Initial Cohort Of Patients Research Articles

Automated tracking of morphologic changes in weekly magnetic resonance imaging during head and neck radiotherapy.

Anatomic changes during head and neck radiotherapy can impact dose delivery, necessitate adaptive replanning, and indicate patient-specific response to treatment. We have developed an automated system to track these changes through longitudinal MRI scans to aid identification and clinical intervention. The purpose of this article is to describe this tracking system and present results from an initial cohort of patients. The Automated Watchdog in Adaptive Radiotherapy Environment (AWARE) was developed to process longitudinal MRI data for radiotherapy patients. AWARE automatically identifies and collects weekly scans, propagates radiotherapy planning structures, computes structure changes over time, and reports important trends to the clinical team. AWARE also incorporates manual structure review and revision from clinical experts and dynamically updates tracking statistics when necessary. AWARE was applied to patients receiving weekly T2-weighted MRI scans during head and neck radiotherapy. Changes in nodal gross tumor volume (GTV) and parotid gland delineations were tracked over time to assess changes during treatment and identify early indicators of treatment response. N=91 patients were tracked and analyzed in this study. Nodal GTVs and parotids both shrunk considerably throughout treatment (-9.7±7.7% and -3.7±3.3% per week, respectively). Ipsilateral parotids shrunk significantly faster than contralateral (-4.3±3.1%vs. -2.9±3.3% per week, p=0.005) and increased in distance from GTVs over time (+2.7±7.2% per week, p<1×10-5 ). Automatic structure propagations agreed well with manual revisions (Dice=0.88±0.09 for parotids and 0.80±0.15 for GTVs), but for GTVs the agreement degraded 4-5weeks after the start of treatment. Changes in GTV volume observed by AWARE as early as one week into treatment were predictive of large changes later in the course (AUC=0.79). AWARE automatically identified longitudinal changes in GTV and parotid volumes during radiotherapy. Results suggest that this system may be useful for identifying rapidly responding patients as early as one week into treatment.

Insulin-like growth factor 2 hypermethylation in peripheral blood leukocytes and colorectal cancer risk and prognosis: a propensity score analysis.

To comprehensively assess and validate the associations between insulin-like growth factor 2 (IGF2) gene methylation in peripheral blood leukocytes (PBLs) and colorectal cancer (CRC) risk and prognosis. The association between IGF2 methylation in PBLs and CRC risk was initially evaluated in a case-control study and then validated in a nested case-control study and a twins' case-control study, respectively. Meanwhile, an initial CRC patient cohort was used to assess the effect of IGF2 methylation on CRC prognosis and then the finding was validated in the EPIC-Italy CRC cohort and TCGA datasets. A propensity score (PS) analysis was performed to control for confounders, and extensive sensitivity analyses were performed to assess the robustness of our findings. PBL IGF2 hypermethylation was associated with an increased risk of CRC in the initial study (ORPS-adjusted, 2.57, 95% CI: 1.65 to 4.03, P<0.0001), and this association was validated using two independent external datasets (ORPS-adjusted, 2.21, 95% CI: 1.28 to 3.81, P=0.0042 and ORPS-adjusted, 10.65, 95% CI: 1.26 to 89.71, P=0.0295, respectively). CRC patients with IGF2 hypermethylation in PBLs had significantly improved overall survival compared to those patients with IGF2 hypomethylation (HRPS-adjusted, 0.47, 95% CI: 0.29 to 0.76, P=0.0019). The prognostic signature was also observed in the EPIC-Italy CRC cohort, although the HR did not reach statistical significance (HRPS-adjusted, 0.69, 95% CI: 0.37 to 1.27, P=0.2359). IGF2 hypermethylation may serve as a potential blood-based predictive biomarker for the identification of individuals at high risk of developing CRC and for CRC prognosis.

CI-452768-4 THE MICRA AV LEADLESS PACEMAKER IN THE REAL-WORLD MEDICARE POPULATION: EARLY RESULTS FROM THE MICRA AV COVERAGE WITH EVIDENCE DEVELOPMENT (CED) STUDY

The Micra AV CED study is a novel analysis of utilization, safety, and outcomes associated with the Micra AV leadless pacemaker in the US Medicare population. To describe the initial cohort of AV CED patients implanted in 2020 and compare them to patients implanted with Micra VR leadless or a traditional dual chamber transvenous (DC TV) pacemaker. Patients implanted with a Micra AV leadless pacemaker (N=2,668), a Micra VR leadless pacemaker (N=4,785), or a DC TV pacemaker (N=46,531) were identified using device registry-linked Medicare administrative claims data. Univariate logistic regression was used to compare unadjusted and propensity score overlap weight–adjusted 30-day acute complication rates. Compared with Micra VR and DC TV patients, Micra AV patients were more likely to have end-stage renal disease (17.8% AV vs. 8.8% VR vs. 2.2% DC, P<0.0001), higher overall comorbidity burden (mean Charlson Comorbidity Index 5.2 AV vs. 5.0 VR vs. 4.0 DC TV, P<0.0001), and were more likely to be admitted for their implant procedure through the emergency department (17.1% AV vs. 10.4% VR vs. 11.0% DC TV, P<0.0001) (figure). An estimated 23% of Micra AV patients were likely to have been precluded from TV pacing. Despite these differences, there was no difference in the unadjusted rate of complications at 30 days between Micra AV and DC TV patients (9.8% vs. 8.8%, P=0.25), and Micra AV patients had significantly lower complications after adjustment for measured baseline characteristics (adj. 9.2% vs. 11.1%, P=0.01). Micra AV patients had higher rates of perforation (adj. 1.4% vs. 0.8%, P=0.003), but lower rates of device complications (adj. 1.9% vs. 4.2%, P<0.0001). Compared to VR patients, Micra AV patients had a higher unadjusted rate of overall complications at 30 days (9.8% vs. 7.2%, P=0.0004); however, these differences were not significant following adjustment (adj. overall complications 9.3% vs. 9.6%, P=0.74). Micra AV and Micra VR patients had similar adjusted rates of perforation (adj. 1.4% vs. 1.1%, P=0.32) and device complications (adj. 1.9% vs. 1.5%, P=0.36). In a real-world study of US Medicare patients, patients implanted with Micra AV leadless pacemaker were significantly sicker and more complex than patients implanted with either a Micra VR leadless or a traditional DC TV pacemaker. Despite these differences, similar rates of overall complications were observed at 30 days.

The Canadian Registry for Amyloidosis Research: A national multi-disciplinary registry for real-world evidence (P12-8.014)

The Canadian Registry for Amyloidosis Research: A national multi-disciplinary registry for real-world evidence (P12-8.014)

Clinical outcomes in patients with scaphoid non-union treated with the vascularized medial femoral condyle technique a case series

IntroductionNon-union is a prevalent complication of scaphoid fractures. Late diagnosis is common and has a clinical impact due to functional limitations for the patient. Multiple treatments have been proposed to manage this complication, ranging from conservative (i.e., orthopedic) to surgical treatment. The vascularized medial femoral condyle technique has shown satisfactory clinical and paraclinical results, mainly in presence of avascular necrosis of the proximal pole but data regarding functional outcomes and patient satisfaction is scarce.This case series aims to describe the clinical and patient-reported outcomes in a consecutive series of patients with non-union of the proximal third of the scaphoid treated with vascularized medial femoral condyle technique. MethodsCase series reporting results for a consecutive – initial cohort of patients who presented with a non united fracture of the proximal pole of the scaphoid, avascular necrosis of the proximal pole was documented by CT od MRI imaging preoperatively in all patients. Measurement instruments include the q-DASH and PRWE questionnaires, radiographic images, goniometry, and assessment of grip strength. ResultsTwelve consecutive patients are included and they represent the initial cases for all surgeons involved; bone union was obtained in 10 patients (83%) after a mean follow-up time of 31 months (6–72), successful improvement in the range of motion and grip strength was documented. A high rate of satisfaction expressed by the patient was obtained, with an average score in Q-DASH of 17.3 and 20.1 in PRWE. ConclusionsThe vascularized medial condyle technique in cases of nonunion of scaphoid fracture is a reproducible treatment in clinical terms, both in imaging and functional terms, and in patient satisfaction. The learning curve is flat for a dedicated multi surgeon team.

Clinical outcomes of dupilumab therapy in chronic rhinosinusitis with nasal polyps in a Canadian tertiary care rhinology practice

BackgroundIn 2020, dupilumab became the first monoclonal antibody therapy to be approved by Health Canada for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP). The primary aim of this study was to characterize the outcomes in an initial cohort of patients with CRSwNP who have undergone dupilumab therapy.MethodsA retrospective study was conducted of patients with CRSwNP who were treated with dupilumab. Demographic information, comorbidities, number of previous surgeries, and insurance information were collected. The primary outcome were changes in the sinonasal outcome test (SNOT-22) scores from baseline to timepoints after receiving dupilumab.ResultsForty-eight patients were considered for dupilumab therapy, and 27 (56%) received coverage or were able to fund the medication independently. Patients waited an average of 3.6 months to obtain access to the medication. The mean age of the patients was 43. Forty-one percent (11/27) of patients had aspirin exacerbated respiratory disease, and 96% (26/27) had a diagnosis of asthma. The mean length of time on dupilumab was 12.1 months. The baseline SNOT-22 score was 60.6. The mean decrease at 1 month, 3 months, 6 months, and 12 months after starting dupilumab was 8.8, 26.5, 42.8, and 33.8, respectively. There were no serious adverse events.ConclusionPatients treated with dupilumab in a Canadian tertiary care rhinology clinic demonstrated substantial clinical improvement as measured by disease-specific sinonasal outcomes. Further studies are needed to determine the longer-term effectiveness and adverse event profile of this novel therapy.

Navigated functional alignment total knee arthroplasty achieves reliable, reproducible and accurate results with high patient satisfaction

PurposeThe decision on which technique to perform a total knee arthroplasty (TKA) has become more complicated over the last decade. Perceived limitations of mechanical alignment (MA) and kinematic alignment (KA) have led to the development of the functional alignment (FA) philosophy. This study aims to report the 2-year results of an initial patient cohort in terms of revision rate, PROMs and complications for Computer Aided Surgery (CAS) Navigated FA TKA.MethodsThis paper reports a single surgeon’s outcomes of 165 consecutive CAS FA TKAs. The final follow-up was 24 months. Pre-operative and post-operative patient-reported outcome measures, WOMAC and KSS, and intra-operative CAS data, including alignment, kinematic curves, and gaps, are reported. Stress kinematic curves were analysed for correlation with CAS final alignment and CAS final alignment with radiographic long-leg alignment. Pre- and post-operative CPAK and knee phenotypes were recorded. Three different types of prostheses from two manufacturers were used, and outcomes were compared. Soft tissue releases, revision and complication data are also reported.ResultsMean pre-operative WOMAC was 48.8 and 1.2 at the time of the final follow-up. KSS was 48.8 and 93.7, respectively. Pre- and post-operative range of motion was 118.6° and 120.1°, respectively. Pre-operative and final kinematic curve prediction had an accuracy of 91.8%. CAS data pre-operative stress alignment and final alignment strongly correlate in extension and flexion, r = 0.926 and 0.856, p < 0.001. No statistical outcome difference was detected between the types of prostheses. 14.5% of patients required soft tissue release, with the lateral release (50%) and posterior capsule (29%) being the most common.ConclusionCAS FA TKA in this cohort proved to be a predictable, reliable, and reproducible technique with acceptable short-term revision rates and high PROMs. FA can account for extremes in individual patient bony morphology and achieve desired gap and kinematic targets with soft tissue releases required in only 14.5% of patients.Level of evidenceIV (retrospective case series review).

A Multidisciplinary Pediatric Neurology Clinic for Systematic Follow-up of Children with Neurologic Sequelae of COVID-19.

Clinical guidance on outpatient follow-up of children hospitalized with acute neurologic complications of SARS-CoV2 infection is needed. We describe the clinical infrastructure of our pediatric neurology post-Covid clinic, including our clinical evaluation and cognitive testing battery specific to this patient population, and a case series of our initial patient cohort. Our findings demonstrate cognitive sequelae in all 4 of our patients months following acute SARS-CoV2 infection with neurologic complications including acute disseminated encephalomyelitis, posterior reversible encephalopathy syndrome, viral encephalitis, and gait difficulties. Verbal and executive function domains were predominantly affected in our cohort, even in patients who did not endorse symptomatic or academic complaints at follow-up. Our recommendations include systematic clinical follow-up for children following hospitalization with SARS-CoV2 infection with a comprehensive cognitive battery to monitor for cognitive sequalae and to assist with developing an individualized education plan for the child as they return to school.

Cardiac function in women receiving dual anti-Her2 antibodies (trastuzumab and pertuzumab) combined with chemotherapy for breast cancer.

Chemotherapy regimens containing a combination of anti-Her2 antibodies are effective but can be associated with cardiac toxicity. We evaluate the outcome with a particular focus on the cardiac function of patients with Her2 over-expressed breast cancer receiving Chemotherapy regimens combined with Trastuzumab and Pertuzumab in routine clinical practice settings. The initial cohort of patients who started Chemotherapy regimens in combination with Trastuzumab and Pertuzumab before September 2019 in four cancer units were reviewed retrospectively. All patients had regular measurements of left ventricular ejection fraction by Doppler ultrasound. Sixty-seven patients were identified. Chemotherapy regimens in combination with Trastuzumab and Pertuzumab treatment were administered in the neoadjuvant and palliative settings in 28 (41.8%) and 39 (58.2%) patients, respectively. All patients underwent left ventricular ejection fraction assessment prior to starting Chemotherapy regimens in combination with Trastuzumab and Pertuzumab treatment and at 3 and 6 months later. Subsequently, left ventricular ejection fraction was measured at 9, 12, 15, 18, 21, and 24 months as long as patients are still receiving any of the treatment components. Compared to baseline, the mean left ventricular ejection fraction was not significantly different at any of the subsequent time points (range; decrease by 0.936% to increase by 1.087%: T-test P value not statistically significant for all comparisons). Trastuzumab and Pertuzumab administration was withheld temporarily for two patients due to clinically suspected cardiac toxicity which was excluded upon further investigations. In the neoadjuvant cohort, 82.3% of patients were relapse free at 3 years. The median progression-free survival was 20 months, and the median overall survival was 41 months in the palliative cohort. In this cohort describing our limited initial experience, dual anti-Her2 antibodies (Trastuzumab and Pertuzumab) combined with chemotherapy is effective and not associated with significant cardiac toxicity when the left ventricular ejection fraction is measured every 3 months. This may suggest that previous concerns about cardiotoxicity may have been overemphasized. Further studies investigating less frequent left ventricular ejection fraction monitoring may be warranted.

A Phase I Clinical Trial of Point-of-Care Manufactured Fresh Anti-CD19/20/22 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Lymphoid Malignancies (Non-Hodgkin Lymphoma, Acute Lymphoblastic Leukemia, Chronic Lymphocytic Leukemia, B Prolymphocytic Leukemia)

Background: CD19-targeted CAR-T cells have transformed the treatment of relapsed/refractory B-cell malignancies. However, relapse occurs in over 50% of patients treated with commercial CD19 directed CAR-T due to antigen escape from selective immune pressure either on the target antigen or due to exhaustion and lack of persistence of CAR-T cells. Hence there is an unmet need for next-generation CAR-Ts that have broad antigen recognition and novel costimulatory domains to promote survival and decrease exhaustion of CAR-Ts. Targeting three B-cell antigens simultaneously is a novel approach to prevent antigen-negative relapse while inclusion of the OX40 domain will promote CAR-Ts persistence and expansion. Whether targeting three commonly expressed antigens is feasible or safe and will result in durable remissions is not known. We hypothesize that this trispecific targeting of CD19/20/22 CAR-T construct will be safe and effective in patients with relapsed, refractory B-cell malignancies. Study Design and Methods: This parallel group phase 1 study follows a 3+3 phase 1 design to determine the safety of the infusion of point-of-care manufactured fresh CAR-T cells targeting CD19/20/22 and to find the recommended phase II dose for this cellular therapy. CAR-T cells will be manufactured over 6 days. Patients will be enrolled in one of the two cohorts: Cohort A (single infusion): Non-Hodgkin's Lymphoma (NHL) with lesions <= 5 cm; Indolent lymphomas; B-PLL (B-Pro lymphocytic leukemia); Chronic Lymphocytic Leukemia -CLL (without Richter's transformation), Cohort B (split infusion): B-ALL (B-Acute lymphoblastic leukemia); Lymphoid blast crisis of Chronic myeloid leukemia; CLL (with Richter's transformation); NHL with lesions > 5 cm and/or lymphoblastic lymphoma, or NHL with circulating lymphoma cells. Patients who are CAR-naïve will be enrolled in this study. The study involves infusion of anti-CD19/20/22 CAR-T cells administered after an immunosuppressive conditioning regimen of fludarabine and cyclophosphamide. Cyclophosphamide 60 mg/kg will be infused intravenously over 60 minutes on day -6. Fludarabine 25 mg/m2 will be infused intravenously daily over 30 minutes on days -5 to -3. In each group, patients will be enrolled sequentially to each dose level, starting with dose level 1. Three CAR-T dose-levels: 5x105, 1x106 & 2x106 cells/kg/dose will be explored to determine MTD. For cohort B patients, the total CAR-T cell dose infused, will be divided in two doses, dose 1 (day 0) is 40% of the total dose and dose 2 (day 7) is 60% of total dose. The minimum number of subjects enrolled in the complete study will be 18 (9 per cohort) and the maximum number in dose escalation will be 36 (18 per cohort). Patients in each cohort will be monitored for 30 days before enrollment of next patientTwo patients have been enrolled in the trial and received fresh infusion of Anti CD19/20/22 CAR-T cells and accrual is ongoing. Updates on the initial cohort of patients will be presented at the meeting. ClinicalTrials.gov NCT: NCT05418088 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Tracking OAR Volume and DVH Variability in the Initial Cohort of Pelvic Patients Treated with CBCT-Guided, Online Adaptive Therapy

<h3>Purpose/Objective(s)</h3> We have recently commissioned and began treatment using a novel, CBCT-guided, online adaptive radiotherapy (ART) platform. We have evaluated the volumetric and dosimetric variation in our initial cohort of patients. <h3>Materials/Methods</h3> We have tracked our 6 initial online adaptive pelvis patients for 208 delivered fractions. A custom script was developed to extract volume and dosimetry data from our second check software. Target and organ-at-risk (OAR) volumes were gathered for every fraction. Structure volume variations were computed relative to the reference plan for each fraction and averaged per patient. Dose-volume histogram (DVH) data was collected for the primary treatment plan for our four prostate patients, all treated to 45 Gy in 25 fractions. The range of OAR DVH values at 20, 30, and 40 Gy and PTV V45 Gy over the primary course of each patient's treatment was computed for both scheduled and daily adapted plans. <h3>Results</h3> OAR variability was very patient dependent. Bladder volumes showed the largest variation, with most patients unable to replicate their bladder filling from simulation. Mean deviations in bladder volume ranged from -47% to +12%, with standard deviations >20% for two-thirds of patients. Rectal volume was also variable, but to a lesser extent, with mean variations ranging from -31% to +16%. DVH data demonstrates that ART produces a much tighter distribution of DVH curves compared to the scheduled plan for all structures while maintaining PTV coverage to within 1% of the reference value. The variability of V40Gy, V30Gy, and V20Gy showed reductions of 13.9%, 29.8%, 30.9% for bladder and 52.6%, 48.9%, and 24.6% for rectum relative to the scheduled plan, respectively. Using only the scheduled plan would result in reductions of up to 8% of target coverage compared to the reference plan. <h3>Conclusion</h3> We have observed considerable OAR interfraction volume variations during the course of pelvic radiation that can be highly patient dependent. Use of ART maintains adequate target coverage while reducing the variability in dose delivery to these nearby OARs. Combined with the large variability in OAR filling, we have demonstrated that ART enables clinicians to have a higher likelihood of delivering their intended doses to targets and OARs compared to standard-of-care radiotherapy.

Sex differences in systemic lupus erythematosus (SLE): an inception cohort of the Chinese SLE Treatment and Research Group (CSTAR) registry XVII.

The onset and clinical presentation of systemic lupus erythematosus (SLE) are sex-related. Few studies have investigated the distinctions in clinical characteristics and treatment preferences in male and female SLE patients in the initial cohort. This study aimed to improve the understanding of Chinese SLE patients by characterizing the different sexes of SLE patients in the inception cohort. Based on the initial patient cohort established by the Chinese SLE Treatment and Research Group, a total of 8713 patients (795 men and 7918 women) with newly diagnosed SLE were enrolled between April 2009 and March 2021. Of these, 2900 patients (347 men and 2553 women) were eligible for lupus nephritis (LN). A cross-sectional analysis of the baseline demographic characteristics, clinical manifestations, laboratory parameters, organ damage, initial treatment regimens, and renal pathology classification was performed according to sex. In the SLE group, as compared to female patients, male patients had a later age of onset (male vs. female: 37.0 ± 15.8 years vs. 35.1 ± 13.7 years, P = 0.006) and a higher SLE International Collaborative Clinic/American College of Rheumatology damage index score (male vs. female: 0.47 ± 1.13 vs. 0.34 ± 0.81, P = 0.015), LN (male vs. female: 43.6% vs. 32.2%, P < 0.001), fever (male vs. female: 18.0% vs. 14.6%, P = 0.010), thrombocytopenia (male vs. female: 21.4% vs. 18.5%, P = 0.050), serositis (male vs. female: 14.7% vs. 11.7%, P = 0.013), renal damage (male vs. female: 11.1% vs. 7.4%, P < 0.001), and treatment with cyclophosphamide (CYC) (P < 0.001). The frequency of leukopenia (male vs. female: 20.5% vs. 25.4%, P = 0.002) and arthritis (male vs. female: 22.0% vs. 29.9%, P < 0.001) was less in male patients with SLE. In LN, no differences were observed in disease duration, SLE Disease Activity Index score, renal biopsy pathological typing, or 24-h urine protein quantification among the sexes. In comparisons with female patients with LN, male patients had later onset ages (P = 0.026), high serum creatinine (P < 0.001), higher end-stage renal failure rates (P = 0.002), musculoskeletal damage (P = 0.023), cardiovascular impairment (P = 0.009), and CYC use (P = 0.001); while leukopenia (P = 0.017), arthritis (P = 0.014), and mycophenolate usage (P = 0.013) rates were lower. Male SLE patients had more severe organ damage and a higher LN incidence compared with female SLE patients; therefore, they may require more aggressive initial treatment compared to female patients.

Abstract 4103: Feasibility and efficacy of a functional precision medicine approach in the management of relapsed/refractory childhood cancers

Abstract Pediatric cancers are fundamentally different from those in adults, with lower frequency of genetic mutations and fewer options for targeted therapies. The implementation of functional precision medicine (FPM) - the integration of ex vivo drug screening and mutation profiling- can, therefore, provide better treatment options for pediatric tumor patients. In this study, we investigated the feasibility and clinical utility of FPM in the management of pediatric patients with recurrent and/or refractory cancers. We use a functional ex vivo drug screening test (DST) panel encompassed 40 formulary drugs frequently used at Nicklaus Children’s hospital and 47 non-formulary drugs approved by FDA for cancer treatment, as well as drugs from phase III and IV clinical trials. Drug sensitivity scores (DSS) were calculated for each drug based on cancer cells’ responses. DST results were then combined with results from targeted mutation profiles to match actionable mutations with selective targeted therapies. We have recruited a total of 21 patients into this ongoing clinical trial (number NCT03860376) and were able to perform drug testing and mutation profiling on 17 patients. We optimized and successfully performed DST on at least 13 different tumor types including acute myeloid leukemia, chronic lymphoblastic leukemia, ependymoma, osteosarcoma, Ewing’s sarcoma, rhabdomyosarcoma, glioblastoma, medulloblastoma, astrocytoma, neuroblastoma, rhabdoid, lung, and liver tumors. Our feasibility study, so far, has demonstrated that ex vivo DST can be performed within a clinically actionable time frame (median: 7 days). Ex vivo DST returned between 10 and 30 treatment options for each patient. These patients showed different responses to the 103 FDA-approved compounds used in the screen. More than half of the evaluated compounds were not active in any of the patients. Remarkably, DST provided valuable information to the oncologists on drug dosing and treatments that may not be effective and should be avoided. DSS synergizes with genomic data to further refine treatment recommendations. FPM-guided treatment regimens resulted in encouraging partial and complete responses as compared to progressive disease in prior regimens and physician choice regimens. Thus, our study shows technical feasibility of integrating functional precision medicine approaches for patients with refractory/relapsed pediatric cancers. Routine clinical integration of FPM for treatment selection is technically feasible and has led to improved treatment of pediatric cancer patients with refractory malignancies in an initial patient cohort, warranting further investigation. Citation Format: Arlet Maria Acanda de la Rocha, Maggie Fader, Ebony Coats, Joseph Dunn, Leat Perez, Cima Saghira, Ileana Sotto, Ziad Khatib, Ossama Maher, Haneen Abdella, Cristina M. Andrade-Feraud, Alexa Jacome, Lilliam Rimblas, Paula S. Espinal, Tomás R. Guilarte, Jennifer McCafferty-Fernandez, Daria Salyakina, Diana J. Azzam. Feasibility and efficacy of a functional precision medicine approach in the management of relapsed/refractory childhood cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4103.

Abstract 3420: Tgfbm3b is a natural germline genetic variant that modifies anti-tumor responses to anti-PD-1 immunotherapy through its action on the tumor microenvironment

Abstract Our goal for this study is to use a mouse genetics approach to identify host germline genetic variants that determine therapeutic responses to cancer immunotherapy (IMT) and to validate these findings in cancer patients treated with α-PD-1. The information gathered may lead to drug targets that potentiate IMT responses and genetic markers may contribute to risk scores for response to IMTs. Immune Checkpoint blockade (ICB) therapy leads to remarkable clinical responses, including highly durable complete responses in a fraction of patients. Consequently, α-PD-1/PDL-1 is now first-line therapy for treating melanoma and NSCLC (non-small cell lung carcinoma). However, most patients do not respond to α-PD-1 therapy, and few show systemic adverse effects. There is therefore an unmet need to develop biomarkers and drug targets that will potentiate therapeutic responses to ICBs. Firstly, we found that blockade of active TGFβ using therapeutic antibodies synergizes with α-PD-1 therapy to potentiate tumor rejection, thus, we hypothesized that variant genetic modifiers of TGFβ1 may influence outcomes of α-PD-1 therapy. By utilizing Tgfbm3b-C57BL/6 (Tgfbm3b-C57) mice carrying a genetic variation of TGFβ1 to study the anti-tumor response to IMT, we confirmed that Tgfbm3b-C57 potentiated anti-tumor responses to α-PD-1 and to combinatorial α-PD-1/α-TGFβ IMT with higher induction of CD8+ T cell-mediated anti-tumor cytotoxicity. The C57 allele contains gene Adam17 that encodes an amino acid variant, L613V, and a charge change at amino acid 113 (D113N). Protein ADAM17 is a sheddase that involves in TNFα biosynthesis and sheds the TGFβ type I receptor (TβRI) to attenuate TGFβ signaling. To understand the molecular function of the variants, the vectors encoding wildtype (NIH) ADAM17 that carries D113, L613 versus the variant (C57) ADAM17 that has N113, V613, are being transfected and tested for the action on a panel of ADAM17 substrates including TNFα and TβRI on NIH3T3 cell line. We are also investigating whether genetic variation within the syntenic human TGFBM3 locus confers differential survival benefit to patients after α-PD-1 therapy. We will confirm the genetic association of ADAM17 SNPs and screen the TGFBM3b locus from LPIN1 to HPCAL1, and YWHAQ to DDEF2. The dataset includes genome-wide association data from progression-free survival analysis of 2000 NSCLC patients following α-PD-1 therapy. The preliminary data from our initial cohort (n=862) of NSCLC patients on PD-1 inhibitors are currently being evaluated. By investigating the molecular and cellular mechanisms by which Tgfbm loci influence ICB outcomes and addressing the relevance to human cancer patients, this project not only addresses an important basic science question but may ultimately lead to novel biomarkers or drug targets that can improve IMT outcomes and reduce adverse effects. Citation Format: Szu-Ying Chen, Ons Mamai, Rosemary Akhurst. Tgfbm3b is a natural germline genetic variant that modifies anti-tumor responses to anti-PD-1 immunotherapy through its action on the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3420.

Selective Thumb Carpometacarpal Joint Denervation for Painful Arthritis: Follow-Up of Long-Term Clinical Outcomes

Thumb carpometacarpal (CMC) joint osteoarthritis is a common problem affecting up to 85% of patients over the age of 70. The most common presenting symptom for patients with CMC arthritis is pain with joint loading. Loss of function due to subluxation or joint destruction is comparatively rare. Carpometacarpal joint denervation is a relatively novel method for managing CMC arthritis, treating the most impactful symptom: pain. In this paper, we present a 4- to 6-year follow-up case series on patients who underwent CMC denervation between 2015 and 2017. Denervation was safe, with less downtime than trapeziectomy with ligament reconstruction with tendon interposition and provided durable complete or partial relief of pain after 5 years in 5 of 9 patients. Four of 9 patients had recurrence of pain by 5 years. Of those with recurrent pain, 3 of 5 eventually underwent trapeziectomy with ligament reconstruction and tendon interposition; the secondary surgery occurred between 17 and 66 months after denervation. Thumb CMC denervation provides effective relief of arthritis pain that was durable at 5+ years after surgery in more than half of our initial cohort of patients treated. Prospective studies with validated patient-reported and objective outcome measures between distinct treatment arms, such as denervation versus ligament reconstruction with tendon interposition, are needed to firmly establish the role of CMC denervation for patients with symptomatic thumb CMC osteoarthritis. Therapeutic/Level IV.

The Cost Effectiveness of Levodopa-Carbidopa Intestinal Gel in the Treatment of Advanced Parkinson's Disease in England.

BackgroundParkinson’s disease is a progressive neurodegenerative disease, which significantly impacts patients’ quality of life and is associated with high treatment and direct healthcare costs. In England, levodopa/carbidopa intestinal gel (LCIG) is indicated for the treatment of levodopa-responsive advanced Parkinson’s disease with troublesome motor fluctuations when available combinations of medicinal products are unsatisfactory.ObjectiveWe aimed to determine the cost effectiveness of LCIG compared to the standard of care for patients with advanced Parkinson’s disease in England, using real-world data.MethodsA Markov model was adapted from previous published studies, using the perspective of the English National Health System and Personal and Social Services to evaluate the cost effectiveness of LCIG compared to standard of care in patients with advanced Parkinson’s disease over a 20-year time horizon. The model comprised 25 health states, defined by a combination of the Hoehn and Yahr scale, and waking time spent in OFF-time. The base case considered an initial cohort of patients with an Hoehn and Yahr score of ≥ 3, and > 4 h OFF-time. Standard of care comprised standard oral therapies, and a proportion of patients were assumed to be treated with subcutaneous apomorphine infusion or injection in addition to oral therapies. Efficacy inputs were based on LCIG clinical trials where possible. Resource use and utility values were based on results of a large-scale observational study, and costs were derived from the latest published UK data, valued at 2017 prices. The EuroQol five-dimensions-3-level (EQ-5D-3L) instrument was used to measure utilities. Costs and quality-adjusted life-years were discounted at 3.5%. Both deterministic and probabilistic sensitivity analyses were conducted.ResultsTotal costs and quality-adjusted life-years gained for LCIG vs standard of care were £586,832 vs £554,022, and 2.82 vs 1.43, respectively. The incremental cost-effectiveness ratio for LCIG compared to standard of care was £23,649/quality-adjusted life-year. Results were sensitive to the healthcare resource utilisation based on real-world data, and long-term efficacy of LCIG.ConclusionsThe base-case incremental cost-effectiveness ratio was estimated to be within the acceptable thresholds for cost effectiveness considered for England.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40273-022-01132-y.

Automated scripting of the dosimetric evaluation of adaptive versus non-adaptive radiotherapy

Objective. To quantify the benefit of adaptive radiotherapy over non-adaptive radiotherapy it is useful to extract and compare dosimetric features of patient treatments in both scenarios. This requires Image-Guided Radiotherapy (IGRT) matching of baseline planning to adaptive fraction imaging, followed by extraction of relevant dose metrics. This can be impractical to retrospectively perform manually for multiple patients. Approach. Here we present an algorithm for automatic IGRT matching of baseline planning with fraction imaging and performing automated dosimetric feature extraction from adaptive and non-adaptive treatment plans, thereby allowing comparison of the two scenarios. This workflow can be done in an entirely automated way via scripting solutions given structure and dose Digital Imaging and Communications in Medicine (DICOM) files from baseline and adaptive fractions. We validate this algorithm against the results of manual IGRT matching. We also demonstrate automated dosimetric feature extraction. Lastly, we combine these two scripting solutions to extract daily adaptive and non-adaptive radiotherapy dosimetric features from an initial cohort of patients treated on an MRI guided linear accelerator (MR-LINAC). Results. Our results demonstrate that automated feature extraction and IGRT matching was successful and comparable to results performed by a manual operator. We have therefore demonstrated a method for easy analysis of patients treated on an adaptive radiotherapy platform. Significance. We believe that this scripting solution can be used for quantifying the benefits of adaptive therapy and for comparing adaptive therapy against various non-adaptive IGRT scenarios (e.g. 6 degree of freedom couch rotation).

A Framework for In Silico Clinical Trials for Medical Devices Using Concepts From Model Verification, Validation, and Uncertainty Quantification

Abstract The rising costs of clinical trials for medical devices in recent years has led to an increased interest in what are called in silico clinical trials, where simulation results are used to supplement or to replace those obtained from human patients. Here we present a framework for executing such a trial. This framework relies heavily on ideas already developed for model verification, validation, and uncertainty quantification. The framework uses results from an initial cohort of human patients as model validation data, recognizing that the best model credibility evidence usually comes from real patients. The validation exercise leads to an assessment of the model's suitability based on predefined acceptance criteria. If the model meets these criteria, then no additional human patients are required and the study endpoints that can be addressed using the model are met using the simulation results. Conversely, if the model is found to be inadequate, it is abandoned, and the clinical study continues using only human patients in a second cohort. Compared to other frameworks described in the literature based on Bayesian methods, this approach follows a strict model build-validate-predict structure. It can handle epistemic uncertainties in the model inputs, which is a common trait of models of biomedical systems. Another idea discussed here is that the outputs of engineering models rarely coincide with measures that are the basis for clinical endpoints. This article discusses how the link between the model and clinical measure can be established during the trial.

Treatment and Outcomes of Atraumatic Subtalar Dislocations in Adult Acquired Flatfoot Deformity

Category:Ankle; HindfootIntroduction/Purpose:Painful adult acquired flatfoot is classified into multiple types, with a one category reserved for those that have rigid deformity. However, there is a subset of patients with rigid progressive collapsed foot deformity (PCFD) in which navicular and calcaneus are subluxed from the talus causing sub-fibular impingement and erosion and fixed abduction of the forefoot. This condition is not well described in the literature. The treatment of these patients can be technically difficult given the attenuation and erosion of soft tissue and articular constraints. In this study we sought to identify reduction technique, shared characteristics, treatments, and outcomes in patients with severe hindfoot valgus deformity with subluxation and subfibular impingement who were treated by subtalar reduction and arthrodesis, and talonavicular arthrodesis at a single institution.Methods:A retrospective chart review was done of all patients who underwent flat foot reconstruction by a single surgeon. Patient were included in the study if on preoperative weight-bearing (WB) CT they met the following radiographic criteria: 3 sequential sagittal cuts of the calcaneus without the talus present, 3 sequential sagittal cuts of the talus without the calcaneus present, and the presence of a calcaneofibular articulation on coronal cuts. Patients with neuromuscular disorders or peripheral neuropathy were excluded. This review evaluated demographic data, comorbidities, complications, and the need for reoperation. Plane radiographs and CT findings were compared to identify subluxation on plane images. Patients were treated with a double, triple, or pantalar arthrodesis based on the treating surgeon’s discretion. A cohort of 23 patients has already been identified, but additional data review is currently underway.Results:The initial patient cohort consisted of twenty-three patients who met the inclusion criteria with an average age of 64.5 (range, 48-79) years. The initial cohort consisted of patients who were treated from 2009-2014. Seven of the twenty-three patients (30.4%) required reoperation for various reasons ranging from late infection to nonunion and symptomatic hardware (Table 1). We found that the average BMI for patients with this disorder was 34kg/m2. Four patients have fibular stress fractures on presentation, these patients had an average BMI of 41.6kg/m2. Specific techniques for reduction included use of distractors at subtalar and TN joints. Radiographic findings on plane films are linked to findings on CT scan. Recurrence of deformity occurred with tilt of the talus requiring bracing in 2 patients. Incomplete correction was common, particularly early in the study period.Conclusion:PCFD is a very problem seen by foot and ankle surgeons. Physicians should be aware of the challenges presented in treating the subset of patients who have atraumatic dislocation of the subtalar joint. Diagnosis can be made on plane radiographs, though WB CT is useful for treatment planning. Treatment of these patients requires careful physical and radiographic examination. Reduction and arthrodesis is the treatment of choice. Patients should also be counseled about the possible need for reoperation given the high rate of reoperation in this population.

A buccal mucosal graft subcoronal resurfacing technique to treat recurrent penile adhesions: the buccal belt.

To outline our step-by-step surgical technique using a subcoronal buccal mucosal graft (BMG) resurfacing technique for the treatment of recurrent penile adhesions. To perform the 'buccal belt' procedure a subcoronal circumferential segment of diseased skin was excised. An appropriately sized BMG was circumferentially secured subcoronally with a proximal and distal anastomosis to the edges of the wound. Quilting stitches were also placed to allow proper graft fixation. A petroleum jelly bolster was secured as a tie-over dressing. Patients were discharged with a Foley catheter and the bolster dressing in place. The bolster and Foley catheter were removed 7 days postoperatively. The patients were then seen for follow-up at 4- to 6-month intervals. A retrospective, international multi-institutional review was conducted to include all patients who underwent this procedure. Surgical complications, evidence of recurrence, and patient-reported outcome measures including visual analogue scale (VAS) and global response assessment (GRA) questionnaires were reviewed. Thirty-one men underwent the procedure across six institutions between March 2014 and September 2020. The mean (range) surgical time was 59 (25-95) min. At the mean (range) follow-up of 27 (4-79) months all patients reported resolution of presenting symptoms and no recurrence of adhesions. The mean VAS score was 8.9 and 9.0 for aesthetics and functional outcomes, respectively. On GRA, overall improvement was reported by all patients (61%, +3; 25%, +2; 14%, +1). There are limited options for the treatment of recurrent penile adhesions. A subcoronal BMG resurfacing is feasible, with no recurrence and overall high satisfaction seen in an initial patient cohort.