A Phase IB/IIA Study of Ex Vivo Expanded Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Perianal Fistulizing Crohn's Disease.

BACKGROUND: Mesenchymal stem cells have been used for the treatment of perianal Crohn's fistulizing disease by direct injection. However, no studies to date have included patients with proctitis, anal canal involvement, and multiple branching tracts. OBJECTIVE: This study aimed to determine safety and efficacy of mesenchymal stem cells for refractory perianal Crohn's disease. DESIGN: Phase IB/IIA randomized controlled trial. SETTINGS: Tertiary IBD referral center. PATIENTS: Adult Crohn's disease patients with perianal fistulizing disease. INTERVENTION: Seventy-five million mesenchymal stem cells were administered with a 22-G needle by direct injection after curettage and primary closure of the fistula tract. A repeat injection of 75 million mesenchymal stem cells at 3 months was given if complete clinical and radiographic healing were not achieved. MAIN OUTCOMES MEASURES: Adverse and serious adverse events occurred at postprocedure day 1, week 2, week 6, month 3, month 6, and month 12. Clinical healing, radiographic healing per MRI, and patient-reported outcomes were collected at the same time points. RESULTS: A total of 23 patients were enrolled and treated; 18 were treatment patients and 5 were control. There were no adverse or serious adverse events reported related to mesenchymal stem cell therapy. At 6 months, 83% of the treatment group and 40% of the control group had complete clinical and radiographic healing. The perianal Crohn's disease activity index, Wexner incontinence score, and VanAssche score had all significantly decreased in treatment patients at 6 months; none significantly decreased in the control group. LIMITATIONS: Single institution and single blinded. CONCLUSIONS: Bone marrow-derived mesenchymal stem cells offer a safe and effective alternative treatment approach for severe perianal fistulizing Crohn's disease. See Video Abstract at http://links.lww.com/DCR/C128 . UN ESTUDIO DE FASE IB/IIA DE CLULAS MADRE MESENQUIMALES DERIVADAS DE MDULA SEA ALOGNICA EXPANDIDA EX VIVO PARA EL TRATAMIENTO DE LA ENFERMEDAD DE CROHN FISTULIZANTE PERIANAL: ANTECEDENTES:Las células madre mesenquimales se han utilizado para el tratamiento de la enfermedad fistulizante de Crohn perianal mediante inyección dirigida. Sin embargo, ningún estudio hasta la fecha ha incluido pacientes con proctitis, afectación del canal anal y vías de ramificación múltiples.OBJETIVO:Determinar la seguridad y eficacia de las células madre mesenquimales para la enfermedad de Crohn perianal refractaria.DISEÑO:Ensayo de control aleatorizado de fase IB/IIA.AJUSTES:Centro de referencia de enfermedad inflamatoria intestinal terciaria.PACIENTES:Pacientes adultos con enfermedad de Crohn con enfermedad fistulizante perianal.INTERVENCIÓN:Se administraron 75 millones de células madre mesenquimales con una aguja 22G mediante inyección directa después del legrado y cierre primario del trayecto de la fístula. Se administró una inyección repetida de 75 millones de células madre mesenquimales a los 3 meses si no se lograba una curación clínica y radiográfica completa.PRINCIPALES MEDIDAS DE RESULTADOS:eventos adversos y adversos graves en el día 1, la semana 2, la semana 6, el mes 3, el mes 6 y el mes 12 después del procedimiento. Curación clínica, curación radiográfica por imagen de resonancia magnética y resultados informados por el paciente en los mismos puntos de tiempo.RESULTADOS:Un total de 23 pacientes fueron reclutados y tratados; 18 fueron de tratamiento y 5 de control. No se informaron eventos adversos o adversos graves relacionados con la terapia con células madre mesenquimales. A los seis meses, el 83 % del grupo de tratamiento y el 40 % del control tenían una curación clínica y radiográfica completa. El índice de actividad de la enfermedad de Crohn perianal, la puntuación de incontinencia de Wexner y la puntuación de VanAssche habían disminuido significativamente en los pacientes de tratamiento a los seis meses; ninguno disminuyó significativamente en el grupo de control.LIMITACIONES:Institución única y simple ciego.CONCLUSIONES:Las células madre mesenquimales derivadas de la médula ósea ofrecen un d tratamiento alternativo seguro y eficaz para la enfermedad de Crohn fistulizante perianal grave. Consulte Video Resumen en http://links.lww.com/DCR/C128 . (Traducción-Dr Yolanda Colorado ).

A phase IB/IIA study of remestemcel-L, an allogeneic bone marrow-derived mesenchymal stem cell product, for the treatment of medically refractory ulcerative colitis: an interim analysis.

AIM: There have been no studies into the direct injection of mesenchymal stem cells (MSCs) for luminal ulcerative colitis (UC). Our aim was to investigate the efficacy of MSCs delivered locally via endoscopic delivery, as is done in the setting of perianal disease, to treat the local site of inflammation directly. METHOD: A phase IB/IIA randomized control clinical trial of remestemcel-L, an ex vivo expanded allogeneic bone marrow-derived MSC product, at a dose of 150 million MSCs versus placebo (2:1 fashion) delivered via direct injection using a 23-gauge sclerotherapy needle at the time of colonoscopy was designed to assess the safety and efficacy of endoscopic delivery of MSCs for UC. The main outcome measures were adverse events, Mayo score and Mayo endoscopic severity score at 2 weeks, 6 weeks and 3 months post-MSC delivery. RESULTS: Six patients were enrolled and treated; four received MSCs and two placebo. All had been on prior anti-tumour necrosis factor or anti-integrin therapy. There were no adverse events related to MSCs. In the treatment group (n = 4), the Mayo endoscopic severity score decreased in all patients by 2 weeks after MSC delivery. At 3 months, all patients were extremely satisfied or satisfied with their MSC treatment based on the inflammatory bowel disease patient-reported treatment impact (IBD-PRTI), and treatment response was described as excellent or good in all patients. In the control group (n = 2), the Mayo endoscopic severity score did not increase as a result of being off alternative therapy. At 3 months, patients were dissatisfied according to the IBD-PRTI, and treatment response was poor or unchanged. CONCLUSION: MSCs may offer a safe therapeutic option for the treatment of medically refractory UC. Early data suggest improved clinical and endoscopic scores by 2 weeks after MSC delivery.

Effect of obesity on ability to lower exposure for detection of low-attenuation liver lesions.

PURPOSE: The purpose of this study was to assess the effect of obesity and iterative reconstruction on the ability to reduce exposure by studying the accuracy for detection of low-contrast low-attenuation (LCLA) liver lesions on computed tomography (CT) using a phantom model. METHODS: A phantom with four unique LCLA liver lesions (5- to 15-mm spheres, -24 to -6 HU relative to 90-HU background) was scanned without ("thin" phantom) and with ("obese" phantom) a 5-cm thick fat-attenuation ring at 150 mAs (thin phantom) and 450 mAs (obese phantom) standard exposures and at 33% and 67% exposure reductions. Images were reconstructed using standard filtered back projection (FBP) and with iterative reconstruction (Adaptive Model-Based Iterative Reconstruction strength 3, ADMIRE). A noninferiority analysis of lesion detection was performed. RESULTS: Mean area under the curve (AUC) values for lesion detection were significantly higher for the thin phantom than for the obese phantom regardless of exposure level (P < 0.05) for both FBP and ADMIRE. At 33% exposure reduction, AUC was noninferior for both FBP and ADMIRE strength 3 (P < 0.0001). At 67% exposure reduction, AUC remained noninferior for the thin phantom (P < 0.0035), but was no longer noninferior for the obese phantom (P ≥ 0.7353). There were no statistically significant differences in AUC between FBP and ADMIRE at any exposure level for either phantom. CONCLUSIONS: Accuracy for lesion detection was not only significantly lower in the obese phantom at all relative exposures, but detection accuracy decreased sooner while reducing the exposure in the obese phantom. There was no significant difference in lesion detection between FBP and ADMIRE at equivalent exposure levels for either phantom.

A phase IB/IIA study of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of rectovaginal fistulizing Crohn's disease.

BACKGROUND: Crohn-related rectovaginal fistulas are notoriously difficult to treat. Studies of mesenchymal stem cells for the treatment of perianal Crohn fistulizing disease have largely excluded rectovaginal fistulas. The aim of this study was to determine the safety and efficacy of mesenchymal stem cells for refractory rectovaginal fistulizing Crohn disease. METHODS: A phase IB/IIA randomized control trial was performed in a 3:1, single-blinded study. Patients included were adult women with an anovaginal/rectovaginal fistula in the setting of Crohn disease. Seventy-five million mesenchymal stem cells were administered with a 22G needle after curettage and primary closure of the fistula tract at day 0 and month 3. Adverse and serious adverse events were recorded at post-procedure day 1, week 2, week 6, month 3, month 6, and month 12, along with clinical healing, magnetic resonance imaging, and patient-reported outcomes. RESULTS: A total of 19 patients were enrolled and treated-15 treatment and 4 control. There were no adverse or serious adverse events related to mesenchymal stem cell therapy. At 6 months, 50% of the treatment group and 0% of the control had complete clinical and radiographic healing; 91.7% of the treatment group had improvement at 6 months with only one patient having a lack of response, whereas only 50% of the control group had improvement at 6 months. CONCLUSION: Bone marrow-derived mesenchymal stem cells offer a safe alternative treatment approach for rectovaginal fistulas in the setting of Crohn disease. Complete healing was achieved in half of the patients.

Treatment effect of ex vivo expanded allogeneic bone marrow-derived mesenchymal stem cells for the treatment of fistulizing Crohn's disease are durable at 12 months.

BACKGROUND: Mesenchymal stem cells have been administered via direct injection to treat perianal Crohn's fistulizing disease. We herein sought to determine the safety and durability of treatment response to 12 months with 3 individual phase IB/IIA clinical trials of mesenchymal stem cells for refractory perianal, rectovaginal, and ileal pouch fistulas in the setting of Crohn disease. METHODS: Three phase IB/IIA randomized placebo-controlled single-blinded clinical trials were performed for (1) perianal fistulas, (2) rectovaginal fistula, and (3) ileal pouch in situ with anovaginal and/or perianal fistulas. Bone marrow-derived mesenchymal stem cells (75 million in 7.5 mL) were injected at the time of exam under anesthesia on day 0 and month 3. Outcome measures were adverse events and combined clinical and pelvic magnetic resonance imaging healing at month 6 and month 12. RESULTS: Across all 3 trials, 64 patients were enrolled; 49 were treatment and 15 were control. At 6 months, combined clinical and radiographic healing was achieved in 83.3%, 33.3%, and 30.8% of the perianal, rectovaginal, and pouch fistula treatment cohorts, respectively. At 12 months, the treatment response was durable, with 67.7% of perianal, 37.5% of rectovaginal, and 46.2% of peripouch fistulas maintaining complete clinical and radiographic healing. Two patients in the perianal fistula control cohort achieved combined clinical and radiographic healing at 12 months, whereas 0% of rectovaginal and pouch control patients healed. CONCLUSION: Bone marrow-derived mesenchymal stem cells offer a safe and effective alternative treatment approach for severe perianal, rectovaginal, and peripouch fistulizing Crohn's disease. Treatment results are durable at 12 months.

Three-dimensional Pouchography: A Proof-of-concept Study of a Breakthrough Technique for Visualising Ileoanal Pouch Anatomy and Morphology in Normal and Mechanical Pouch Complication Patients.

BACKGROUND: Herein, we present a proof-of-concept study of three-dimensional [3D] pouchography using virtual and printed 3D models of ileal pouch-anal anastomosis [IPAA] in patients with normal pouches and in cases of mechanical pouch complications. METHODS: We performed a retrospective, descriptive case series of a convenience sample of 10 pouch patients with or without pouch dysfunction, who had CT scans appropriate for segmentation who were identified from our pouch registry. The steps involved in clinician-driven automated 3D reconstruction are presented. RESULTS: We included three normal patients who underwent CT imaging and were found to have no primary pouch pathology, and seven patients with known pouch pathology identifiable with 3D reconstruction [including pouch strictures, megapouch, pouch volvulus, and twisted pouches], underwent 3D virtual modelling; one normal and one twisted pouch were 3D-printed. We discovered that 3D pouchography reliably identified staple lines [pouch body, anorectal circular and transverse, and tip of J], the relationship between staple lines, and variations in pouch morphology and pouch pathology. CONCLUSION: Three-dimensional reconstruction of IPAA morphology is highly feasible using readily available technology. In our practice, we have found 3D pouchography to be an extremely useful adjunct to diagnose various mechanical pouch complications and improve planning for pouch salvage strategies. Given its ease of use and helpfulness in understanding the pouch structure and function, we have started to routinely integrate 3D pouchography into our clinical pouch referral practice. Further study is needed to formally assess the value of this technique to aid in the diagnosis of pouch pathology.

Keeping Patient Data Secure in the Age of Radiology Artificial Intelligence: Cybersecurity Considerations and Future Directions.

Artificial intelligence (AI)-based solutions are increasingly being incorporated into radiology workflows. Implementation of AI comes along with cybersecurity risks and challenges that practices should be aware of and mitigate for a successful and secure deployment. In this article, these cybersecurity issues are examined through the lens of the "CIA" triad framework-confidentiality, integrity, and availability. We discuss the implications of implementation configurations and development approaches on data security and confidentiality and the potential impact that the insertion of AI can have on the truthfulness of data, access to data, and the cybersecurity attack surface. Finally, we provide a checklist to address important security considerations before deployment of an AI application, and discuss future advances in AI addressing some of these security concerns.

A Phase I Study of Ex Vivo Expanded Allogeneic Bone Marrow-Derived Mesenchymal Stem Cells for the Treatment of Pediatric Perianal Fistulizing Crohn's Disease.

BACKGROUND: Perianal fistulizing Crohn's disease is notoriously difficult to treat. Recent studies of mesenchymal stem cells have demonstrated safety and efficacy of this novel treatment approach. However, no studies to date have included pediatric patients. We sought to determine safety and efficacy of mesenchymal stem cells for pediatric perianal fistulizing Crohn's disease. METHODS: This was a phase I clinical trial to evaluate safety and feasibility of mesenchymal stem cells in pediatric perianal Crohn's patients 13 to 17 years of age. At the time of an exam under anesthesia, following curettage of the fistula tract and closure of the internal opening with absorbable suture, 75 million mesenchymal stem cells were administered with a 22-gauge needle. This was repeated at 3 months if complete clinical and radiographic healing were not achieved. Adverse and serious adverse events at were measured at postprocedure day 1, week 2, week 6, month 3, month 6, and month 12. Clinical healing, radiographic healing per magnetic resonance imaging, and patient-reported outcomes were measured at the same time points. RESULTS: Seven pediatric patients were enrolled and treated (6 male; median age of 16.7 years). There were no adverse or serious adverse events related to the investigational product or injection procedure. At 6 months, 83% had complete clinical and radiographic healing. The perianal Crohn's Disease Activity Index, Wexner incontinence score, and Van Assche score had all decreased at 6 months. CONCLUSIONS: Bone marrow-derived mesenchymal stem cells offer a safe, and likely effective, treatment approach for pediatric perianal fistulizing Crohn's disease.

A Phase IB/IIA Study of Allogeneic, Bone Marrow-derived, Mesenchymal Stem Cells for the Treatment of Refractory Ileal-anal Anastomosis and Peripouch Fistulas in the Setting of Crohn's Disease of the Pouch.

BACKGROUND AND AIMS: Mesenchymal stem cells [MSCs] have been used for the treatment of perianal Crohn's fistulising disease by direction injection. No studies to date have included patients with an ileal pouch-anal anastomosis [IPAA] in situ. METHODS: A phase IB/IIA, randomised, control trial of bone marrow-derived, allogeneic MSCs via direct injection to treat adult patients with a peripouch fistula[s] was conducted; 75 million MSCs were administered with a 22 G needle, with repeat injection at 3 months if complete clinical and radiographic healing was not achieved. Adverse and serious adverse events at post-procedure Day 1, Week 2, Week 6, Month 3, Month 6, and Month 12 were assessed. Clinical healing, radiographic healing per pelvic magnetic resonance imaging [MRI], and patient-reported outcomes were assessed at the same time points. RESULTS: A total of 22 patients were enrolled and treated; 16 were treated and six were controls. There were no adverse or serious adverse events related to MSC therapy. At 6 months, 31% of the treatment group and 20% of the control had complete clinical and radiographic healing. When stratifying the treatment group into perianal [n = 7] and ano-vaginal [n = 8] fistulas, 6-month healing in the treatment groups was 57% and 0%, respectively. The perianal Crohn's disease activity index [PCDAI], Wexner incontinence score, and van Assche score all significantly decreased in treatment patients at 6 months; only the PCDAI decreased in the control group. CONCLUSION: Bone marrow-derived, allogeneic MSCs offer a safe and effective alternative treatment approach for peripouch fistulas in the setting of a Crohn's like phenotype of the pouch [ClinicalTrials.gov Identifier: NCT04519684.].

Influence of Enema and Dietary Restrictions on Prostate MR Image Quality: A Multireader Study.

PURPOSE: To evaluate the effect of enema and dietary restrictions on prostate MR image quality metrics and to assess inter-reader agreement for these metrics. METHODS: This retrospective study included 195 men divided into groups based on their compliance with preparation instructions before prostate MRI (Enema + Diet, n = 98; Enema, n = 42; Diet, n = 35; Control [no compliance], n = 20). Four readers independently assessed six image quality metrics on a 5-point scale. Between-group comparisons were made using Wilcoxon rank sum test. Inter-reader agreement was calculated using Fleiss' kappa. RESULTS: Compared with the Control group, image quality with respect to rectal stool/gas, distortion of diffusion-weighted images, overall image quality, and confidence in assessment was higher in the Enema + Diet, Enema, and Diet groups (p  < 0.05 for all comparisons). The Enema + Diet and Enema groups had significantly higher scores than the Diet group for rectal stool/gas (p < 0.001 and 0.005, respectively). The Enema + Diet and Diet groups had higher scores than the Control group for rectal peristalsis (p = 0.027 and 0.009, respectively), but there were no significant differences in motion artifacts on T2-weighted images. Agreement among readers was fair, with kappa values ranging from 0.25 to 0.37. CONCLUSION: Enema and dietary restriction can improve the quality of prostate MRI by decreasing rectal distension and distortion of diffusion-weighted images and by increasing reader confidence in image assessment. Inter-reader agreement using subjective criteria for analysis of MRI quality is fair.

Assessment of ventilation-perfusion scans in patients with chronic thromboembolic pulmonary hypertension before and after surgery and correlation with clinical parameters.

PURPOSE: We did a comparative analysis of matched and mismatched defects in pre- and post-operative V/Q scans in CTEPH patients. We correlated the number of these defects with pre-operative clinical and hemodynamic parameters. METHODS: This was a retrospective study on 27 patients with CTEPH who underwent surgery. Pre- and post-operative V/Q scans were graded for each lung segment as normal, matched or mismatched defect. Additional pre- and post-operative clinical and hemodynamic parameters that were collected include New York Heart Association functional class, six-minute walk distance in feet, N-terminal pro b-type natriuretic peptide, forced expiratory volume in one second/forced vital capacity, diffusing capacity of the lung for carbon monoxide, pulmonary arterial pressure (systolic, diastolic and mean), right atrial pressure, cardiac output and cardiac index. Pulmonary vascular resistance was then calculated. RESULTS: On a segmental basis, 176 mismatched defects were noted in 27 patients, of which 111 improved post-surgery (63%). 22 of the 34 matched defects improved following surgery (64%). 31 new mismatched defects were observed. The number of pre-operative matched defects per patient ranged from 0 to 6. No statistically significant associations were observed between the number of pre-operative matched defects and pre-operative clinical parameters. No statistically significant associations were observed between the number of improved matched defects and the change in clinical parameters (pre- to post-surgery). CONCLUSION: Both matched and mismatched defects on preoperative V/Q scans can show normalization post-surgery. The extent of matched defects on a preoperative V/Q scan does not correlate significantly with other clinical and hemodynamic parameters.