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To evaluate the safety and utility of an investigational robotic-assisted cochlear implant insertion system.Prospective, single-arm, open-label study under abbreviated Investigational Device Exemption requirements.All procedures were performed, and all data were collected, at a single tertiary referral center.Twenty-one postlingually deafened adult subjects that met Food and Drug Administration indication criteria for cochlear implantation.All patients underwent standard-of-care surgery for unilateral cochlear implantation with the addition of a single-use robotic-assisted insertion device during cochlear electrode insertion.Successful insertion of cochlear implant electrode array, electrode array insertion time, postoperative implant function.Successful robotic-assisted insertion of lateral wall cochlear implant electrode arrays was achieved in 20 (95.2%) of 21 patients. One insertion was unable to be achieved by either robotic-assisted or manual insertion methods, and the patient was retrospectively found to have a preexisting cochlear fracture. Mean intracochlear electrode array insertion time was 3 minutes 15 seconds. All implants with successful robotic-assisted electrode array insertion (n = 20) had normal impedance and neural response telemetry measures for up to 6 months after surgery.Here we report the first human trial of a single-use robotic-assisted surgical device for cochlear implant electrode array insertion. This device successfully and safely inserted lateral wall cochlear implant electrode arrays from the three device manufacturers with devices approved but he Food and Drug Administration.

Background Outcomes for patients with metastatic renal cell carcinoma (mRCC) and tumour thrombus remain poor. Recent data suggest limited role for cytoreductive nephrectomy (CN) and data on thrombus response to systemic therapy (ST) is scarce. Here, we describe response and survival of patients with de novo mRCC and thrombi treated with ST with or without CN. Methods Demographics, disease characteristics and survival of patients with de novo mRCC were collected. Progression-free survival (PFS) and overall survival (OS) in months (m) was calculated using the Kaplan–Meier method (log-rank). Results Between 2002 and 2019, 226 patients with mRCC were identified, 64 (28.3%) had tumour thrombus out of which 18 (28.1%) received only ST. Among 12 evaluable patients, thrombus response, stability and progression were seen in 3 (25%), 6 (50%) and 3 (25%) patients, respectively. Median OS was similar for patients with and without tumour thrombus treated with systemic therapy alone [OS: 12.1 m (8.8–27.7) vs. 13.9 m (7.9–21.5), p = 0.87]. CN predicted for better OS in patients with tumour thrombus [OS: 29.4 m (17.4–48.9) vs. 12.1 m (8.8–27.7), p = 0.01]. Conclusion In this retrospective series of patients with mRCC and tumour thrombus, addition of CN to ST improved outcomes. Validation of these findings with contemporary regimens is needed.

Background ECCO-ESPGHAN updated the guideline on the management of paediatric Crohn’s disease (CD) in 2021. This promoted a move to early risk stratification and a ‘top-down’ (anti-TNF within 4 weeks of diagnosis) approach for patients who were deemed high-risk. High-risk was defined by extensive panenteric or severe disease, perianal, stricturing and/or penetrating behaviour. We sought to compare the use of anti-TNF therapy against the new guidance by conducting a Scottish nationwide retrospective multi-centre study (all three regional PGHAN units). Methods We analysed a prospectively identified nationwide cohort of all new paediatric CD patients ( Results 419 patients were included (259/419 male; median age at diagnosis 13.2 yrs). Disease phenotype and behaviour are shown in tables 1 and 2. 225/419 (54%) were classified as high-risk and 194/419 (46%) as low/medium-risk. 171/225 (76%) high-risk and 78/194 (40%) low/medium-risk patients received anti-TNF within 18 months of diagnosis, with median start at 5 months (IQR: 1- 8 m) and 6.5 months (IQR: 3 – 13 m) respectively. Figure 1 demonstrates cumulative anti-TNF new starts by month. Of these patients, 49/171 (40%) high-risk and 12/78 (15.3%) low-risk received anti-TNF within 4 weeks of diagnosis. High-risk patients were more likely to receive anti-TNF (76.0% vs 40.2%, p Conclusion The ECCO-ESPGHAN guidance seeks to shift practice towards “top-down” anti-TNF therapy in high-risk patients. Our real-world data supports this view by showing that high-risk patients are more likely to require biologics within 18 months and more likely to require surgery than low/medium-risk patients. The ECCO-ESPGHAN approach would however have led to unnecessary anti-TNF in 24% of our high-risk cohort within 18 months of diagnosis. The financial cost and risk:benefit profile of this group should be considered carefully both in clinical practice and future guidance.

Background Treatment options for metastatic renal cell carcinoma (mRCC) include cytoreductive nephrectomy (CN) and systemic therapy (ST). Results from the CARMENA and SURTIME trials suggest that CN before ST may not be the optimal treatment strategy for mRCC. Objective To use real-world data to evaluate and compare outcomes for patients with mRCC who underwent CN before, after, or without ST to those patients who only received ST. Design, setting, and participants The Canadian Kidney Cancer information system (CKCis) database was used to identify patients diagnosed with mRCC between January 2011 and April 2020. Only patients with synchronous disease, treated within 12 mo from their initial RCC diagnosis, with International Metastatic Renal Cell Carcinoma Database Consortium intermediate/high risk, and confirmed RCC histology were included. Outcome measurements and statistical analysis Patients were classified into four groups according to the initial treatment received for mRCC. Inverse probability of treatment weighting using propensity scores was used to balance the treatment groups. Cox proportional hazards models were used to assess the impact of CN after adjusting for potential confounding variables in the weighted cohorts. Results and limitations A total of 788 patients were included in the study cohort. Of these 383 patients underwent CN before ST, 73 underwent CN after ST, 80 underwent CN only, and 252 patients received ST only. The median patient age was 63 yr and 73% of the cohort were men. In weighted analysis, the groups undergoing CN before ST (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.52–0.82) and CN after ST (HR 0.41, 95% CI 0.28–0.60) both had better survival compared to the ST only group. No survival benefit was observed for CN only compared to ST only, or for CN before ST compared to CN after ST. Conclusions We evaluated the association between different sequences of treatment with CN and survival in patients with mRCC using CKCis real world data. The results demonstrate that the selected patients who undergo CN, whether performed before or after ST, have an associated improvement in survival. Patient summary Two of the treatment options for metastatic kidney cancer are surgery and systemic therapy (chemotherapy or immunotherapy). We used data from the Canadian Kidney Cancer information system to determine whether there are differences in survival according to the sequencing of these treatments. Patients who had both surgery and systemic therapy, regardless of which treatment was first, had better survival than patients who only received systemic therapy.

The simple, accurate, and rapid detection of foodborne pathogens is essential for public health. Development of an immunomagnetic separation (IMS) multiplex touchdown PCR (IMS–multiplex TD–PCR) assay for simultaneous detection and distinguishing of C. jejuni and C. coli is reported herein. Polyclonal antibody (pAb) against multiepitope antigen (MEA) was conjugated to ferromagnetic nanoparticles (FMNs) to produce anti-MEA FMNs. Optimal anti-MEA FMNs loading yielded 26.7 μg of immunoglobulin G (IgG) molecules per mg of FMNs with an average size of 72 ± 9 nm, corresponding to an 83% rate of pAb conjugation. Anti-MEA FMNs (20 μg) for IMS captured culturable C. jejuni cells at 3.54 × 10 2 colony-forming unit (CFU)/mL in pure culture, while higher amounts (40 and 60 μg) reduced the recovery. The scanning electron microscope (SEM) analysis revealed the attachment of anti-MEA FMNs to target bacteria, forming aggregated cells and magnetic nanoparticles in ellipse-like shapes. The subsequent multiplex TD–PCR assay simultaneously detected and distinguished C. jejuni and C. coli at 104 CFU/mL in mixed culture and at 103 CFU/mL for each individual species. Furthermore, the limit of detection (LOD) of the IMS–multiplex TD–PCR assay was 104 CFU/g in spiked chicken breast samples. Specificity was 100% for both C. jejuni and C. coli as none of the amplicons were detected in control samples where Campylobacter was absent. This assay is able to detect and distinguish C. jejuni and C. coli simultaneously and is simple, accurate, and rapid with a time to result of 4 h without an enrichment step, making it a promising approach for rapid and culture-free detection of Campylobacter in chicken products.

Biological activity; Solid tumors Actividad biológica; Tumores sólidos Activitat biològica; Tumors sòlids A phase I trial (NCT03447314; 204686) evaluated the safety and efficacy of GSK1795091, a Toll-like receptor 4 (TLR4) agonist, in combination with immunotherapy (GSK3174998 [anti-OX40 monoclonal antibody], GSK3359609 [anti-ICOS monoclonal antibody], or pembrolizumab) in patients with solid tumors. The primary endpoint was safety; other endpoints included efficacy, pharmacokinetics, and pharmacodynamics (PD). Manufacturing of GSK1795091 formulation was modified during the trial to streamline production and administration, resulting in reduced PD (cytokine) activity. Fifty-four patients received GSK1795091 with a combination partner; 32 received only the modified GSK1795091 formulation, 15 received only the original formulation, and seven switched mid-study from the original to the modified formulation. Despite the modified formulation demonstrating higher systemic GSK1795091 exposure compared with the original formulation, the transient, dose-dependent elevations in cytokine and chemokine concentrations were no longer observed (e.g., IP-10, IL10, IL1-RA). Most patients (51/54; 94%) experienced ≥1 treatment-emergent adverse event (TEAE) during the study. Safety profiles were similar between formulations, but a higher incidence of TEAEs associated with immune responses (chills, fatigue, pyrexia, nausea, and vomiting) were observed with the original formulation. No conclusions can be made regarding GSK1795091 anti-tumor activity due to the limited data collected. Manufacturing changes were hypothesized to have caused the change in biological activity in this study. Structural characterization revealed GSK1795091 aggregate size in the modified formulation to be twice that in the original formulation, suggesting a negative correlation between GSK1795091 aggregate size and PD activity. This may have important clinical implications for future development of structurally similar compounds. This study was funded by GlaxoSmithKline (204686; NCT03447314).

Background: Although metastatic germ cell tumor (GCT) is highly curable with initial cisplatin-based chemotherapy (CT), 20–30% of patients relapse. Salvage CT options include conventional (CDCT) and high dose chemotherapy (HDCT), however definitive comparative data remain lacking. We aimed to characterize the contemporary practice patterns of salvage CT across Canada. Methods: We conducted a 30-question online survey for Canadian medical and hematological oncologists with experience in treating GCT, assessing treatment availability, patient selection, and management strategies used for relapsed GCT patients. Results: There were 30 respondents from 18 cancer centers across eight provinces. The most common CDCT regimens used were TIP (64%) and VIP (25%). HDCT was available in 13 centers (70%). The HDCT regimen used included carboplatin and etoposide for two cycles (76% in 7 centers), three cycles (6% in 2 centers), and the TICE protocol (11%, in 2 centers). “Bridging” CDCT was used by 65% of respondents. Post-HDCT treatments considered include surgical resection for residual disease (87.5%), maintenance etoposide (6.3%), and surveillance only (6.3%). Conclusions: HDCT is the most commonly used GCT salvage strategy in Canada. Significant differences exist in the treatment availability, selection, and delivery of HDCT, highlighting the need for standardization of care for patients with relapsed testicular GCT.

Background Treatment with the CD-TREAT solid food diet improves disease activity indices, faecal calprotectin (FCAL) levels and quality of life in adults and children with active Crohn’s disease (CD); particularly in patients who adhere to the diet. Here we describe changes in faecal microbiome parameters during therapy with CD-TREAT and explore these changes against adherence. Methods Children and adult patients with active CD completed an 8-week treatment with CD-TREAT. The levels of FCAL, pH, total sulphide (colorimetry), short chain fatty acids (SCFA), branched chain fatty acids (BCFA) (gas chromatography), total bacterial load (qPCR for total 16S rRNA gene copy number/g) were measured in baseline faecal samples and at four and eight weeks of CD-TREAT. Liquid chromatography mass spectrometry (LC-MS) faecal metabolomics and 16s rRNA sequencing of the faecal microbiome were performed at the same timepoints. Since CD-TREAT is gluten-free, detection of the gluten immunogenic peptide (GIP) in faeces was used as an objective biomarker of treatment adherence. Data are presented as median (IQR). Results Forty patients [17 children, age: 14.0 (11.3-15.1) years; 23 adults, age: 33.9 (27.8-45.9) years] participated. Eighteen (45%) patients had detectable GIP in at least one of the two follow-up timepoints, suggesting incomplete adherence; the remaining 22 (55%) patients had undetectable GIP throughout the treatment course. Baseline FCAL levels decreased significantly in the group of patients with undetectable GIP [mg/kg, baseline: 1,190 (3,611-129); 8 weeks: 534 (92-1,230), p Conclusion We have identified that full adherence with CD-TREAT only occurs in ~55% of recipients, however a significant reduction in calprotectin is seen in those who adhere, and this is associated with microbial and metabolic changes which parallel those seen in successful exclusive enteral nutrition.

Background The fungal community (mycobiome) and immunological responses to specific fungi have been implicated in Crohn’s disease (CD) pathogenesis and its phenotype. There is limited data on profiling the mycobiome in paediatric CD and how it changes during treatment Methods Fungal (ITS2) and bacterial (16S rRNA) microbiome analysis in faecal samples (n=124) from n=34 CD children before, during (30 and 60 days) and after exclusive enteral nutrition (EEN) at food reintroduction (within 60 days of EEN completion), and from 31 healthy controls were profiled. IgA and IgG anti-Saccharomyces cerevisiae antibodies (ASCA) analysis by enzyme-linked immunosorbent assay, in blood, was also carried out for CD patients prior to EEN initiation. Results The global mycobiome composition (β diversity) was different between CD and healthy children (R2=0.050; p=0.007) and presented lower Chao1 richness (mean 24.3 vs 33.0; p=0.005) for the CD cases; 13 fungal operational taxonomic units (OTUs) differed between the two groups. Similar signals were observed for the bacterial microbiome but the difference in global community structure (β diversity) was more profound than the fungal community (R2=0.094; p250 mg/kg). 29 fungal OTUs were significantly different between these two groups in samples taken during food reintroduction, following EEN. Patients who were ASCA positive had a higher abundance of three OTUs of S. cerevisiae. In co-occurrence network analysis, Simplicillium chinense, presented significant more interactions with members of the bacterial community, particularly OTUs which changed during EEN. After participants had returned to their regular diets these microbial effects reversed and community structure moved towards that observed prior to EEN. Conclusion The mycobiome of children with CD present features of dysbiosis similar to the bacterial microbiome and improvement in disease condition during EEN is strongly associated with changes in its composition.

We evaluated pembrolizumab monotherapy in patients with advanced salivary gland carcinoma on the phase 2 KEYNOTE-158 study (NCT02628067).Eligible patients had histologically/cytologically confirmed advanced salivary gland carcinoma with prior failure or intolerance to standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1., and ECOG performance status 0-1. Patients were enrolled irrespective of tumour PD-L1 expression. Patients received pembrolizumab 200 mg Q3W for up to 35 cycles (∼2 years). Radiographic imaging occurred every 9 weeks through month 12, then every 12 weeks. PD-L1 positivity was defined as combined positive score ≥1 (evaluated using PD-L1 IHC 22C3 pharmDx). The primary endpoint was objective response rate per RECIST v1.1.In total, 109 patients were enrolled (PD-L1-positive, 25.7%). At the data cutoff (October 5, 2020), median follow-up was 53.3 (range, 50.8-56.3) months. Objective response rate was 4.6% (95% CI, 1.5-10.4%) among all patients (complete response, n = 1; partial response, n = 4) and was 10.7% (95% CI, 2.3-28.2%) in patients with PD-L1-positive disease and 2.6% (95% CI, 0.3-9.1%) in patients with PD-L1-negative disease. Duration of response was ≥24 months for all 5 responders; median duration of response was not reached (range, 25.1-49.8+ months). Median progression-free survival and overall survival were 4.0 (95% CI, 2.6-4.2) and 21.1 (95% CI, 15.9-25.5) months, respectively. Treatment-related adverse events occurred in 75.2% (grade 3-4, 15.6%; grade 5, 0%) of patients. Immune-mediated adverse events occurred in 22.0% of patients (grade 3, 5.5%; grade 4-5, 0).A small subset of patients with advanced salivary gland carcinoma treated with pembrolizumab had a response; all had response duration ≥2 years. The safety profile of pembrolizumab was manageable.

Background: Although metastatic GCT is highly curable with initial cisplatin-based chemotherapy (CT), 20-30% of patients relapse. Salvage CT options include conventional (CDCT) and high dose chemotherapy (HDCT), however definitive comparative data remains lacking. We aimed to characterize the contemporary practice patterns of salvage CT across Canada. Methods: We conducted a 30-question online survey for Canadian medical and hematological oncologists with experience in treating GCT, assessing treatment availability, patient selection, and management strategies used for relapsed GCT patients. Results: Respondents included 30 staff; from 18 cancer centers across provinces. The most common CDCT regimens used were TIP (64%) and VIP (25%). HDCT was available for (70%) in 13 centers. HDCT regimen used included carboplatin and etoposide for 2 cycles (76% in 7 centers), 3 cycles (6% in two centers), and the TICE protocol (11%, in 2 centers). “Bridging” CDCT was used by 65% respondents. Post HDCT treatments considered include surgical resection for residual disease (87.5%), maintenance etoposide (6.3%) and sur-veillance only (6.3%). Conclusions: HDCT is the most commonly used GCT salvage strategy in Canada. Significant differences exist in the treatment availability, selection and delivery of HDCT, highlighting the need for standardization of care for patients with relapsed testicular GCT.