Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK.

Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B-cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein-to-vein time and infusion rate did not differ between bridging modalities. RT-bridged patients had favourable outcomes with 1-year progression-free survival (PFS) of 56% for single modality and 47% for CMT (1-year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high-risk disease, with low dropout rates and excellent outcomes.

Mast cells are upregulated in hidradenitis suppurativa tissue, associated with epithelialized tunnels and normalized by spleen tyrosine kinase antagonism.

Mast cells have traditionally been associated with allergic inflammatory responses; however, they play important roles in cutaneous innate immunity and wound healing. The Hidradenitis Suppurativa tissue transcriptome is associated with alterations in innate immunity and wound healing-associated pathways; however, the role of mast cells in the disease is unexplored. We demonstrate that mast cell-associated gene expression (using whole tissue RNAseq) is upregulated, and in-silico cellular deconvolution identifies activated mast cells upregulated and resting mast cells downregulated in lesional tissue. Tryptase/Chymase positive mast cells (identified using IHC) localize adjacent to epithelialized tunnels, fibrotic regions of the dermis and at perivascular sites associated with Neutrophil Extracellular Trap formation and TNF-alpha production. Treatment with Spleen Tyrosine Kinase antagonist (Fostamatinib) reduces the expression of mast cell-associated gene transcripts, associated biochemical pathways and the number of tryptase/chymase positive mast cells in lesional hidradenitis suppurativa tissue. This data indicates that although mast cells are not the most abundant cell type in Hidradenitis Suppurativa tissue, the dysregulation of mast cells is paralleled with B cell/plasma cell inflammation, inflammatory epithelialized tunnels and epithelial budding. This provides an explanation as to the mixed inflammatory activation signature seen in HS, the correlation with dysregulated wound healing and potential pathways involved in the development of epithelialized tunnels.

Baseline clinical, hormonal and molecular markers associated with clinical response to IL-23 antagonism in hidradenitis suppurativa: A prospective cohort study.

Hidradenitis suppurativa is a complex inflammatory disease in which predicting therapeutic response remains challenging. IL-23 interacts with sex hormones but the relationships between the two in HS remains uninvestigated. To assess whether baseline clinical, hormonal or molecular markers are associated with clinical response to IL-23 antagonism with risankizumab in hidradenitis suppurativa. Twenty six individuals with Hurley stage 2/3 disease were administered risankizumab 150 mg Week 0, 4, 12. Baseline sex hormones and skin biopsies were taken. Clinical response at Week 16 assessed by the HiSCR, and differences between responders and non-responders assessed. Eighteen of 26 participants achieved HiSCR50 at week 16 (69.2%). Clinical response to IL-23 antagonism was associated with male gender, elevated total serum testosterone and decreased levels of FSH. Stratification by clinical responders/nonresponders identified differentially expressed genes including PLPP4 and MAPK10. Immunohistochemistry identified elevated numbers of CD11c, IL-17A and IL-17F positive cells compared to nonresponders. CD11c + cells significantly correlated with serum levels of total testosterone and inversely correlated with serum FSH. Clinical response to IL-23 antagonism in HS is associated with serum sex hormones, Th17 polarized inflammation in lesional tissue and CD11c + cells. These potential therapeutic biomarkers require further validation in larger cohorts but may suggest potential targeted HS therapy.

The first patients treated with MR-CBCT soft-tissue matching in a MR-only prostate radiotherapy pathway.

INTRODUCTION: Magnetic Resonance (MR)-only radiotherapy for prostate cancer has previously been reported using fiducial markers for on-treatment verification. MR-Cone Beam Computed Tomography (CBCT) soft-tissue matching does not require invasive fiducial markers and enables MR-only treatments to other pelvic cancers. This study evaluated the first clinical implementation of MR-only prostate radiotherapy using MR-CBCT soft-tissue matching. METHODS: Twenty prostate patients were treated with MR-only radiotherapy using a synthetic (s)CT-optimised plan with MR-CBCT soft-tissue matching. Two MR sequences were acquired: small Field Of View (FOV) for target delineation and large FOV for organs at risk delineation, sCT generation and on-treatment verification. Patients also received a CT for validation. The prostate was independently contoured on the small FOV MR, copied to the registered CT and modified if there were MR-CT soft-tissue alignment differences (MR-CT volume). This was compared to the MR-only volume with a paired t-test. The treatment plan was recalculated on CT and the doses compared. Independent offline CT-CBCT matches for 5/20 fractions were performed by three therapeutic radiographers using the MR-only contours and compared to the online MR-CBCT matches using two one-sided paired t-tests for equivalence within ±1 mm. RESULTS: The MR-only volumes were significantly smaller than MR-CT (p = 0.003), with a volume ratio 0.92 ± 0.02 (mean ± standard error). The sCT isocentre dose difference to CT was 0.2 ± 0.1%. MR-CBCT soft-tissue matching was equivalent to CT-CBCT (p < 0.001), with differences of 0.1 ± 0.2 mm (vertical), -0.1 ± 0.2 mm (longitudinal) and 0.0 ± 0.1 mm (lateral). CONCLUSIONS: MR-only radiotherapy with soft-tissue matching has been successfully clinically implemented. It produced significantly smaller target volumes with high dosimetric and on-treatment matching accuracy. IMPLICATIONS FOR PRACTICE: MR-only prostate radiotherapy can be safely delivered without using invasive fiducial markers. This enables MR-only radiotherapy to be extended to other pelvic cancers where fiducial markers cannot be used.

Large-scale serum analysis identifies unique systemic biomarkers in psoriasis and hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is now recognized as a systemic inflammatory disease, sharing molecular similarities with psoriasis. Direct comparison of the systemic inflammation in HS with psoriasis is lacking. OBJECTIVES: To evaluate the serum proteome of HS and psoriasis, and to identify biomarkers associated with disease severity. METHODS: In this cross-sectional study, 1536 serum proteins were assessed using the Olink Explore (Proximity Extension Assay) high-throughput panel in patients with moderate-to-severe HS (n = 11), patients with psoriasis (n = 10) and age- and body mass index-matched healthy controls (n = 10). RESULTS: HS displayed an overall greater dysregulation of circulating proteins, with 434 differentially expressed proteins (absolute fold change ≥ 1·2; P ≤ 0·05) in patients with HS vs. controls, 138 in patients with psoriasis vs. controls and 503 between patients with HS and patients with psoriasis. Interleukin (IL)-17A levels and T helper (Th)1/Th17 pathway enrichment were comparable between diseases, while HS presented greater tumour necrosis factor- and IL-1ß-related signalling. The Th17-associated markers peptidase inhibitor 3 (PI3) and lipocalin 2 (LCN2) were able to differentiate psoriasis from HS accurately. Both diseases presented increases of atherosclerosis-related proteins. Robust correlations between clinical severity scores and immune and atherosclerosis-related proteins were observed across both diseases. CONCLUSIONS: HS and psoriasis share significant Th1/Th17 enrichment and upregulation of atherosclerosis-related proteins. Despite the greater body surface area involved in psoriasis, HS presents a greater serum inflammatory burden.

Antimicrobial peptides in hidradenitis suppurativa: a systematic review.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease of the hair follicle defined by recurrent nodules, tunnels and scarring involving the intertriginous regions. HS is associated with microbial dysbiosis and immune dysregulation. In HS, an increasing number of studies have investigated antimicrobial peptides (AMPs). OBJECTIVES: To provide an overview of the literature on AMPs in HS, and to discuss the potential role of AMPs in the pathogenesis of HS. METHODS: PubMed, Embase and the Cochrane Library were searched. The titles, abstracts and full texts of all articles were manually screened. Additionally, the reference lists of the included articles were screened and hand searched for relevant studies. RESULTS: The final literature sample comprised 18 retrospective and prospective studies (no reviews or commentaries) published between 2009 and 2020. CONCLUSIONS: This review demonstrates the multitude of AMPs in HS. Although the methodology of the studies varied, the included studies indicate a consistent overexpression of human ß-defensin (hBD)-2, S100A7, S100A8 and S100A9 at both the mRNA and protein levels, and a decreased expression of hBD-1. Overall, the studies point to a dysregulation of AMPs in both lesional and nonlesional HS skin.

Doppler ultrasound-based noninvasive biomarkers in hidradenitis suppurativa: evaluation of analytical and clinical validity.

BACKGROUND: There is a need for valid and reliable biomarkers in hidradenitis suppurativa (HS) for diagnosis and disease activity monitoring. Imaging-based biomarkers have the potential to fulfil this unmet need but no evaluation of analytical or clinical validity has yet been undertaken. OBJECTIVES: To evaluate the analytical and clinical validity of sonographic epidermal thickness, Doppler ultrasound and dermal tunnel diameter in patients with HS. METHODS: Twenty-two participants with HS were recruited and underwent a total of 65 matched ultrasound and skin biopsies of lesional, perilesional and unaffected tissue. Ultrasound measurements were performed in triplicate with mean values used. Skin biopsies underwent immunohistochemistry as per previously published methods. Analytical validity was assessed in individual ultrasound-biopsy pairs (n = 65) by comparisons of sonographic variables with histological correlates. Clinical validity was assessed in individual patients (n = 22) by comparing measures of overall disease activity with sonographic outcomes. RESULTS: Epidermal thickness, dermal tunnel diameter and power Doppler intensity were assessed. Sonographic epidermal thickness and dermal tunnel diameter have high analytical validity with corresponding histological measurements. Power Doppler intensity demonstrated high correlation with dermal CD3+ and CD11c+ cell counts but not neutrophil elastase-positive cells. Power Doppler ultrasound has significant correlation with pain scores, abscess and nodule count, International HS Severity Scoring System score and number of draining tunnels. CONCLUSIONS: Sonographic epidermal thickness and dermal tunnel diameter have acceptable levels of analytical validity in the assessment of HS lesions. Power Doppler intensity demonstrates acceptable clinical and analytical validity, suggesting it is a valid imaging-based biomarker in HS.

Dermal tunnels influence time to clinical response and family history influences time to loss of clinical response in patients with hidradenitis suppurativa treated with adalimumab.

BACKGROUND: Clinical response in hidradenitis suppurativa (HS) is most commonly assessed using the Hidradenitis Suppurativa Clinical Response (HiSCR) measure. Dermal tunnels, increased body mass index, smoking and antibiotic use significantly decrease the odds of achieving HiSCR. However, there are few data exploring if clinical features are also associated with length of time to achieve clinical response and/or time to lose clinical response. AIM: To explore whether variables associated with achievement of HiSCR are associated with time to achieve HiSCR and time to loss of HiSCR in patients with HS treated with adalimumab 40 mg weekly in the PIONEER open-label extension study. METHODS: Time-to-event analyses were performed to estimate time to achieve HiSCR and time to loss of HiSCR. The log rank test was used to compare cumulative incidence curves for a priori patient- and disease-associated factors. Cox regression analysis was performed to compare time-to-event outcomes in the presence of a priori variables. All statistical analyses were completed with R software (V3.5.3). RESULTS: Presence of dermal tunnels significantly increased the time to achieve HiSCR (median 32.6 vs. 14.3 weeks, P = 0.02) and the hazard ratio (HR) was significant after controlling for patient and disease factors (HR = 0.70, 95% CI 0.51-0.96, P = 0.03). A positive family history of HS significantly decreased the time to loss of HiSCR (median 11.4 vs. 18 weeks, P < 0.001) and remained significant in Cox regression analysis (HR = 2.01, 95% CI 1.40-2.88, P < 0.001). CONCLUSION: The presence of dermal tunnels significantly influences the odds of achieving HiSCR and the time to achieve HiSCR, while family history influences time to loss of HiSCR.

Malignancy and infection risk during adalimumab therapy in hidradenitis suppurativa.

BACKGROUND: The association of adalimumab therapy with malignancy and infection is established in other inflammatory diseases; however, rates of hidradenitis suppurativa (HS) are based on case reports or retrospective healthcare data and the effect of adalimumab therapy on these rates is unknown. Previously reported rates in the PIONEER OLE Phase 3 study reported on rates only in a subpopulation of 88 participants rather than the entire cohort. AIM: To quantify rates of malignancy and serious infection in all patients with HS treated with adalimumab 40 mg weekly. METHODS: Reanalysis was undertaken of individual patient data from the PIONEER 1, PIONEER 2 and PIONEER open-label extension Phase 3 trial data encompassing 591 unique patients with HS administered adalimumab 40 mg weekly without concurrent antibiotic exposure. Incidence rates of serious infection and malignancy were calculated. RESULTS: Incidence rates of serious infection and malignancy were 2.14 and 0.46 per 100 patient-years, respectively. Rates of infection and malignancy were comparable to those in other inflammatory conditions examined. CONCLUSION: Incidence of serious infection in patients with HS on adalimumab is comparable to those with psoriasis and inflammatory arthropathies, but the incidence of malignancy is increased. This may reflect disease-specific malignancy risk rather than an effect of adalimumab.

Optimising Radium 223 Therapy for Metastatic Castration-Resistant Prostate Cancer -5-year Real-World Outcome: Focusing on Treatment Sequence and Quality of Life.

AIMS: Real-world evidence of radium 223 (Ra-223) for the treatment of men with metastatic castration-resistant prostate cancer is emerging. In this prospective single-centre service evaluation, we report for the first time in the UK, real-world quality of life (QoL) and survival outcomes, including the sequencing impact, in 228 treated patients. We aim to share our 5-year experience on how to optimise Ra-223 treatment. MATERIALS AND METHODS: Patients who received Ra-223 therapy between 2014 and 2018 at the Northern Centre for Cancer Care, Newcastle upon Tyne, UK were included in this evaluation. Demographics, clinical characteristics, blood parameters, treatment sequencing and QoL data using abbreviated Functional Assessment of Cancer Therapy-Prostate questionnaires were prospectively collected and analysed. RESULTS: In total, 228 patients were included; median age 72 years (51-87). The medium overall survival was 11.1 months. Overall survival in post-chemotherapy and chemotherapy-naïve patients was 8.1 and 12.3 months, respectively (P = 0.02, hazard ratio 1.52, 95% confidence interval 1.06-2.17); in pre-enzalutamide and post-enzalutamide patients was 11.3 and 10.4 months, respectively (P = 0.65, hazard ratio 0.92, 95% confidence interval 0.63-1.33); in pre-abiraterone and prednisolone and post-abiraterone and prednisolone patients was 11.8 and 10.5 months, respectively (P = 0.08, hazard ratio 0.74, 95% confidence interval 0.51-1.06); in this latter group, the fracture rate was 24% (15/63). QoL post Ra-223 (n = 101 evaluated) showed that pain scores improved in 54%, there was no change in 17% and pain scores worsened in 30% of treated patients. Overall QoL scores showed a similar trend. QoL was not significantly associated with overall survival. CONCLUSIONS: Ra-223 palliates pain and improves disease-related QoL in most patients in the real-world setting. Our survival outcome is comparable with other real-world studies. Chemotherapy-naïve patients seemed to have better survival than those who received prior chemotherapy. No significant survival differences were observed between pre- and post-abiraterone and prednisolone or enzalutamide patients. The fracture rate in the post-abiraterone and prednisolone group seemed to be high. Bone health evaluation and protection should be incorporated as standard of care.