate in Kienböck Disease.

PURPOSE: To describe an uncommon subset of fractured lunates in Kienböck disease that is salvageable by internal fixation. METHODS: We performed a retrospective review for patients with Kienböck disease treated by internal fixation. Demographic data, objective and radiographic measurements, patient-reported outcome measures (Disabilities of the Arm, Shoulder, and Hand and Patient-Rated Wrist Evaluation) and pain (visual analog scale) scores were collected. RESULTS: Of the 7 patients treated, 5 were available for review. At an average follow-up of 7.1 years (range, 1.5-15 years), all patients had activity-related wrist pain but were pain-free at rest. Radiographic assessment showed union in all lunates and a normal radioscaphoid angle and Stahl index. The modified carpal height ratio was reduced in 4 patients and normal in one. There was no observed narrowing or irregularity of the radiocarpal or midcarpal joints. Patient-reported outcome measures in 2 patients were unsatisfactory. CONCLUSIONS: Computed tomography of the lunate in Kienböck disease is an important investigative tool. A coronal split fracture of these lunates can be salvageable by internal fixation. Revascularization of the lunate can be performed when the fragment is of sufficient size. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

A comparison of concentric and eccentric glenospheres in reverse shoulder arthroplasty: a randomized controlled trial.

BACKGROUND: Inferior scapular notching following reverse shoulder arthroplasty is due to mechanical impingement and, in some studies, has been associated with poorer functional scores, lower patient satisfaction, and more limited shoulder motion. We aimed to test the hypothesis that inferior positioning of the center of rotation with eccentric glenosphere designs decreases the adduction deficit before impingement occurs and improves clinical outcome. METHODS: A randomized, controlled, double-blinded trial was performed. According to the results of a power analysis, fifty patients undergoing reverse shoulder arthroplasty for the diagnosis of cuff tear arthropathy were randomized intraoperatively to receive either a concentric or eccentric glenosphere. The glenoid baseplate was positioned flush to the inferior border of the glenoid before the glenosphere was then attached. Notching was assessed using an anteroposterior radiograph, and clinical outcome was assessed using the visual analog pain scale score, shoulder function rating, American Shoulder and Elbow Surgeons score, and Oxford shoulder score. Active forward elevation and external rotation were assessed. The outcome assessor was blinded to the treatment group. The mean follow-up period for the groups was forty-three and forty-seven months. RESULTS: Patient demographics and preoperative scores were similar between the groups. At the time of the final follow-up, four patients (14.8%) in the concentric group had developed inferior scapular notching (two with Nerot grade I and two with Nerot grade II), ranging in size from 1.1 to 7.4 mm, compared with one patient (4.3%; Nerot grade I) in the eccentric group (p = 0.36). No notching occurred in any patient with glenoid overhang of >3.5 mm. No significant difference between the groups was seen with respect to functional outcome scores, patient satisfaction, or shoulder motion. CONCLUSIONS: There were no differences in notching rates or clinical outcomes between concentric and eccentric glenospheres following reverse shoulder arthroplasty. Inferior glenosphere overhang of >3.5 mm, however, prevented notching. This may be achieved with a modified surgical technique, but eccentric glenospheres provide an additional option. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Comparing sterile bag rubbing and paint on technique in skin preparation of the hands.

BACKGROUND: The aim of this study was to compare two techniques for surgical site skin preparation in hand surgery. METHODS: We compared the standard sponge paint technique versus a plastic bag immersion technique using a 10% povidone-iodine with alcohol solution (Betadine, ORION Laboratories Pty Ltd, Balcatta,WA,Australia) to prepare surgical site skin for hand surgery. This sterile bag rubbing technique involves using a sterile plastic bag filled with 60 mL of Betadine solution to immerse the subjects' hand. Samples were taken from 10 subjects for bacteria colony-forming unit (CFU) counts before and 3 min after surgical site preparation in each group. Outcome measures were preparation time and CFU reduction with a plate impression test using commercially available agar slides. RESULTS: The sterile bag rubbing technique significantly reduced (P < 0.0001) the time required for surgical site skin preparation (28 s) compared with the standard technique (86 s). Both techniques were found to have similar efficacy in the reduction of CFU. CONCLUSIONS: The sterile bag rubbing technique is a quicker alternative method for surgical site preparation in hand surgery and has comparable efficacy to the widely practised standard paint-on technique.

Biomechanical evaluation of different designs of glenospheres in the SMR reverse total shoulder prosthesis: range of motion and risk of scapular notching.

BACKGROUND: Reverse total shoulder arthroplasty is a treatment option for cuff tear arthropathy. Scapular notching remains a concern. This biomechanical study compared the range-of-motion in different designs of glenospheres and hence the relative risk of scapular notching. METHOD: A precision coordinate device was used to investigate four different designs of glenospheres (SMR prosthesis); 36 mm concentric (Standard), 36 mm eccentric, 44 mm concentric, and 44 mm eccentric glenospheres. The centre of rotation in each design was first established. The position of the humeral prosthesis was recorded in the plane of the scapula to compare the degree of adduction and the total range-of-motion. RESULTS: Eccentric glenospheres were found to improve range-of-motion by allowing a higher degree of adduction. Larger diameter glenospheres were found to improve range-of-motion by increasing adduction and abduction. Compared to the 36 mm concentric (standard) glenosphere, the 36 mm eccentric glenosphere improved adduction by 14.5 degrees, the 44 mm concentric glenosphere improved adduction by 11.6 degrees, the 44 mm eccentric glenosphere improved adduction by 17.7 degrees. CONCLUSION: Eccentric glenospheres with a center-of-rotation placed more inferiorly were shown to improve adduction. This design may reduce the clinical incidence of scapular notching.