Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing.

CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into a CD3δ SCID patient's HSPCs resulted in a 71.2% ± 7.85% (n = 3) correction of the pathogenic mutation. Edited HSPCs differentiated in artificial thymic organoids produced mature T cells exhibiting diverse TCR repertoires and TCR-dependent functions. Edited human HSPCs transplanted into immunodeficient mice showed 88% reversion of the CD3D defect in human CD34+ cells isolated from mouse bone marrow after 16 weeks, indicating correction of long-term repopulating HSCs. These findings demonstrate the preclinical efficacy of ABE in HSPCs for the treatment of CD3δ SCID, providing a foundation for the development of a one-time treatment for CD3δ SCID patients.

Association of Standardized Radiology Reporting and Management of Abdominal CT and MRI With Diagnosis of Pancreatic Cancer.

BACKGROUND & AIMS: Follow-up of abdominal computed tomography (CT) and magnetic resonance imaging (MRI) findings suspicious for pancreatic cancer may be delayed if documentation is unclear. We evaluated whether standardized reporting and follow-up of imaging results reduced time to diagnosis of pancreatic cancer. METHODS: We used a quasi-experimental stepped-wedge cluster design to evaluate the effectiveness of newly implemented radiology reporting system. The system standardizes the reporting of CT and MRI reports using hashtags that classify pancreatic findings. The system also automates referral of patients with findings suspicious for pancreatic cancer to a multidisciplinary care team for rapid review and follow-up. The study examined 318,331 patients who underwent CT or MRI that included the abdomen from 2016 through 2019 who had not had an eligible CT or MRI in the preceding 24 months. We evaluated the association of the intervention with incidence of pancreatic cancer within 60 days and 120 days after imaging. RESULTS: Thirty-eight percent of patients received the intervention, and 1523 patients (0.48%) were diagnosed with pancreatic cancer. In multivariable analysis accounting for age, race/ethnicity, sex, Charlson comorbidity, history of cancer, diabetes, and 4-month calendar period, the intervention was associated with nearly 50% greater odds of diagnosing pancreatic cancer within 60 days (adjusted odds ratio, 1.47; 95% confidence interval, 1.05-2.06) and 120 days (adjusted odds ratio, 1.46; 95% confidence interval, 1.04-2.06). CONCLUSIONS: In this large quasi-experimental, community-based observational study, implementing standardized reporting of abdominal CT and MRI reports with clinical navigation was effective for increasing the detection and diagnosis of pancreatic cancer.

Generation of antigen-specific mature T cells from RAG1-/-RAG2-/-B2M-/- stem cells by engineering their microenvironment.

Pluripotent stem cells (PSCs) are a promising source of allogeneic T cells for off-the-shelf immunotherapies. However, the process of differentiating genetically engineered PSCs to generate mature T cells requires that the same molecular elements that are crucial for the selection of these cells be removed to prevent alloreactivity. Here we show that antigen-restricted mature T cells can be generated in vitro from PSCs edited via CRISPR to lack endogenous T cell receptors (TCRs) and class I major histocompatibility complexes. Specifically, we used T cell precursors from RAG1-/-RAG2-/-B2M-/- human PSCs expressing a single TCR, and a murine stromal cell line providing the cognate human major histocompatibility complex molecule and other critical signals for T cell maturation. Possibly owing to the absence of TCR mispairing, the generated T cells showed substantially better tumour control in mice than T cells with an intact endogenous TCR. Introducing the T cell selection components into the stromal microenvironment of the PSCs overcomes inherent biological challenges associated with the development of T cell immunotherapies from allogeneic PSCs.

Central skull base osteomyelitis in patients without otitis externa: imaging findings.

BACKGROUND AND PURPOSE: Skull base osteomyelitis typically arises as a complication of ear infection in older diabetic patients, involves the temporal bone, and has Pseudomonas aeruginosa as the usual pathogen. Atypical skull base osteomyelitis arising from the sphenoid or occipital bones without associated external otitis occurs much less frequently and initially may have headache as the only symptom. The purpose of this study was to review the clinical and MR imaging features of central skull base osteomyelitis. METHODS: We retrospectively reviewed MR images obtained in six patients with central skull base osteomyelitis. No patient had predisposing external otitis or osteomyelitis of the temporal bone. RESULTS: All of our patients presented with headache, no external ear pain, and cranial nerve deficits. Five of six patients had a predisposition to infection, and the erythrocyte sedimentation rate was elevated in the five patients in whom it was checked. In each case, the diagnosis was delayed until MR imaging demonstrated central skull base abnormality, and the diagnosis was then confirmed with tissue sampling. The most consistent imaging findings were clival bone marrow T1 hypointensity and preclival soft tissue infiltration. Five of six patients were cured with no recurrence of skull base infection over a 2-4-year follow-up period. CONCLUSION: In the setting of headache, cranial neuropathy, elevated erythrocyte sedimentation rate, and abnormal clival imaging findings, central skull base osteomyelitis should be considered as the likely diagnosis. Early tissue sampling and appropriate treatment may prevent or limit further complications such as intracranial extension, empyema, or death.

Perineural spread of malignant melanoma of the head and neck: clinical and imaging features.

BACKGROUND AND PURPOSE: Extension of malignant melanoma along cranial nerves is a little-known complication of malignant melanoma of the head and neck. We describe the clinical and MR imaging findings of perineural spread of malignant melanoma to cranial nerves, emphasizing that this entity occurs more commonly with desmoplastic histology and may have a long latent period following primary diagnosis. METHODS: At two institutions, we identified and retrospectively reviewed eight cases of malignant melanoma of the head and neck that had MR imaging evidence of perineural spread of disease. All patients underwent confirmatory tissue sampling. RESULTS: Seven patients had melanomas of the facial skin or lip, and one patient had a primary sinonasal lesion. By histopathology, these melanomas included five desmoplastic, two mucosal, and one poorly differentiated melanotic spindle-cell tumor. All patients developed symptomatic cranial neuropathy an average of 4.9 years from the time of initial diagnosis. MR imaging demonstrated postgadolinium enhancement of at least one branch of the trigeminal nerve in all cases and of at least one other cranial nerve in five cases. Other findings included abnormal contrast enhancement and soft tissue thickening in the cavernous sinus, Meckel's cave, and/or the cisternal segment of the trigeminal nerve. CONCLUSION: Although perineural spread of disease occurs most commonly with squamous cell carcinoma and adenoid cystic carcinoma, malignant melanoma must also be included in this differential diagnosis, particularly if the patient's pathology is known to be desmoplastic. Similarly, any patient with malignant melanoma of the head and neck who undergoes MR imaging should receive an imaging assessment focused on the likely routes of perineural spread.

Tophaceous gout of the first costochondral junction in a heart transplant patient.

We report the case of a 49-year-old man with a 10-year history of gout, who presented with a painful left first costochondral junction mass. A computed tomography (CT)-guided biopsy of the mass revealed foreign body giant cell reaction and crystalline deposition consistent with tophaceous gout.

DTI-based three-dimensional tractography detects differences in the pyramidal tracts of infants and children with congenital hemiparesis.

PURPOSE: To test the hypothesis that there is greater asymmetry in diffusion properties between right and left pyramidal tracts in patients with congenital hemiparesis than in patients with normal motor function. MATERIALS AND METHODS: Four congenitally hemiparetic patients and four age-matched controls underwent magnetic resonance diffusion tensor imaging (DTI)-based three-dimensional tractography of the pyramidal tracts. Relative anisotropy, individual eigenvalues, and directionally averaged apparent diffusion coefficient were measured and degree of asymmetry was calculated. RESULTS: Compared with age-matched controls, congenitally hemiparetic patients had greater asymmetry in all measured diffusion properties. The asymmetry was characterized primarily by lower anisotropy, lower parallel diffusion, higher transverse diffusion, and slightly higher mean diffusivity in the pyramidal tract contralateral to the hemiparesis (i.e., affected pyramidal tract) compared with the unaffected pyramidal tract. CONCLUSIONS: There appears to be greater diffusion asymmetry between the pyramidal tracts in congenitally hemiparetic patients compared to controls. These differences suggest that there are alterations in the microstructure of the pyramidal tract that controls the motor function of the hemiparetic side. Our results suggest that DTI-based three-dimensional tractography is potentially useful in the assessment of motor dysfunction in infants and children with congenital hemiparesis.