Efficacy and Safety of Continued Treatment With Mirikizumab in a Phase 2 Trial of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Mirikizumab is an antibody against the p19 subunit of interleukin 23 that has demonstrated clinical efficacy and was well tolerated following 12 weeks of induction treatment in a phase 2 trial of patients with moderate to severe ulcerative colitis. We present results of the open-label extended induction period in patients who did not initially respond to treatment with mirikizumab. METHODS: This study was a continuation of I6T-MC-AMAC, a double-blind trial, performed at 75 sites in 14 countries, in which patients with moderate to severe ulcerative colitis were randomly assigned to 12 weeks induction therapy with 50 mg, 200 mg, or 600 mg mirikizumab or placebo. Patients without a clinical response (a 9-point decrease in Mayo subscore of ≥2 points and ≥35% from baseline and either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 were offered the opportunity to participate in an open-label, extended induction study for another 12 weeks, in which they received either 600 mg intravenous mirikizumab (n = 20) or, following a protocol amendment, 1000 mg intravenous mirikizumab (n = 64) every 4 weeks. At week 24, patients with a clinical response continued the extension maintenance period and received 200 mg subcutaneous mirikizumab. Endpoints included clinical remission (Mayo subscores of 0 for rectal bleeding, 0 or 1 with a 1-point decrease from baseline), clinical response, endoscopic remission (Mayo endoscopic subscore of 0), or endoscopic improvement (endoscopic subscore of 0 or 1), at study weeks 24 and 52. Data were analysed for patients who received mirikizumab or placebo during the induction phase of the study. RESULTS: Among participants who did not respond to induction mirikizumab, 50.0% of those who received the 12-week extension of 600 mg mirikizumab and 43.8% who received the extension of 1000 mg mirikizumab achieved a clinical response; 15.0% and 9.4% achieved clinical remission, respectively. Endoscopic improvement was achieved by 20.0% of subjects in the 600 mg mirikizumab group and 15.6% subjects in the 1000 mg mirikizumab group. Among initial nonresponders to mirikizumab who had clinical response at study week 24 and continued into maintenance therapy, 65.8% maintained the clinical response, 26.3% achieved clinical remission, and 34.2% had endoscopic improvement at week 52. No new safety concerns were identified. CONCLUSIONS: Extended doses of mirikizumab (600 mg and 1000 mg) for an additional 12 weeks produce a clinical response in up to 50% of patients who did not have a clinical response to 12 weeks of induction doses (50 mg, 200 mg, or 600 mg). Most of the responders to the extended doses maintained clinical response for up to 52 weeks. Clinicaltrials.gov no: NCT02589665.

Deconvolution of monocyte responses in inflammatory bowel disease reveals an IL-1 cytokine network that regulates IL-23 in genetic and acquired IL-10 resistance.

OBJECTIVE: Dysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine. DESIGN: We performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples. RESULTS: We characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1ß and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease. CONCLUSION: Our work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn's disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1ß-targeting therapies upstream of IL-23.

Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Interleukin 23 contributes to the pathogenesis of ulcerative colitis (UC). We investigated the effects of mirikizumab, a monoclonal antibody against the p19 subunit of interleukin 23, in a phase 2 study of patients with UC. METHODS: We performed a trial of the efficacy and safety of mirikizumab in patients with moderate to severely active UC, enrolling patients from 14 countries from January 2016 through September 2017. Patients were randomly assigned to groups given intravenous placebo (N = 63), mirikizumab 50 mg (N = 63) or 200 mg (N = 62) with exposure-based dosing, or mirikizumab 600 mg with fixed dosing (N = 61) at weeks 0, 4, and 8. Of assigned patients, 63% had prior exposure to a biologic agent. Clinical responders (decrease in 9-point Mayo score, including ≥2 points and ≥35% from baseline with either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 who had received mirikizumab were randomly assigned to groups that received maintenance treatment with mirikizumab 200 mg subcutaneously every 4 weeks (N = 47) or every 12 weeks (N = 46). The primary endpoint was clinical remission (Mayo subscores of 0 for rectal bleeding, with 1-point decrease from baseline for stool frequency, and 0 or 1 for endoscopy) at week 12. A multiple testing procedure was used that began with the 600-mg dose group, and any nonsignificant comparison result ended the formal statistical testing procedure. RESULTS: At week 12, 15.9% (P = .066), 22.6% (P = .004), and 11.5% (P = .142) of patients in the 50-mg, 200-mg, and 600-mg groups achieved clinical remission, respectively, compared with 4.8% of patients given placebo. The primary endpoint was not significant (comparison to 600 mg, P > .05). Clinical responses occurred in 41.3% (P = .014), 59.7% (P < .001), and 49.2% (P = .001) of patients in the 50-mg, 200-mg, and 600-mg groups, respectively, compared with 20.6% of patients given placebo. At week 52, 46.8% of patients given subcutaneous mirikizumab 200 mg every 4 weeks and 37.0% given subcutaneous mirikizumab 200 mg every 12 weeks were in clinical remission. CONCLUSIONS: In a randomized trial of patients with UC, mirikizumab was effective in inducing a clinical response after 12 weeks. Additional studies are required to determine the optimal dose for induction of remission. Mirikizumab showed durable efficacy throughout the maintenance period. Clinicaltrials.gov, Number NCT02589665.

Predictive biomarker modeling of pediatric atopic dermatitis severity based on longitudinal serum collection.

The pathogenesis of atopic dermatitis (AD) results from complex interactions between environmental factors, barrier defects, and immune dysregulation resulting in systemic inflammation. Therefore, we sought to characterize circulating inflammatory profiles in pediatric AD patients and identify potential signaling nodes which drive disease heterogeneity and progression. We analyzed a sample set of 87 infants that were at high risk for atopic disease based on atopic dermatitis diagnoses. Clinical parameters, serum, and peripheral blood mononuclear cells (PBMCs) were collected upon entry, and at one and four years later. Within patient serum, 126 unique analytes were measured using a combination of multiplex platforms and ultrasensitive immunoassays. We assessed the correlation of inflammatory analytes with AD severity (SCORAD). Key biomarkers, such as IL-13 (rmcorr=0.47) and TARC/CCL17 (rmcorr=0.37), among other inflammatory signals, significantly correlated with SCORAD across all timepoints in the study. Flow cytometry and pathway analysis of these analytes implies that CD4 T cell involvement in type 2 immune responses were enhanced at the earliest time point (year 1) relative to the end of study collection (year 5). Importantly, forward selection modeling identified 18 analytes in infant serum at study entry which could be used to predict change in SCORAD four years later. We have identified a pediatric AD biomarker signature linked to disease severity which will have predictive value in determining AD persistence in youth and provide utility in defining core systemic inflammatory signals linked to pathogenesis of atopic disease.

Discrepant salivary gland response after radioiodine and MIBG therapies.

BACKGROUND: A retrospective study using PET/CT imaging with 124I-labeled metaiodobenzylguanidine (124I-MIBG) was performed to estimate the (radiation) absorbed dose to the salivary glands in neuroendocrine cancer patients undergoing 131I-MIBG therapy and to compare these results with those in radioiodine (131I-iodide) therapy. METHODS: Twenty-seven patients received individual 124I-MIBG-PET/CT dosimetries, among whom 18 had not previously undergone any MIBG therapies (patient group before treatment) and 9 had already received MIBG therapies prior to the tracer dosimetries (patient group after treatment). For each patient, three or four 124I-MIBG PET/CT scans were performed at approximately 4 and 24 hours, as well as at approximately 48 or/and ≥96 hours after tracer injection. The absorbed doses per administered 131I-MIBG activity to the submandibular and parotid glands were calculated based on the MIRD concept, with its assumption of a uniform glandular activity distribution. RESULTS: The mean±standard deviation of the (self-)absorbed dose per activity averaged over both patient groups and salivary gland types was 0.53±0.24 Gy/GBq (median, 0.49 Gy/GBq; range, 0.17-1.38 Gy/GBq). The absorbed doses per activity of the patient group before treatment did not significantly deviate from those of the patient group after treatment (P=0.67). In the patient group after treatment, the mean±standard deviation of the cumulative 131I-MIBG activity was 20±12 GBq (median, 16 GBq; range, 10-50 GBq). Among the patient groups, no significant absorbed dose difference was found between the submandibular and parotid glands (P>0.24). In comparison to radioiodine therapy, the estimated absorbed dose per activity in MIBG was significantly higher (P<0.001), on average twice as high, contradicting the relationship between the absorbed dose and clinical observation of glandular side effects. CONCLUSIONS: The discrepant salivary gland responses in MIBG and radioiodine therapies suggest a different radiotherapeutical distribution on microscopic scale within the glandular tissue and prove the clinical relevance of a microdosimetric analysis.

Biodistribution and radiation dosimetry of 124I-mIBG in adult patients with neural crest tumours and extrapolation to paediatric models.

AIM: Positron emission tomography (PET) using 124I-mIBG has been established for imaging and pretherapeutic dosimetry. Here, we report the first systematic analysis of the biodistribution and radiation dosimetry of 124I-mIBG in patients with neural crest tumours and project the results to paediatric patient models. METHODS: Adult patients with neural crest tumours who underwent sequential 124I-mIBG PET were included in this retrospective single-center analysis. PET data were acquired 4, 24, 48, and/or 120 h after administration of a mean of 43 MBq 124I-mIBG. Whole-body counting and blood sampling were performed at 2, 4, 24, 48 and 120 h after administration. Absorbed organ dose and effective dose coefficients were estimated in OLINDA/EXM 2.2 according to the MIRD formalism. Extrapolation to paediatric models was performed based on mass-fraction scaling of the organ-specific residence times. Biodistribution data for adults were also projected to 123I-mIBG and 131I-mIBG. RESULTS: Twenty-one patients (11 females, 10 males) were evaluated. For adults, the organs exposed to the highest dose per unit administered activity were urinary bladder (1.54 ± 0.40 mGy/MBq), salivary glands (0.77 ± 0.28 mGy/MBq) and liver (0.65 ± 0.22 mGy/MBq). Mean effective dose coefficient for adults was 0.25 ± 0.04 mSv/MBq (male: 0.24 ± 0.03 mSv/MBq, female: 0.26 ± 0.06 mSv/MBq), and increased gradually to 0.29, 0.44, 0.69, 1.21, and 2.94 mSv/MBq for the 15-, 10-, 5-, 1-years-old, and newborn paediatric reference patients. Projected mean effective dose coefficients for 123I-mIBG and 131I-mIBG for adults were 0.014 ± 0.002 mSv/MBq and 0.18 ± 0.04 mSv/MBq, respectively. CONCLUSION: PET-based derived radiation dosimetry data for 124I-mIBG from this study agreed well with historical projected data from ICRP 53. The effective dose coefficients presented here may aid in guidance for establishing weight-based activity administration protocols.

Efficacy and Safety of 124I-MIBG Dosimetry-Guided High-Activity 131I-MIBG Therapy of Advanced Pheochromocytoma or Neuroblastoma.

We aim to evaluate the efficacy and safety of 124I-metaiodobenzylguanidine (MIBG) dosimetry-guided high-activity 131I-MIBG therapy of advanced pheochromocytoma or neuroblastoma. Methods: Fourteen patients with advanced pheochromocytoma or neuroblastoma, age 9-69 y, underwent 124I-MIBG PET scans and whole-body retention measurements to assess the whole-body dose as a surrogate of bone marrow toxicity and tumor (absorbed) dose per unit of administered activity. Dosimetry results together with individual patient characteristics were combined to guide a single therapeutic activity to achieve a high tumor dose without exceeding toxicity threshold. Toxicity was assessed for hematologic, hepatic, and renal function. Response was evaluated by RECIST, International Society of Pediatric Oncology Europe Neuroblastoma-like score, change in PET uptake, and quantitative PET parameters (SUVmax, SUVpeak, metabolic tumor volume, total lesion glycolysis), as well as visual decrease in number or in visual intensity of lesions on baseline to follow-up 124I-MIBG PET/CT. Results: The average therapeutic activity was 14 GBq. Eleven of 14 patients (79%) received each more than 10 GBq. One male patient was treated with a single activity of 50 GBq. Three patients were treated with lower activities between 3.5 and 7.0 GBq. Median overall survival was 85 mo (95% CI), and median progression-free survival was 25 mo (95% CI). Four (29%) and 5 (36%) patients demonstrated response (complete response or partial response) by RECIST and functional imaging, respectively. One patient exceeded whole-body dose of 2 Gy and demonstrated grade 3 hematologic toxicity, which resolved spontaneously within 12 mo after the therapy without the need for further treatment. Three patients (21%) demonstrated transient grade 1 renal toxicity. Conclusion: 124I-MIBG dosimetry-guided high-activity 131I-MIBG therapy in patients with advanced pheochromocytoma or neuroblastoma resulted in durable responses with a low rate of manageable adverse events. Efficacy of 124I-MIBG-guided activity escalation should further be assessed in a prospective setting.

Mirikizumab Regulates Genes Involved in Ulcerative Colitis Disease Activity and Anti-TNF Resistance: Results From a Phase 2 Study.

INTRODUCTION: Mirikizumab, a monoclonal antibody targeting the p19 subunit of interleukin (IL)-23, demonstrated efficacy and was well-tolerated in a phase 2 randomized clinical trial in patients with moderate-to-severe ulcerative colitis (UC) (NCT02589665). We explored gene expression changes in colonic tissue from study patients and their association with clinical outcomes. METHODS: Patients were randomized to receive intravenous placebo or 3 mirikizumab induction doses. Patient biopsies were collected at baseline and week 12, and differential gene expression was measured using a microarray platform and compared in all treatment groups to determine differential expression values between baseline and week 12. RESULTS: The greatest improvement in clinical outcomes and placebo-adjusted change from baseline in transcripts at week 12 was observed in the 200 mg mirikizumab group. Transcripts significantly modified by mirikizumab correlate with key UC disease activity indices (modified Mayo score, Geboes score, and Robarts Histopathology Index) and include MMP1, MMP3, S100A8, and IL1ß. Changes in transcripts associated with increased disease activity were decreased after 12 weeks of mirikizumab treatment. Mirikizumab treatment affected transcripts associated with resistance to current therapies, including IL-1ß, OSMR, FCGR3A and FCGR3B, and CXCL6, suggesting that anti-IL23p19 therapy modulates biological pathways involved in resistance to antitumor necrosis factor and Janus kinase inhibitors. DISCUSSION: This is the first large-scale gene expression study of inflamed mucosa from patients with UC treated with anti-IL23p19 therapy. These results provide molecular evidence for mucosal healing from an extensive survey of changes in transcripts that improve our understanding of the molecular effects of IL-23p19 inhibition in UC.

The oral spleen tyrosine kinase inhibitor fostamatinib attenuates inflammation and atherogenesis in low-density lipoprotein receptor-deficient mice.

OBJECTIVE: Spleen tyrosine kinase (SYK) has come into focus as a potential therapeutic target in chronic inflammatory diseases, such as rheumatoid arthritis and asthma, as well as in B-cell lymphomas. SYK has also been involved in the signaling of immunoreceptors, cytokine receptors, and integrins. We therefore hypothesized that inhibition of SYK attenuates the inflammatory process underlying atherosclerosis and reduces plaque development. METHODS AND RESULTS: Low-density lipoprotein receptor-deficient mice consuming a high-cholesterol diet supplemented with 2 doses of the orally available SYK inhibitor fostamatinib for 16 weeks showed a dose-dependent reduction in atherosclerotic lesion size by up to 59±6% compared with the respective controls. Lesions of fostamatinib-treated animals contained fewer macrophages but more smooth muscle cells and collagen-characteristics associated with more stable plaques in humans. Mechanistically, fostamatinib attenuated adhesion and migration of inflammatory cells and limited macrophage survival. Furthermore, fostamatinib normalized high-cholesterol diet -induced monocytosis and inflammatory gene expression. CONCLUSIONS: We present the novel finding that the SYK inhibitor fostamatinib attenuates atherogenesis in mice. Our data identify SYK inhibition as a potentially fruitful antiinflammatory therapeutic strategy in atherosclerosis.

Therapeutic targeting of Syk in autoimmune diabetes.

In APCs, the protein tyrosine kinase Syk is required for signaling of several immunoreceptors, including the BCR and FcR. We show that conditional ablation of the syk gene in dendritic cells (DCs) abrogates FcgammaR-mediated cross priming of diabetogenic T cells in RIP-mOVA mice, a situation phenocopied in wild-type RIP-mOVA mice treated with the selective Syk inhibitor R788. In addition to blocking FcgammaR-mediated events, R788 also blocked BCR-mediated Ag presentation, thus broadly interrupting the humoral contributions to T cell-driven autoimmunity. Indeed, oral administration of R788 significantly delayed spontaneous diabetes onset in NOD mice and successfully delayed progression of early-established diabetes even when treatment was initiated after the development of glucose intolerance. At the DC level, R788 treatment was associated with reduced insulin-specific CD8 priming and decreased DC numbers. At the B cell level, R788 reduced total B cell numbers and total Ig concentrations. Interestingly, R788 increased the number of IL-10-producing B cells, thus inducing a tolerogenic B cell population with immunomodulatory activity. Taken together, we show by genetic and pharmacologic approaches that Syk in APCs is an attractive target in T cell-mediated autoimmune diseases such as type 1 diabetes.

Diagnostic Performance of 124I-Metaiodobenzylguanidine PET/CT in Patients with Pheochromocytoma.

123/131I-metaiodobenzylguanidine (MIBG) scintigraphy has shown a high specificity for imaging pheochromocytoma and paraganglioma, but with low sensitivity because of low spatial resolution. 124I-MIBG PET may be able to overcome this limitation and improve the staging of patients with (suspected) pheochromocytoma. Methods: We analyzed the sensitivity, specificity, and positive and negative predictive values of 124I-MIBG PET in 43 consecutive patients with suspected (recurrence of) pheochromocytoma using histopathologic (n = 25) and clinical validation (n = 18) as the standard of truth. Furthermore, we compared the detection rate of 124I-MIBG PET versus contrast-enhanced (CE) CT on a per-patient and per-lesion basis in 13 additional patients with known metastatic malignant pheochromocytoma. Results:124I-MIBG PET/CT was positive in 19 (44%) of 43 patients with suspected pheochromocytoma. The presence of pheochromocytoma was confirmed in 22 (51%) of 43. 124I-MIBG PET/CT sensitivity, specificity, and positive and negative predictive values were 86%, 100%, 100%, and 88%, respectively. 124I-MIBG PET was positive in 11 (85%) of 13 patients with malignant pheochromocytoma. Combined 124I-MIBG PET and CE CT detected 173 lesions, of which 166 (96%) and 118 (68%) were visible on 124I-MIBG PET and CE CT, respectively. Conclusion:124I-MIBG PET detects pheochromocytoma with high accuracy at initial staging and a high detection rate at restaging. Future assessment of 124I-MIBG PET for treatment guidance, including personalized 131I-MIBG therapy, is warranted.

Proteomic characterisations of ulcerative colitis endoscopic biopsies associate with clinically relevant histological measurements of disease severity.

AIMS AND METHODS: Accurate protein measurements using formalin-fixed biopsies are needed to improve disease characterisation. This feasibility study used targeted and global mass spectrometry (MS) to interrogate a spectrum of disease severities using 19 ulcerative colitis (UC) biopsies. RESULTS: Targeted assays for CD8, CD19, CD132 (interleukin-2 receptor subunit gamma/common cytokine receptor gamma chain), FOXP3 (forkhead box P3) and IL17RA (interleukin 17 receptor A) were successful; however, assays for IL17A (interleukin 17A), IL23 (p19) (interleukin 23, alpha subunit p19) and IL23R (interleukin 23 receptor) did not permit target detection. Global proteome analysis (4200 total proteins) was performed to identify pathways associated with UC progression. Positive correlation was observed between histological scores indicating active colitis and neutrophil-related measurements (R2=0.42-0.72); inverse relationships were detected with cell junction targets (R2=0.49-0.71) and ß-catenin (R2=0.51-0.55) attributed to crypt disruption. An exploratory accuracy assessment with Geboes Score and Robarts Histopathology Index cut-offs produced sensitivities/specificities of 72.7%/75.0% and 100.0%/81.8%, respectively. CONCLUSIONS: Pathologist-guided MS assessments provide a complementary approach to histological scoring systems. Additional studies are indicated to verify the utility of this novel approach.

The production of [124I]iodine and [86Y]yttrium.

The use of paired tracers such as (124)I/(131)I and (86)Y/(90)Y allows pretherapy PET imaging with positron emitting radioisotopes of the same element as used for therapy. Whereas nowadays most therapy nuclides are produced by reactors or generators, the production of the corresponding PET isotopes requires the irradiation of adequate targets using particle accelerators such as cyclotrons. This paper describes the production routes for (124)I and (86)Y.

The influence of saliva flow stimulation on the absorbed radiation dose to the salivary glands during radioiodine therapy of thyroid cancer using 124I PET(/CT) imaging.

PURPOSE: A serious side effect of high-activity radioiodine therapy in the treatment of differentiated thyroid cancer is radiogenic salivary gland damage. This damage may be diminished by lemon-juice-induced saliva flow immediately after 131I administration. The aim of this study was to assess the effect of chewing lemon slices on the absorbed (radiation) doses to the salivary glands. METHODS: Ten patients received (pretherapy) 124I PET(/CT) dosimetry before their first radioiodine therapy. The patients underwent a series of six PET scans at 0.5, 1, 2, 4, 48 and ≥96 h and one PET/CT scan at 24 h after administration of 27 MBq 124I. Blood samples were also collected at about 2, 4, 24, 48, and 96 h. Contrary to the standard radioiodine therapy protocol, the patients were not stimulated with lemon juice. Specifically, the patients chewed no lemon slices during the pretherapy procedure and neither ate food nor drank fluids until after completion of the last PET scan on the first day. Organ absorbed doses per administered 131I activity (ODpAs) as well as gland and blood uptake curves were determined and compared with published data from a control patient group, i.e. stimulated per the standard radioiodine therapy protocol. The calculations for both groups used the same methodology. RESULTS: A within-group comparison showed that the mean ODpA for the submandibular glands was not significantly different from that for the parotid glands. An intergroup comparison showed that the mean ODpA in the nonstimulation group averaged over both gland types was reduced by 28% compared to the mean ODpA in the stimulation group (p=0.01). Within each gland type, the mean ODpA reductions in the nonstimulation group were statistically significant for the parotid glands (p=0.03) but not for the submandibular glands (p=0.23). The observed ODpAs were higher in the stimulation group because of increased initial gland uptake rather than group differences in blood kinetics. CONCLUSION: The 124I PET(/CT) salivary gland dosimetry indicated that lemon juice stimulation shortly after 131I administration in radioiodine therapy increases the absorbed doses to the salivary glands.

In vivo biodistribution of calcium phosphate nanoparticles after intravascular, intramuscular, intratumoral, and soft tissue administration in mice investigated by small animal PET/CT.

Calcium phosphate nanoparticles were covalently surface-functionalized with the ligand DOTA and loaded with the radioisotope 68Ga. The biodistribution of such 68Ga-labelled nanoparticles was followed in vivo in mice by positron emission tomography in combination with computer tomography (PET-CT). The biodistribution of 68Ga-labelled nanoparticles was compared for different application routes: intravenous, intramuscular, intratumoral, and into soft tissue. The particle distribution was measured in vivo by PET-CT after 5 min, 15 min, 30 min, 1 h, 2 h, and 4 h, and ex vivo after 5 h. After intravenous injection (tail vein), the nanoparticles rapidly entered the lungs with later redistribution into liver and spleen. The nanoparticles remained mostly at the injection site following intramuscular, intratumoral, or soft tissue application, with less than 10 percent being mobilized into the blood stream. STATEMENT OF SIGNIFICANCE: The in vivo biodistribution of DOTA-terminated calcium phosphate nanoparticles was followed by PET/CT. To our knowledge, this is the first study of this kind. Four different application routes of clinical relevance were pursued: Intravascular, intramuscular, intratumoral, and into soft tissue. Given the high importance of calcium phosphate as biomaterial and for nanoparticular drug delivery and immunization, this is most important to assess the biofate of calcium phosphate nanoparticles for therapeutic application and also judge biodistribution of nanoscopic calcium phosphate ceramics, including debris from endoprostheses and related implants.

Microbiological and Clinical Outcomes of Treating Non-Mycobacterium Avium Complex Nontuberculous Mycobacterial Pulmonary Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Pulmonary disease caused by nontuberculous mycobacteria (NTM) is steadily increasing worldwide. METHODS: A systematic review of non-Mycobacterium avium complex studies published prior to October 2016 was conducted with respect to microbiological and clinical outcomes of current treatment regimens. RESULTS: We retrieved 352 citations, which yielded 24 studies eligible for evaluation. Sixteen studies were retrospective chart reviews, three studies were prospective, and only five studies were randomized. The weighted average proportion of sputum culture conversion (SCC) after subtracting posttreatment relapses for patients with M abscessus was 41.2% (95% CI, 28.6%-54.5%) but was 69.8% (95% CI, 41.0%-91.9%) with subspecies M massiliense in macrolide-containing regimens, 80.2% (95% CI, 58.4%-95.2%) in patients with M kansasii, 32.0% (95% CI, 16.5%-49.8%) for M xenopi (MX) and 54.4% (95% CI, 34.7%-73.4%) for M malmoense. SCCs in the total of 55 patients who underwent lung resection and had MX or M abscessus was high at 75.9%. The risk of bias was low in four of five randomized studies. However, heterogeneous use of outcome parameters (eight definitions of "relapse," eight of "treatment success," and four of "cure") hampered comparison of nonrandomized studies as well as producing possible bias by a posteriori exclusion (13.3%) and uncompleted treatment of participants (25.3%). CONCLUSIONS: As a sustained microbiological response without surgery is unsatisfactory in treating M abscessus, MX, and M malmoense, functional and quality of life aspects should be given more emphasis in the individual evaluation of treatment outcome. Further, properly planned studies with sufficient power are needed, as are new drugs or better-tolerated application of current antibiotics, or both.

124I PET Assessment of Response of Bone Metastases to Initial Radioiodine Treatment of Differentiated Thyroid Cancer.

Iodine-positive bone metastases (BMs) are often resistant after initial radioiodine therapy applying the standard-activity approach. A comprehensive lesion-based response study for BMs has not, to our knowledge, yet been performed. In this study, pretherapy and follow-up 124I PET/CT data on BMs from differentiated thyroid cancer patients were retrospectively analyzed to assess the relationship between absorbed dose (AD) of radiation and response after initial radioiodine treatment. METHODS: Before and after initial radioiodine therapy, patients underwent serial PET/CT scanning after administration of 20-40 MBq of 124I. The pretherapy PET data were used to segment BM volumes and to predict the average ADs after administration of dosimetry-guided 131I activity. The lower volume limit of determinability of the applied segmentation method was a sphere volume of 0.16 mL. This volume limit classified the BMs into known-volume and fixed-volume groups with their respective average and minimum ADs. Follow-up 124I and 18F-FDG PET/CT data after treatment were analyzed to assess lesion-based therapy response. Response rates at different AD thresholds were calculated and were expressed as the percentage of completely responding BMs above the respective AD threshold. BMs with a maximum extent greater than twice the PET spatial resolution were visually scored for nonuniformity. RESULTS: In total, 61 BMs in 10 patients were included, of which 46 and 15 comprised the known-volume group and the fixed-volume group, respectively. The median follow-up time was 5.6 mo (range, 3.7-23.2 mo). The median average and median minimum ADs in therapy were 183 Gy (range, 39-3,600 Gy) and 270 Gy (range, 63-1,300 Gy), respectively. A range of response rate of 70%-80% was achieved at an AD threshold range of 350-650 Gy. There were 26 BMs that were amenable to visual assessment of nonuniformity, of which two thirds (17/26) were scored as clearly nonuniform, and the majority (11/17) of these nonuniform BMs responded incompletely. CONCLUSION: Both the high AD threshold associated with high response rates and the low median AD per unit of 131I activity elucidate the difficulty in achieving therapeutic efficacy for BMs when a single standard activity is administered. The relatively high AD threshold range is possibly a result of distinct levels of spatial nonuniformity in ADs.

The role of the inhibitors of interleukin-6 signal transduction SHP2 and SOCS3 for desensitization of interleukin-6 signalling.

The immediate early response of cells treated with IL-6 (interleukin-6) is the activation of the signal transducer and activator of transcription (STAT)3. The Src homology domain 2 (SH2)-containing protein tyrosine phosphatase SHP2 and the feedback inhibitor SOCS3 (suppressor of cytokine signalling) are potent inhibitors of IL-6 signal transduction. Impaired function of SOCS3 or SHP2 leads to enhanced and prolonged IL-6 signalling. The inhibitory function of both proteins depends on their recruitment to the tyrosine motif 759 within glycoprotein gp130. In contrast to inactivation, desensitization of signal transduction is regarded as impaired responsiveness due to prestimulation. Usually, after activation the sensing receptor becomes inactivated by modifications such as phosphorylation, internalization or degradation. We designed an experimental approach which allows discrimination between desensitization and inactivation of IL-6 signal transduction. We observed that pre-stimulation with IL-6 renders cells less sensitive to further stimulation with IL-6. After several hours, the cells become sensitive again. We show that not only signal transduction through previously activated receptors is affected by desensitization but signalling through receptors which were not targeted by the first stimulation was also attenuated ( trans -desensitization). Interestingly, in contrast to inhibition, desensitization does not depend on the presence of functional SHP2. Furthermore, cells lacking SOCS3 show constitutive STAT3 activation which is not affected by pre-stimulation with IL-6. All these observations suggest that desensitization and inhibition of signalling are mechanistically distinct.

Syk inhibitors as treatment for allergic rhinitis.

Allergic rhinitis is characterized by a hypersensitive immune response in the upper airways to seasonal or perennial allergens leading to episodes of sneezing, itching, runny nose and nasal congestion. These symptoms are mainly the manifestations of a large number of mediators released by mast cells and basophils localized in the nasal mucosa, following their activation via allergen-specific immunoglobulin E (IgE) receptors. Current medications antagonize the action of distinct mediators such as histamine and leukotrienes for symptom relief, or block the production of pro-inflammatory cytokines to suppress allergic inflammation. Notably, rather than neutralizing individual mediators, Syk kinase inhibitors can block the allergen-induced release of all mast cell mediators and the production of most eicosanoids and cytokines. Thus, Syk kinase represents an attractive therapeutic target for acute and chronic allergic inflammation. Syk kinase inhibitors are now entering clinical trials. Using cell-based structure-activity relationships with primary human mast cells, a series of 2,4-diaminopyrimidine Syk kinase inhibitors was developed. One of these compounds, referred to as R112, exhibited suitable characteristics for intranasal delivery and was tested for safety and efficacy in allergic rhinitis patients. In a park environment, R112 showed remarkable amelioration of acute allergic rhinitis symptoms with rapid onset of action. These results demonstrate the clinical significance of inhibiting Syk in allergic upper airway disorders.

IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex.

IL-33 (IL-1F11) is a recently described member of the IL-1 family of cytokines that stimulates the generation of cells, cytokines, and Igs characteristic of a type 2 immune response. IL-33 mediates signal transduction through ST2, a receptor expressed on Th2 and mast cells. In this study, we demonstrate that IL-33 and ST2 form a complex with IL-1R accessory protein (IL-1RAcP), a signaling receptor subunit that is also a member of the IL-1R complex. Additionally, IL-1RAcP is required for IL-33-induced in vivo effects, and IL-33-mediated signal transduction can be inhibited by dominant-negative IL-1RAcP. The implications of this shared usage of IL-1RAcP by IL-1(alpha and beta) and IL-33 are discussed.