Local Site Research Articles

The ACR Mammography Positioning Improvement Collaborative: A Multicenter Improvement Program Within a Learning Network Framework

Purpose/ObjectiveTo share the experience and results of the first cohort of the ACR Mammography Positioning Improvement Collaborative, in which participating sites aimed to increase the mean percentage of screening mammograms meeting the established positioning criteria to 85% or greater and show at least modest evidence of improvement at each site by the end of the improvement program. MethodsThe sites comprising the first cohort of the collaborative were selected on the basis of strength of local leadership support, intra-organizational relationships, access to data and analytic support, and experience with quality improvement initiatives. During the improvement program, participating sites organized their teams, developed goals, gathered data, evaluated their current state, identified key drivers and root causes of their problems, and developed and tested interventions. A standardized image quality scoring system was also established. The impact of the interventions implemented at each site was assessed by tracking the percentage of screening mammograms meeting overall passing criteria over time. ResultsSix organizations were selected to participate as the first cohort, beginning with participation in the improvement program. Interventions developed and implemented at each site during the program resulted in improvement in the average percentage of screening mammograms meeting overall passing criteria per week from a collaborative mean of 51% to 86%, with four of six sites meeting or exceeding the target mean performance of 85% by the end of the improvement program. Afterward, all respondents to the postprogram survey indicated that the program was a positive experience. ConclusionUsing a structured improvement program within a learning network framework, the first cohort of the collaborative demonstrated that improvement in mammography positioning performance can be achieved at multiple sites simultaneously and validated the hypothesis that local sites’ shared experiences, insights, and learnings would not only improve performance but would also build a community of improvers collaborating to create the best experience for technologists, staff, and patients.

Correlation of previous local vaccination site “flares” during immunotherapy for metastatic melanoma with complete responses to therapy.

e21534 Background: mRNA vaccines have been shown to stimulate T-cells targeting patient-specific tumor neoantigens. When combined with immune checkpoint inhibitors (ICI) in a randomized Phase II trial, mRNA vaccines demonstrated improvement in recurrence free survival and distant metastasis free survival compared to ICI alone. We retrospectively examined patients (pts) with advanced melanoma treated more than 5 years ago on clinical trials with adjuvant NYESO1 or mRNA vaccine therapies (VT) then ICI upon recurrence and analyzed biomarkers correlating with treatment response. Methods: This retrospective study examined 22 pts with advanced melanoma treated between 2004-2017 with adjuvant vaccine therapies (VT). 10 of the 22 pts subsequently developed recurrent disease and were treated with ICI. We evaluated disease free interval following ICI, sex, age, BRAF status, HLA type, site of primary and metastatic disease, initial vaccine treatment, vaccine toxicities, stage and sites of melanoma recurrence, ICI treatment, response and toxicities, vaccine site flares or cutaneous immune related adverse events (irAEs) following ICI. Results: Of the 22 patients (11 male, 11 female) treated with adjuvant VT, median age at first vaccine was 53 years old. HLA type was known for 11 pts. Stage at initial VT was IIB to IIIC. 14 pts recurred following adjuvant VT. Median time from vaccine initiation to melanoma recurrence was 3.2 years (range 6.5 months to 11 years). 10 pts received ICI for recurrent melanoma, 3 pts received ipilimumab, 2 anti-PD1 monotherapy, 4 ipilimumab and nivolumab, and 1 nivolumab/relatlimab. Stage at first ICI was IIIB to IV M1d. 9 pts experienced cutaneous irAEs. 7 pts experienced local vaccine site flare reactions following ICI treatment. Additionally, 2 pts experienced vitiligo, 2 with dermatologic flares (bullous pemphigoid and psoriatic rash), 2 with generalized rash that resolved with steroid cream. 1 pt did not experience rash, vaccine site flare, nor irAE dermatologic flare. Of the pts who recurred, 2 pts had BRAF V600E mutations, and 1 of these pts experienced vaccine flare, the other did not. 1 pt with a BRAF Q16L mutation did not have vaccine flare. 6 out of 7 BRAF wild type pts who recurred and received ICI experienced a localized vaccine site flare. Median disease-free interval following ICI treatment was 1.5 years (range 3 months to 9 years). All 10 pts are disease-free and off ICI being closely monitored. Conclusions: Evidence of prior localized vaccination “flare” may be a biomarker for a complete immunologic response in pts with metastatic disease treated with immunotherapy. ICI targeting CTLA-4 and/or PD-1 both triggered this localized vaccination site response, suggesting that T cell memory and immunologic activation against melanoma antigens translate into clinical responses.

Privacy-Preserving Federated Learning With Domain Adaptation for Multi-Disease Ocular Disease Recognition.

As one of the effective ways of ocular disease recognition, early fundus screening can help patients avoid unrecoverable blindness. Although deep learning is powerful for image-based ocular disease recognition, the performance mainly benefits from a large number of labeled data. For ocular disease, data collection and annotation in a single site usually take a lot of time. If multi-site data are obtained, there are two main issues: 1) the data privacy is easy to be leaked; 2) the domain gap among sites will influence the recognition performance. Inspired by the above, first, a Gaussian randomized mechanism is adopted in local sites, which are then engaged in a global model to preserve the data privacy of local sites and models. Second, to bridge the domain gap among different sites, a two-step domain adaptation method is introduced, which consists of a domain confusion module and a multi-expert learning strategy. Based on the above, a privacy-preserving federated learning framework with domain adaptation is constructed. In the experimental part, a multi-disease early fundus screening dataset, including a detailed ablation study and four experimental settings, is used to show the stepwise performance, which verifies the efficiency of our proposed framework.

Clinical, molecular, and immunologic profiling of brain metastases (BM) in head and neck squamous cell carcinoma (HNSCC).

6036 Background: BM is a rare complication of HNSCC that carries a high rate of morbidity and poor prognosis. Clinical risk factors, molecular characteristics, and the immunogenicity of HNSCC BM are not well defined, leaving a critical knowledge gap in this field. We performed one of the largest multi-institutional analyses summarizing the clinical, molecular, and immunologic profile of 61 cases of BM-HNSCC. Methods: We conducted a pooled analysis of the clinical characteristics pertaining to BM-HNSCC from 3 academic institutions (n=24). Next-generation sequencing (NGS) and immune profiling (IP) of primary and BM specimens was conducted on a subset of cases (n=19 and n=16, respectively); there were 3 paired samples for NGS and 0 for IP. Four samples (2 BM and 2 non-BM) were submitted to Phase Genomics, Inc for evaluation of structural variants in BM genomes by proximity ligation sequencing (PLS). These results were complimented by a comparative analysis of genomic alterations in an additional cohort of BM (n=37) and local samples (n=4082) submitted for NGS at Foundation Medicine, Inc (FMI). Statistical comparisons were done using Fisher’s exact testing of 2x2 contingency tables with p-values controlled for FDR by the Benjamini-Hochberg procedure. Results: Clinical features were as follows: median age at diagnosis 59 years, 75% male, 55% current/former smokers, 75% oropharyngeal primary, and 84% HPV+ or p16+. The most frequently altered genes in BM specimens (62% HPV/p16+) were ATM (54%), KMT2A (54%), PTEN (46%), RB1 (46%), and TP53 (46%). BM and non-BM samples demonstrated significant levels of structural rearrangement ranging from 9 to 90 variants by PLS. IP identified lower densities of CD8+, PD1+, PDL1+, and FOXP3+ cells in BMs compared to primary tumors. PDL1 combined positive scores were <1% in 12/13 unpaired samples (92%; 10 BM and 2 primary). The FMI BM-HNSCC cohort (51% HPV+) identified CDKN2A (40.5%), TP53 (37.8%), and PIK3CA (27.0%) as the most frequently altered genes. Enrichment analysis of the FMI cohort showed MAP2K2 alterations significantly enriched in BM (11.8% vs 6.4%, P=0.005) and TSC1 alterations significantly enriched in the local site (67.3% vs 37.8%, P=0.008). HPV+ was also significantly enriched in the BM cohort (51.25% vs 26.11%, P=0.001). Overall survival from BM diagnosis was 6m (range 0-27m). Conclusions: HNSCC patients with BM have higher-than-expected proportions of oropharyngeal primary site and HPV/p16-positivity. The most frequent molecular alterations in BM samples are also commonly found in non-BM HNSCC, including targetable PIK3CA alterations. MAP2K2 alterations were significantly enriched in BM compared to non-BM samples, which warrants further investigation. BM samples also tended to have lower markers of immunogenicity. This latter finding could have important clinical implications when considering immunotherapy or immune-modulating drugs.

Demographic and survival data of patients with primary diffuse large B-cell lymphoma of the head and neck: A single center experience.

e19069 Background: Head and neck malignancies account for around 10% of lymphomas, with diffuse large B-cell lymphoma (DLBCL) being the most prevalent histologic subtype. Head and neck lymphoma is as the second most pervasive location for extra-nodal lymphoma, following the gastrointestinal system. This study focused on examining the demographic characteristics, main localization distribution, and survival rate of patients with head and neck lymphoma at the Çukurova University Medical Oncology Clinic. Methods: We conducted a retrospective analysis of 97 individuals diagnosed with single-center, head, and neck diffuse large B-cell lymphoma (DLBCL) from 2011 to 2020. Data pertaining to patients was acquired from electronic medical records. The patients were categorized based on anatomical localization, and survival rates and survival data were computed for each primary localization. Results: Out of the total number of patients, 48 (49.5%) were female, and 49 (50.5%) were male. The patients had a median age of 59.5 years. Waldeyer's ring was the most frequent site of primary head and neck tumor localization in patients with DLBCL, accounting for 42.4% of cases. The distribution of anatomical sites was as follows: nasopharynx accounted for 30.8%, nasal cavity accounted for 10.3%, thyroid accounted for 6.2%, parotid accounted for 5.2%, oral cavity accounted for 3.9%, and other anatomical sites accounted for 1.2%. Based on the Ann Arbor staging approach, 65% of the patients were classified as stage I-II. The 3-year survival rate was 71%, while the 5-year survival rate was 61%. The overall survival of individuals with nasopharyngeal lymphoma was considerably shorter when compared to those with non-nasopharyngeal lymphomas (p=0.0372). Conclusions: We conducted a thorough analysis of the data pertaining to lymphomas characterized by diffuse large B-cell lymphoma (DLBCL) occurring in the head and neck region. The study found that when the nasopharynx is affected, it is linked to a worse prognosis and may necessitate more intensive treatment. Our work is a retrospective study conducted at a single center. However, future investigations with a more significant number of participants and a prospective design is necessary.

The effect of resistance exercise on multimodal pain thresholds in local and systemic muscle sites.

Dynamic resistance exercise may produce reductions in pain locally at the exercising muscle and systemically at non-exercising sites. However, limited research has examined these changes with multiple noxious stimuli. This study examined changes in heat pain threshold (HPT) and pressure pain threshold (PPT) on different musculature after an upper and lower body exercise to compare local and systemic effects. A crossover design with 28 participants (mean age: 21 ± 4 years, 21 female) completed three sessions. Visit one included baseline quantitative sensory testing and 5-repetition maximum (RM) testing for upper (shoulder press) and lower (leg extension) body. In subsequent sessions, participants performed upper or lower body exercises using an estimated 75% 1-RM with pre/post assessment of HPT and PPT at three sites: deltoid, quadriceps, and low back. A significant three-way interaction was observed for HPT (F (1.71, 3.80) = 2.19, p = 0.036, η2p = 0.12) with significant increases in HPT over the quadriceps (p = 0.043) after leg extension and over the deltoid (p = 0.02) after shoulder press. Significant systemic changes were not observed for HPT or PPT. Local but not systemic effects were demonstrated after an acute bout of exercise. Peripheral pain sensitivity may be more responsive to heat stimuli after resistance exercise.

Phase 1/2 of EO2463 immunotherapy as monotherapy and in combination with lenalidomide and/or rituximab in indolent NHL (EONHL1-20/SIDNEY).

7058 Background: Follicular and marginal zone B cell lymphoma (FL; MZL) demonstrate an indolent course with heterogeneous outcomes anda potential for spontaneous remissions indicating immune system intervention. Therapeutic immunization is therefore an attractive approach but new antigens that evoke a strong immune response are needed. EO2463 expands pre-existing memory CD8+ T cells recognizing non-self protein sequences from gut bacteria which cross-react with B cell antigens and can kill HLA-A2 restricted cells (T2) loaded with target peptides. EO2463 includes 4 HLA-A2 synthetically produced epitopes which exhibit molecular mimicry with the B cell markers CD20, CD22, CD37, and CD268 (BAFF-receptor), as well as a the CD4 helper-epitope UCP2 derived from hTERT. EO2463 is being used to drive anti-tumor activity against B cell malignancies. Methods: Patients (pts) with FL and MZL, stage 1-3A, and HLA-A2, are eligible. In the safety lead-in pts with relapsed/refractory (R/R) disease were given EO2463 SC q2 weeks (w) x 4, then q4w, for a max of 12 months; at w7 lenalidomide (20 mg/day for 21/28 days up to 12 cycles) is added (EL), and if no complete remission (CR) at w19, rituximab (375 mg/m2 IV, q1w x 4, then q4w x 4) is also added (ER2). Doses evaluated: 150 μg and 300μg/peptide. Results: 3 pts received 150 μg/peptide and 6 pts 300 μg/peptide (EO2463 1 pat, EL 2 pts, ER2 6 pts): 2 MZL, 7 FL pts with median 2 lines (range 1-4) of prior systemic therapy. No related grade ≥3 adverse events were seen with EO2463 monotherapy. Most common related events were grade 1 to 2 local administration site reactions in 5/9 pts. Adverse events during combination treatment were as expected for R2. PET-CT on w6 after EO2463 monotherapy suggested clinical activity in 4/9 pts (1 PR, 1 pt size reduction 15%, 1 pt 20% reduced tracer uptake, 1 pt 5/6 target lesions reduced metabolic activity). Overall objective responses (OR) were seen in 6/9 pts (67%; 1st OR on EO2463 1 pat, EL 4 pts, ER2 1 pat), with CR in 5/9 (56%) pts; median time to response was 18w (range 8-43w), response ongoing in 5 pts, range 24-76w. Expansion of specific CD8+ T cells against mimic peptides and targeted B cell antigens were detected in all responding pts, incl. 2 pts with no measurable B cells at baseline (prior anti-CD20). Expansion of specific T cells was detected at w5 in 5/6 pts and was maintained as long as currently tested (up to w94, 43w after last EO2463 dose). No decline in expansions were seen after start rituximab. Conclusions: EO2463 (300 μg/peptide) monotherapy, EL, and ER2 are well tolerated, with encouraging clinical activity with EO2463 monotherapy and with subsequent CR in 5/9 pts on combo. Rapid and durable expansion of specific CD8+ T cells was seen in all responding pts, consistent with the preclinical hypothesis. Additional cohorts investigate EO2463 alone or in combination in newly diagnosed or R/R pts. Results will be reported at the meeting. Clinical trial information: NCT04669171 .

Graftless Syndactyly Release.

Syndactyly release aims to address skin deficits by resurfacing web spaces and sides of digits to allow independent digital motion while minimizing the risk of web creep and scar contractures. Conventional methods include the use of a dorsal and interdigitating flaps with full-thickness skin grafts. More recently, there have been several descriptions of "graftless" syndactyly release without skin grafts, thus avoiding a further (usually distant) donor site. However, the indications of when and when not to use these techniques remain unclear. In addition, the inevitable scarring from extra recruitment of local adjacent skin is perhaps underemphasized. In this article, we revisit the trilobed flap technique which serves to balance the amount of skin needed for resurfacing digits while minimizing local donor site scarring. The geometry and nuances of the flap inset are illustrated in detail to guide those embarking on this technique. The trilobed syndactyly release technique is a reproducible, safe, and reliable method for the release of simple syndactyly.

Subcutaneous (SC) nivolumab (NIVO) vs intravenous (IV) NIVO in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Safety and patient-reported outcomes (PROs) of the randomized phase 3 CheckMate 67T trial.

4532 Background: CheckMate 67T (NCT04810078), a multicenter, randomized, open-label, phase 3 study, evaluated pharmacokinetics and objective response rate (ORR) noninferiority of NIVO SC vs IV in previously treated patients with advanced/metastatic ccRCC. Noninferiority endpoints of exposure (time-averaged serum concentration over the first 28 days and trough serum concentration at steady state) and efficacy (ORR by BICR) were met. Safety was comparable in the SC vs IV arms. NIVO-related immunogenicity was as expected for SC administration and further assessments did not identify apparent clinically meaningful impact. This report focuses on additional safety analyses and PROs. Methods: Patients were randomized 1:1 to NIVO SC 1200 mg + recombinant human hyaluronidase PH20 Q4W (n = 248) or NIVO IV 3 mg/kg Q2W (n = 247). Eligibility criteria were previously reported. Safety analyses were performed for all-causality adverse events (AEs) across weight categories (< 50 kg, ≥ 50 kg–< 70 kg, ≥ 70–< 90 kg, ≥ 90 kg–< 110 kg, and ≥ 110 kg). The onset, management, and resolution of treatment-related select AEs were studied; duration and grade of local site reactions and the effect of immunogenicity on local site reactions were reported. PROs were assessed using the Functional Assessment of Chronic Illness Therapy (FACIT) GP5 item. Results: The overall AE incidence rates in the SC arm were generally comparable to or lower than in the IV arm across weight categories, but limited by small sample sizes in the < 50 kg and ≥110 kg subgroups. Across the treatment-related select AE categories, most events were manageable with established algorithms and resolved with immune-modulating medications. Local site reactions were mild to moderate with a median duration of 2.0 and 0.01 days in the SC and the IV arms, respectively; most resolved without treatment. The proportion of patients with a local site reaction of any grade was 8.1% in the SC arm and 2.0% in the IV arm. In patients testing NIVO-specific anti-drug antibody (ADA)-positive, 15.2% of patients in the SC arm reported a local site reaction, but all were grade 1–2 and most resolved without treatment. No hypersensitivity/infusion reaction select AEs were reported in ADA-positive patients in either arm. A majority of patients in SC and IV arms reported minimal bother by treatment side effects in their FACIT GP5 scores. Conclusions: The safety profile of SC was consistent with IV, supporting the use of NIVO SC as an option improving patient experience. This aligns with patient preference for SC administration over IV. Analyses based on weight and ADA subgroups were consistent with the known NIVO safety profile. Toxicity was manageable with immune-modulating medications. FACIT GP5 scores indicated no bother by treatment side effects. Clinical trial information: NCT04810078 .

Pilot study to evaluate automated laboratory data transfer into Medidata Rave for NCI-supported pediatric cooperative group trials in the Pediatric Early Phase Clinical Trials Network (PEP-CTN) and Pediatric Brain Tumor Consortium (PBTC).

e23017 Background: Electronic data capture (EDC) has the potential to improve data accuracy and efficiency. As an initial step toward improvement in the accuracy and completeness of data acquisition for clinical trials, PEP-CTN and PBTC conducted a pilot project to assess the feasibility of automated transfer of laboratory data from participating institutions’ electronic health records to the NCI Medidata Rave EDC that is housed within each consortium’s Uniform Resource Locator (URL). The pilot aimed to assess feasibility of automated laboratory data extraction and transfer and to evaluate discrepancies between laboratory data obtained retrospectively through automated extraction and data manually ascertained during the original conduct of the study. Methods: Data from patients treated on 7 completed PEP-CTN or PBTC trials at 7 sites were included. Each consortium created a Rave EDC study to receive data. Sites used the ExtractEHR R package or local methods to map and extract laboratory data for designated patients. Post-extraction data were uploaded via a file transfer protocol (FTP) periodically polled by the Rave Batch Uploader (BU) that uploaded data into Rave EDC. After successful upload, extracted data (EHR) were compared to laboratory data that had been manually reported when patients were enrolled on the trials (MANUAL) and discrepancies were identified. Discrepancy types were categorized and 2 sites reviewed discrepancies at their sites to identify reasons. Results: Preparation and support for automated extraction and upload required significant central operations and local site effort. All sites successfully extracted specified laboratory data and had at least one complete upload via BU to Rave EDC. There were more laboratory data in the EHR datasets than MANUAL datasets across most sites. These results were due to multiple EHR results on a given day or from additional days in the study window than specified in MANUAL. Sites verified that laboratory data in MANUAL and not EHR were stored in un-extractable formats (e.g. PDFs) or outside laboratories. Most discrepant results in both EHR and MANUAL were mismatched values or units. Conclusions: This pilot demonstrated the feasibility of implementing automated laboratory data extraction and transfer in the cooperative group setting. Automated data transfer requires significant central operational support as well as detailed protocols, data specifications, and case report forms and engagement of site technical teams to be successful, but also permits collection of more comprehensive data with reduced manual data entry. Clinical trial information: NCT05020951 .

ImmunoSarc II master trial (phase II of sunitinib and nivolumab): Results from the dedifferentiated chondrosarcoma (DDCS) cohort—A GEIS, ISG and UCL study.

11506 Background: Dedifferentiated chondrosarcoma (DDCS) is a rare aggressive CS subtype with a dismal prognosis and no standard of care systemic therapy. For those with advanced, metastatic disease, retrospective chemotherapy studies demonstrate short-term median progression-free survival (PFS) of around 3 to 5.5 months. Benefit from checkpoint and tyrosine kinase inhibitors has been reported, however clinical trial data is scarce, and endpoints are not well defined, thus benchmarking outcomes is challenging. The IMMUNOSARC I master-trial exploring sunitinib plus nivolumab in multiple sarcoma subtypes, detected potential activity in DDCS leading to a specific cohort within the phase II trial IMMUNOSARC II (NCT03277924). Methods: Patients (pts) with ECOG 0-1, centrally confirmed and progressive, measurable DDCS were eligible and treated with sunitinib 37.5 mg/d for 14 days (induction phase), followed by 25 mg/d, in combination with nivolumab 240 mg every 2 weeks until progressive disease (PD) or intolerance. Imaging assessments were performed every 8 weeks. Main endpoint was 6-m PFSR with one-arm survival design (type I error α 0.05, power 0.90, H0 40%, H1 70%) and a Brookmeyer-Crowley like test was assumed with at least 14 of 23 pts required without progression at 6 months. Results: Between December 2019 and October 2023, 24 pts with a median age of 60 years (38-76) were enrolled in 7 centres. Sixteen pts (66%), were male. Pts had received a median of 1 (0-2) prior lines of therapy. In total, 23 pts were evaluable with a median follow-up of 20.1 months (95%CI: 11.6-28.6). Median PFS, according to local site assessment, was 5.6 months (95%CI: 4.5-6.7); the 6m-PFSR was 10 of 23 pts (46%); (95%CI: 23-66) and median overall survival 10.3 months (95%CI: 6.7-13.9). In 19 pts with RECIST measurable response, 5 pts (26.3%) achieved a partial response; 10 (52.6%) stable disease and 4 (21.1%) PD. End-of-treatment reasons were PD in 21 pts (87%), toxicity 1 pt (4.2%) with two pts (8.4%) ongoing. For safety population, the most relevant study drug-related G3-4 toxicities were neutropenia (20.9%), anemia (16.7%), and increased ALT (12.5%). Conclusions: Sunitinib and nivolumab demonstrated encouraging activity in advanced DDCS that did not meet the primary endpoint, but compares favourably with previous analyses of cytotoxic and targeted therapy. The combination is worthy of further exploration in conjunction with reaching a consensus on clinically meaningful endpoints in this challenging population. Translational studies to identify potential predictive biomarkers are ongoing. Clinical trial information: NCT03277924 .

Real world tebentafusp-tebn experience at a tertiary care referral center.

e21526 Background: Tebentafusp-tebn is an FDA approved therapy specifically for patients with metastatic uveal melanoma (MUM). The major challenge of this treatment is the weekly infusion schedule and potentially significant toxicity during the dose escalation and induction phase (Cycle 1). To overcome this challenge, we developed a treatment model consisting of an induction phase at a tertiary center of MUM and subsequent treatments at a local cancer center. Methods: This retrospective cohort study included patients who received Cycle 1 at our institution since FDA approval. Patients who received initial induction doses at other health systems were excluded. Data was collected by chart review. Cytokine release syndrome (CRS) was graded by ASTCT consensus guidelines. Results: From 3/14/2022-11/7/23, 26 patients received at least one dose of tebentafusp-tebn at our institution. 14/26 were female and median age was 69 (range 51-80). 24/26 patients had metastatic disease to the liver, followed by bone (6/26), lung (3/26), and others (5/26). Patients underwent a median of 2 (range 0-5) lines of therapy prior to tebentafusp-tebn initiation. Major side effects during Cycle 1 included CRS (22/26), rash/itching (24/26), and nausea (3/26). One patient developed grade 4 liver enzyme elevations. Of the patients who developed CRS, 77.3% (17/22) were grade 1, 13.7% (3/22) were grade 2, and 9.1% (2/22) were grade 3. 5/26 (19.2%) patients required at least one dose of steroid for management of CRS. The median number of hospitalizations for Cycle 1 was 3 (range 3-6). After Cycle 1, 21/26 (80.8%) patients were successfully transitioned to local health systems to continue outpatient weekly tebentafusp-tebn infusions, including 2 patients who went were able to continue of therapy in their home countries. 1 patient is in the process of transferring, 1 patient discontinued after dose escalation due to disease progression, and 3 patients decided to continue treatment at our institution. 19 patients who were transitioned to their local cancer centers in the US traveled a median of 107 miles (range 30-298 miles) for Cycle 1 at our institution, and a median of 23 miles (range 4-58 miles) after transition to local health systems. The median number of days patients received therapy was 203 days (range 22-610 days). Median time to progression was 12.6 weeks (range 5.8-65.6). 6/26 (23.1%) patients have received additional therapy upon progression while continuing tebentafusp-tebn. 12/26 patients are currently receiving therapy and 2 patients were lost to follow up after transferring to a local site. At time of review 19/26 patients were alive. Conclusions: This hybrid model of treatment (Cycle 1 at a tertiary center followed by continuation at a local cancer center) made weekly tebentafusp-tebn treatment safe and feasible for patients with MUM. Our single center experience demonstrates side effects and outcomes similar to what has been reported in the clinical trial.

High-Precision Fiber Noise Detection and Comparison over a 260 km Field Fiber Link.

In this paper, we present a high-precision optical frequency noise detection and comparison technique using a two-way transfer method over a 260 km field fiber link. This method allows for the comparison of optical frequencies between remote optical references without the need for data transfer through communication. We extend a previously established two-way comparison technique to obtain all data at the local site. Two optical carrier signals are injected into the bidirectional fiber from both ends, and one carrier is reflected back from the remote end. This enables the phase comparison of the two carrier signals at a single site without the need to transmit experimental data. The common-mode frequency noise induced by the bidirectional fiber link is detected and effectively suppressed without the need for sophisticated active fiber noise control. Our demonstration system, which uses a 260 km field fiber link and a common laser source, achieves a fractional instability of 2.5×10-17 at 1 s averaging time and scales down to 3.5×10-21 at 8000 s. This scheme offers the distinct advantage of completing the comparison at a single site, eliminating the need for remote data transfer via communication. This method is expected to enhance reliability for high-precision frequency comparisons between remote optical clocks and advanced atomic clocks.

Seismic wave amplification in a weakly nonlinear two-layered soil deposit

Based on numerous observations, local soil site conditions can significantly affect the formation of seismic responses. In this paper, we examine seismic responses caused by shear waves propagating through a two-layered soil deposit. The aim of the research is to study the phenomenon of amplification of shear waves due to the resonant properties of the soil deposit and the nonlinear characteristics of partial layers, which are assumed to be the cubically nonlinear continuous media. The target problem relates to a nonlinear boundary value problem, the solution of which is carried out using a semi-analytical approach. According to the approach, the problem’s solution is sought using the method of separation of variables, while the solution to the corresponding spectral problem is derived in the form of a power series. Additionally, good agreement is shown between theoretical studies and numerical simulations. The developed approach allows one to evaluate the amplification factor for a nonlinear two-layered soil deposit and to detect changes in the shape of amplification factor profiles when the frequency of an incident wave on a rigid bedrock is varied.

Short- and medium-chain chlorinated paraffins in surface sediment from Lake Ontario.

Concentrations of short- and medium-chain chlorinated paraffins (SCCPs and MCCPs) were analyzed and investigated in surficial sediment collected in 2018 from ten different nearshore sites in Lake Ontario and the St. Lawrence River influenced by inputs from varying urban and historical land uses. Sites were grouped into two categories of tributary and lake according to their location. Results show that tributary sites had higher concentrations of total chlorinated paraffin (CP) than lake sites. Humber Bay, a lake site, had the highest total CP concentration (55,000ng/gTOC) followed by Humber River, a tributary site (50,000ng/gTOC). The lowest concentrations were found in eastern Lake Ontario and Lake St. Francis in the St. Lawrence River (540ng/gTOC). Higher concentrations of chlorinated paraffins (CPs) were found where runoff and wastewater inputs from urban areas, current industrial activities, and population were the greatest. Levels of MCCPs were higher than SCCPs at all sites but one, Lake St. Francis. Among the SCCPs, C13 and among the MCCPs C14 were the dominant chain length alkanes, with C14 being the highest among both groups. The SCCPs and MCCPs profiles suggest that they can be used to distinguish between sites impacted by local sources vs. sites impacted by short-/long-range transport of these chemicals.

Selective laser spectroscopy of yttrium scandate doped with ytterbium ion

The spectral-kinetic properties of Yb3+ optical centers in YScO3 crystal fiber were studied using selective laser spectroscopy. Three distinct types of Yb3+ optical centers were identified. Various spectral characteristics of the Yb3+ optical centers were determined, including homogeneous and inhomogeneous broadening values, Stark level splitting, and the Yb3+ ions lifetime. The first optical center, with a lifetime of τI77K = 4.05 ms, was formed due to the substitution of Y3+ for Yb3+ ions in the local site of С3i. The other two Yb3+ optical centers, with lifetimes of τI77K = 1.0 ms (СII2(Y3+) center) and τII77K = 0.620 ms (СII2(Sc3+)), respectively, were formed as a result of the substitution of Y3+ and Sc3+ for Yb3+ in the local site of C2.

Effect of Preoperative Bilateral Ultrasound-Guided Quadratus Lumborum Nerve Block on Quality of Recovery After Minimally Invasive Hysterectomy in an Enhanced Recovery After Surgery (ERAS) Setting

Study ObjectiveTo assess the effect of preoperative bilateral ultrasound-guided quadratus lumborum nerve block (QLB) on quality of recovery after minimally invasive hysterectomy, in an Enhanced Recovery After Surgery (ERAS) setting. DesignRandomized, controlled, double-blinded trial (Canadian Task Force level I) SettingUniversity affiliated tertiary medical center PatientsAll women undergoing an elective robotic or laparoscopic hysterectomy. Women with chronic pain, chronic anticoagulation, and body mass index (BMI) > 50 kg/m2 were excluded. InterventionPatients were randomized with a 1:1 allocation, to one of the following two arms, and stratified based on robotic versus laparoscopic approach.1. QLB: QLB (Bupivacaine) + Sham local trocar sites infiltration (normal saline). 2. Local Infiltration: Sham QLB (normal saline) + local infiltration (Bupivacaine) Measurements and Main ResultsThe primary outcome was defined as the quality of recovery score based on the validated questionnaire (QOR-40), completed 24-hours postoperatively. Secondary outcomes included: dynamic pain scores, accumulated opioid consumption up to 24-hours, post-operative nausea and vomiting, surgical complications, length of hospital stay, time to first pain medication administration in the post-anesthesia care unit (PACU) and adverse events. 76 women were included in the study. Demographic characteristics were similar in both groups. Median age was 44 (IQR 39-50) years, 47% of the participants were African American and mean BMI was 32.8 (SD 8.1) kg/m2. The mean QOR-40 score was 179.1 (+/- 10.3SD) in the QLB and 175.6 (+/- 9.7SD) for the local anesthesia group (p=0.072). All secondary outcomes were comparable between groups. ConclusionsQLBs do not significantly improve quality of recovery after elective robotic or laparoscopic hysterectomy compared to local anesthetic port site infiltration.

Brown tumors: Retrospective analysis of 26 cases.

Brown tumors are reactive osteolytic lesions caused by hyperparathyroidism. These rare lesions are non-neoplastic processes that result from bone resorption. The purpose of this study was to retrospectively review a 34-year experience with brown tumors in our institution. We retrospectively analyzed the records of 26 consecutive patients with brown tumor who were treated in our institution between May 1988 and October 2020, with a mean follow-up of 36,1 months. 17 male (65,4%) and 9 female (34,6%) patients with a mean age of 41,6 were included in the study. Localized bone pain was present in 13 cases (50,0%) as the first presenting symptom. 3 patients (11,5%) presented with diffuse bone pain. 7 patients (26,9%) were diagnosed with brown tumor while being investigated for pathological fractures. The other 3 patients (11,5%) were diagnosed while being evaluated for hypercalcemia symptoms. 7 patients (26,9%) had solitary lesions, while 19 patients (73,1%) had multiple lesions. Pelvis, femur, ribs, tibia, proximal humerus and mandible were the most common sites of localization. 23 patients (88,5%) were diagnosed with primary hyperparathyroidism, while the other 3 patients (11,5%) had secondary hyperparathyroidism. A total of the 65 lesions, 23 (35.4%) underwent orthopedic surgery, and 42 (64.6%) were followed up conservatively after parathyroidectomy. Orthopedic surgery was performed in 21 of 26 patients, the other 5 cases were followed up conservatively. Intralesional curettage was performed in 19 cases (82,6%). The resulting cavity was filled with bone cement in 11 cases (47,8%). Bone grafting was applied in 8 cases (34,8%). No recurrence was observed in any of the patients. The diagnosis of brown tumor begins with clinical suspicion. Endocrinology and general surgery consultation is important before surgery. Treatment of brown tumors requires a multidisciplinary approach.

Differentiation of high frequency near field versus far-field potentials in low voltage zones during sinus rhythm improves discrimination of local sites of termination during ventricular tachycardia

Abstract Background Ventricular tachycardia (VT) with structural heart disease (SHD) is often bad tolerated or presents with several inducible morphologies, this support mapping the arrhythmic substrate during sinus rhythm (SR). Poor discrimination between near-field (NF) and far-field (FF) electrogram (EGM) components in low voltage (LV) areas is the main limitation. The peak frequency (PF) associated with bipolar EGMs may distinguish NF from FF EGMs (Panel D). Objective To evaluate if PF combined with voltage mapping during SR enhances discrimination of the region of VT termination by radiofrequency application (RFa). Methods Bipolar activation and voltage maps were generated with a 16-pole grid catheter (HD Grid) during SR (Panel B). PF maps were retrospectively computed (Panel C). The maps were only analyzed if acute termination was achieved by focal RFa within a boundary diameter <1.5cm (Panel A). The mapped surface area (SA) was sub-regioned in termination (T-ZONE) and non-termination (NT-ZONE) zones. The T-ZONE surface was centered about the termination site and was allowed to extend to a rectangular kernel >0.5cm and <1.5cm across perpendicular axes, with the NT-ZONE encompassing the remainder mapped SA. Sensitivity (SE) and specificity (SP) of discrimination of the T-ZONE vs. NT-ZONE were measured according to the %SA covered at different LV thresholds (0.1-1.0mV in increments of 0.1mV - Panel F). LV high PF (LVHF) areas at different PF cutoffs from 150Hz (LVHF150) to 300Hz (LVHF300) were also assessed. Results 15 patients with SHD and sustained monomorphic VT were enrolled. 4 had 5 VT’s terminated by 1.4±0.9 focal RF lesions (60-74 y/o, 3 ischemic). All termination sites were located in a LVHF region mapped during SR (Panels B,C,E). The T-ZONE occupied 0.41±0.33cm /92.75±13.31cm global SA and consisted of 15±10 EGM points/1432±337 global points. T-ZONE voltage during SR (0.50±0.32mV) was significantly lower vs. global voltage (2.01±0.69mV, P<0.001), while T-ZONE PF was higher (324±51Hz) vs. global (270±37Hz, P<0.001). ROC discrimination of the T-ZONE yielded AUC’s of 0.79-LV alone, 0.87- LVHF150, 0.91-LVHF200 (Delta +12.2% vs LV alone, Panel F), 0.85-LVHF250 and 0.77-LVHF300. At a 0.7mV cutoff, LVHF200 yielded a balanced SE/SP of 0.89/0.87 vs. LV alone (0.90/0.63). Conclusion Assessment of regions with LVHF during SR improves SP for discrimination of sites of VT termination compared to LV alone.TV near field

Review of Evolocumab for the Reduction of LDL Cholesterol and Secondary Prevention of Atherosclerotic Cardiovascular Disease.

Elevated low-density lipoprotein cholesterol (LDL-C) is a major causal factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide. Statins are the recommended first-line lipid-lowering therapy (LLT) for patients with primary hypercholesterolemia and established ASCVD, with LLT intensification recommended in the substantial proportion of patients who do not achieve levels below guideline-recommended LDL-C thresholds with statin treatment alone. The proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody evolocumab has demonstrated significant LDL-C reductions of 60% in the clinical trial and open-label extension settings, with LDL-C reductions observed early post-evolocumab initiation and maintained long term, during up to 8.4 years of follow-up. Evolocumab therapy, when added to a statin, also conferred a significant reduction in major cardiovascular (CV) events, including a 20% reduction in the composite of CV death, myocardial infarction (MI), or stroke. The absolute benefits were enhanced among various patient types at high and very high risk for secondary ASCVD (e.g., with recent MI, multiple events or peripheral artery disease). Importantly, evolocumab treatment resulted in incremental CV risk reductions during the extended follow-up, including a 23% reduction in CV mortality and no apparent LDL-C level below which there is no further CV risk reduction. Hence, the evolocumab clinical data support the need for early and significant LDL-C lowering, especially in vulnerable ASCVD patients, in order to derive the greatest benefit in the long term. Importantly, evolocumab had no impact on any treatment emergent adverse events apart from a small increase in local injection site reactions. A growing body of real-world evidence (RWE) for evolocumab in heterogeneous populations is consistent with the trial data, including robust LDL-C reductions below guideline-recommended thresholds, a favourable safety profile even at the lowest levels of LDL-C achieved, and a high treatment persistence rate of 90%. Altogether, this review highlights findings from 50 clinical trials and RWE studies in 51,000 patients treated with evolocumab, to demonstrate the potential of evolocumab to address the healthcare gap in LDL-C reduction and secondary prevention of ASCVD in a variety of high- and very high-risk patients.