Landmark Approach Research Articles

Dynamic prediction of survival via Landmark method using the asthma prevention trial in young children.

This paper focuses on the applications of Landmark method for obtaining dynamic predictions of survival by using Landmark approach to the data of asthma prevention trial in young children. This work focuses on the different ways to model recurrent events by considering various time scales according to how subjects in the dataset experienced multiple events. Landmark models can be used to dynamically estimate the effect of treatments effects whilst also taken into consideration the history of previous asthma attacks. Our analysis show that the treatment effect should be modelled with a time varying effect and the effect of the previous attack reduces with the passage of time.

Impact of Symptom Benefit and Transfusion Response on Survival in Myelofibrosis Patients Treated with Pacritinib: PERSIST-2 Landmark Survival Analysis

Background: Pacritinib is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that demonstrated symptom benefit measured by TSS (v2.0, excluding tiredness) vs best available therapy (BAT) in PERSIST-2, which enrolled cytopenic myelofibrosis patients with platelets ≤100×10 9/L. Recent datashowed that in patients with cytopenic MF, a ≥10% reduction in spleen volume at 12 weeks is associated with improved survival in patients treated with pacritinib ( Ajufo H, et al., J Clin Oncol;2023:14(16):Suppl). Surprisingly, this association was not confirmed in patients treated with BAT (82% of whom were on ruxolitinib). The association between other important measures of clinical benefit such as symptom burden reduction and anemia improvement on survival in patients treated with pacritinib has not previously been described. Methods: Patients randomized to pacritinib 200 mg BID and to BAT on PERSIST-2 were included if they were alive and on study at the start of the week 12 efficacy assessment period. Survival was assessed by Total Symptom Score (TSS; v2.0 excluding tiredness) reduction at various thresholds (≥50%, ≥20%, ≥10%, >0%) and transfusion independence (TI) response. TI was assessed among patients who required red blood cell (RBC) transfusion at baseline (within 90 days) and was defined, for the purposes of a landmark survival analysis, as the absence of RBC transfusions over any 12-week period from first dose through week 14 (allowing for a ±2-week window around week 12). Overall survival (OS) was estimated via the K-M method following the landmark approach; survival in responders vs non-responders was compared using the log-rank test. Results: Of the 59 patients treated with pacritinib who had a reduction of TSS≥10%, the median age was 67 years, 25% had a baseline high-risk DIPSS, median platelet count was 61 x10 9/L, median hemoglobin was 9.7 g/dL, and baseline TSS was 19.1. Reduction of TSS≥10% was associated with improved OS, with 1 death among 59 responders vs 4 deaths among 30 non-responders (hazard ratio [HR]=0.12, 95% confidence interval [CI]: 0.01, 0.79] P=0.021, Fig 1a). Similar to spleen volume reduction, the association between TSS response and OS weakened at more stringent TSS response thresholds (Fig 1c, e), with the BAT arm not showing an association between TSS response and OS at any threshold. (Fig 1b, d, f). In order to assess the relationship of specific TSS domains and survival , a landmark OS analysis was performed based on ≥20% reduction in physical function scores (sum of ‘tiredness’ and 'inactivity'), spleen-related symptom scores (sum of 'abdominal discomfort', ‘early satiety’, and 'left rib pain'), and cytokine-related symptom scores (sum of 'itching', ‘night sweats’, and ‘bone pain‘). For cytokine-related symptoms, the number of deaths in PAC responders was significantly different compared to non-responders, with 0 deaths among 35 responders vs 2 among 15 non-responders ( P=0.0325). Conversely the deaths among responders (2/22) vs non-responders (2/20) were not significantly different in the BAT arm. For the physical function and spleen-related symptom subscales, no significant differences between PAC responders and non-responders was observed (HR=0.60; 95% CI [0.05, 6.74] P=0.679) and (HR=0.26; 95% CI 0.02, 2.93, P=0.2435) respectively. Among 36 patients on PAC who received RBC transfusions at baseline, 7 achieved TI over at least a 12-week period up to the time of the landmark analysis. There were no deaths among TI responders compared to 2 (6.9%) among TI non-responders. There were too few TI responders on BAT (only 2 out of 38) to assess the impact on survival. Conclusion: In cytopenic myelofibrosis patients enrolled in PERSIST-2, having a reduction of TSS≥10% on full-dose PAC was associated with OS benefit - a finding that has not been noted with other JAK inhibitors to date. By contrast, this association was not found with BAT, (82% of these patients received ruxolitinib). Thus, reductions in TSS in patients treated with PAC were associated with an OS benefit. It is possible that pacritinib, with its distinctive mechanism of action, may offer a unique survival advantage for MF patients with moderate or severe thrombocytopenia, and further studies are required to understand the potential mechanisms of these distinct clinical observations. Study funded by CTI BioPharma Corp., a Sobi company.

Integrative Genomic and Transcriptomic Analysis Reveals Genetic Alterations Associated with the Early Progression of Follicular Lymphoma

Background Follicular lymphoma (FL), the most common indolent lymphoma, is a clinically and genetically heterogeneous disease. However, the prognostic value of driver gene mutations and copy number alterations has not been systematically assessed. Patients and Methods Here, we analyzed clinical-biological features of 415 FL patients to identify variables associated with disease within 24 months of first-line therapy (POD24). In addition, we applied whole exome sequencing (WES) to identify genomic alterations that predict POD24 based on 102 FL patients. Furthermore, we characterized the cellular and molecular heterogeneity within and across patients through bulk RNA sequencing and single-cell RNA sequencing. ResultsPOD24 occurred in 21% of evaluable FL patients. To further examine the effect of POD24 on OS, we used a 24-month landmark approach for Kaplan-Meier curve analysis. As expected, POD24 was related to poor OS, and the 3- and 5-year survival probabilities of patients in whom the disease progressed within the first 24 months were 89.2% (95% CI, 84.5-93.9) and 78.6% (95% CI, 70.4-86.8), respectively, compared with 98.5% (95% CI, 97.8-99.2) and 96.2% (95% CI, 95.0-97.4) in patients who were progression free at 24 months, respectively. Moreover, patients without progression at 24 months were more likely to exhibit a CR to front-line treatment (54% vs. 35%, P = 0.001) compared to the POD24 cohort. Patients with B symptoms, elevated lactate dehydrogenase and β2-microglobulin levels, unfavorable baseline haemoglobin levels, advanced stage, and high-risk FL International Prognostic Index (FLIPI) scores had an increased risk of POD24, with FLIPI being the most important factor in logistic regression. HIST1H1D, known as a driver mutation, was correlated with POD24. Gains of 6q22.2 ( HIST1H1D) and 18q21.33 ( BCL2) and loss of 1p36.13 ( NBPF1) predicted POD24 independent of FLIPI. Integration of the four variants led to the identification of 76% of POD24 patients. Gene expression profiling of FL samples showed that the POD24 cohort was significantly enriched in the inflammatory response (mediated by interferon and tumor necrosis factor), cell cycle regulation (transcription, replication and proliferation) sets and PI3K-AKT-mTOR signaling. This result was further validated with transcriptome-wide information provided by RNA-seq at single-cell resolution. ConclusionOur study, performed on a large cohort of FL patients, highlights the importance of distinctive genetic alterations and gene expression relevant to disease diagnosis and early progression.

Effectiveness of Ultrasound-guided versus Landmark-based Glucocorticoid Injection in the Treatment of First Carpometacarpal Joint Osteoarthritis

Background: Osteoarthritis is a debilitating degenerative disease more pronounced in elderly affecting many joints. The first carpometacarpal joint (CMC1) is commonly affected. Pain is the major complaint, which can impact patient’s daily activities. Intra-articular glucocorticoid injection can be considered if conservative measures fail and ultrasound guided injection might be superior to the traditional anatomic landmark-guided technique. Objective: The aim of this study is to evaluate the effectiveness of ultrasound-guided versus landmark-based approach to intra-articular CMC1 injection using the Australian Canadian osteoarthritis hand index (AUSCAN). Methods: Adult patients diagnosed with symptomatic CMC1 osteoarthritis who failed conservative measures were enrolled. In this prospective observational cohort study, utilizing a convenience sample, intra-articular corticosteroid injection was administered either by ultrasound-guided technique or landmark-based approach. Pain, stiffness and function in 10-points scale at baseline, 6 and 12 weeks were collected and analyzed using descriptive analysis. Results: There were 33 patients enrolled. Mean age was 63 years, with females making up the majority of participants (n = 28, 84.8%). Mean duration of CMC1 pain was 10 months (SD=2.5) up to the point of receiving the injection. Ultrasound guided injection was performed in 60.6% (n=20), while 39.4% (n=13) had the landmark approach. Both groups achieved a statistically and clinically significant level of change in AUSCAN score at week 6 (P≤ 0.05) but with a recurrence of symptoms at week 12 (P ≤ 0.05). At both intervals the AUSCAN scores were better than baseline (P ≤ 0.05). There was no difference between the two groups regarding baseline pain VAS score (mean ultrasound group= 6.6 vs landmark group= 7.5; P = 0.18). No significant differences were identified between two groups in terms of changes from baseline to 6, 12 and between 6 to 12 weeks in pain, stiffness and hand function (P > 0.05). Conclusion: No difference was found between the ultrasound-guided and landmark-based approaches for CMC1 injection on pain score, stiffness, or function.

A Prospective Cohort Study to Evaluate Needle Passes Using a Portable Ultrasound Device versus Traditional Landmark Approach for Epidural Anesthesia in a Busy Obstetric Tertiary Care Center

Despite its many cited benefits, ultrasound guidance for neuraxial procedures is not widespread in anesthesiology. Some cited limitations include device cost and accessibility. We test the hypothesis that a handheld and relatively inexpensive ultrasound can improve neuraxial proficiency (e.g., decreased needle manipulations and block time). This prospective study compared the number of needle passes, redirections, and procedural time between epidural placed with a handheld ultrasound versus landmarks. Needle passes and attempts were defined as the number of times the Tuhoy needle was redirected, and the times skin was punctured (re-insertion). Procedural time was defined as the time from local anesthetic infiltration until loss of resistance was obtained. The impact of level of training and accuracy of the device were also analyzed. 302 patients receiving labor epidural were included in the study. No difference in body mass index (BMI) nor distribution of level of training was noted between the groups. Regression analysis adjusted for BMI demonstrated a decrease in needle passes (-1.75 (95% CI -2.62, -0.89), p < 0.001), needle attempts (-0.51 (95% CI -0.97, -0.04), p = 0.032) and procedural time (-154.67s 95% CI -303.49s, -5.85s), p = 0.042) when a handheld ultrasound was utilized. The mean (95% Confidence interval) difference between needle depth and ultrasound depth was 0.39 cm (0.32, 0.46), p < 0.001. The use of a handheld device resulted in statistically significant decrease of needle manipulations and block time. More research is needed to evaluate the impact of and increase in accessibility of ultrasound technology.

Abstract 16045: Fluoroless Arterial Access and Closure for VT Ablation: Feasibility and Safety of an Ultrasound Guided Landmark Approach

Introduction: Ultrasound (US) guided access has become the gold standard of care for central access cannulation. The FAUST1 trial demonstrated that routine real-time US guidance was equivalent to fluoroscopic guidance but improved common femoral artery (CFA) access success and reduced complications in patients with high CFA bifurcations. The utilization of non radiation imaging modalities over the past decade has resulted in significantly reduced radiation exposure and orthopedic problems associated with prolonged electrophysiology procedures2. Hypothesis: Why do many operators still use fluoroscopy and arteriograms in addition to ultrasound guided access? Methods: A prospective single center multi-operator study was performed on patients undergoing premature ventricular contractions (PVC) or Ventricular Tachycardia (VT) ablation with arterial access. CFA access was obtained using a US guided landmark identification protocol. US probe is utilized in short and long access to identify upper and lower borders of the femoral head in relation to the CFA bifurcation. CFA access is then obtained with a modified Seldinger approach within femoral head landmarks. After arterial sheath insertion, the artery is again evaluated for closure appropriateness, assessed by absence of arterial calcifications within 5mm of arrteriotomy or stenosis <5mm in diameter. Results: 20 consecutive patients undergoing PVC or PVT ablation were included. All patients underwent US only guided access to the right common femoral artery. All patients underwent successful closure with a hemostasis device. There were no vascular complications. Conclusions: Real-time US only guided CFA access is feasible and safe. Appropriate utilization of US is sufficient to avoid intravenous contrast and radiation exposure without increased complication rate.

Validation of POD24 As a Robust Early Clinical End Point of Poor Survival in Mantle Cell Lymphoma from 1280 Patients on Clinical Trials

Background The prognosis of mantle cell lymphoma (MCL) has largely improved in the past decade; however, the disease is characterized by a heterogeneous clinical course. Several retrospective studies identified early progression of disease (i.e. within two years, POD24) as a potential overall survival (OS) surrogate, but this has not been validated in cohorts of patients prospectively included in clinical trials in rituximab maintenance era. Methods We performed a pooled analysis of French patients with MCL included in six randomized clinical trials (EU-MCL younger NCT00209222, LyMA NCT00921414, LyMA101 NCT02896582, EU-MCL elderly NCT00209209, MCL-R2 NCT01865110 and RiBVD NCT01457144). Survival analysis using Landmark approach evaluated the association of POD24 status with post-event OS for all patients: starting from POD24 event or two years for patients without POD24 event. Logistic regression models were used to evaluate the association between POD24 status and (1) clinico-biological factors at diagnosis; (2) autologous stem cell transplantation at end-of-induction (ASCT) and anti-CD20 maintenance (RM) in responding patients after induction only. Results Among 1386 MCL patients, 106 censored for clinical follow-up before 24 months were excluded from the analysis, leading to 1280 patients evaluable for POD24 status: 299 with a POD24 event and 981 without. The 299 (23%) patients with a POD24 event had a post-event median OS of 9.3 months (95% CI 8.4-11.8) versus not reached in patients without POD24 event (95% CI 97.8-NR). Within the 981 non-POD24 patients, 314 presented a late relapse with a post-relapse median OS of 49.4 months (95% CI 30.4-56.8), significantly longer than OS of POD24 patients (HR=0.39; 95%CI 0.31-0.48; p<0.001). Compared to patients without a POD24 event, POD24 patients were older, had more frequently a performance status >1, elevated LDH and higher leucocytes leading to higher MIPI scores (high-risk MIPI 61% vs. 29%; p<0.001), more frequent blastoid variant (24% vs. 9%; p<0.001) and Ki67 > 30% (45% vs. 23%, p<0.001). Regarding treatment, POD24 patients had less frequently received high-dose cytarabine (21% vs. 39%, p<0.001) as well as ASCT (26% vs. 47%, p<0.001). In a final model, including baseline factors and treatment strategies, induction was not associated with risk of POD24, and only baseline variables (age, performance status, LDH, leucocytes and Ki67>30%) remained significantly associated with POD24 status. Within responding patients only (CR/CRu/PR at end-of-induction, n=1000), 150 had a POD24 event, and ASCT or RM were not significantly associated with POD24 status whereas age, LDH and Ki67>30% remained significant. Conclusion Using this large dataset of patients included in clinical trials, we confirm that POD24 can be used as a surrogate for OS in MCL. ASCT as well as RM have not a clear benefit to prevent early relapse within two years after the diagnosis in responding patients at end-of-induction.

Increased Cardiac Risk After a Second Malignant Neoplasm Among Childhood Cancer Survivors: A FCCSS Study

BackgroundChildhood cancer survivors (CCS) are at an elevated risk of developing both a second malignant neoplasm (SMN) and cardiac disease. ObjectivesThis study sought to assess the excess of occurrence of cardiac disease after a SMN among CCS. MethodsAnalyses included 7,670 CCS from the French Childhood Cancer Survivors Study cohort diagnosed between 1945 and 2000. To account for the time dependence of the occurrence of a SMN, we employed a landmark approach, considering an additive regression model for the cumulative incidence of cardiac disease. We estimated the effect of a SMN on the instantaneous risk of cardiac disease using a proportional cause-specific hazard model, considering a SMN as a time-dependent exposure. In both models, we adjusted for demographic and treatment information and considered death as a competing event. ResultsIn 7,670 CCS over a median follow-up of 30 years (IQR: 22-38 years), there were 378 cases of cardiac disease identified, of which 49 patients experienced a SMN. Patients who survived 25 years after their childhood cancer diagnosis and had a SMN in that time frame had a significantly increased cumulative incidence of cardiac disease, which was 3.8% (95% CI: 0.5% to 7.1%) higher compared with those without a SMN during this period. No SMN-induced excess of cardiac disease was observed at subsequent landmark times. SMNs were associated with a 2-fold increase (cause-specific HR: 2.0; 95% CI: 1.4-2.8) of cardiac disease. ConclusionsThe occurrence of a SMN among CCS is associated with an increased risk of cardiac disease occurrence and risk at younger ages.

How hazardous are hazard ratios? An empirical investigation of individual patient data from 27 large randomized clinical trials.

The use of hazard ratios as the standard treatment effect estimators for randomized trials with time-to-event outcomes has been the subject of repeated criticisms in recent years, e.g., for its non-collapsibility or with respect to (causal) interpretation. Another important issue is the built-in selection bias, which arises when the treatment is effective and when there are unobserved or not included prognostic factors that influence time-to-event. In these cases, the hazard ratio has even been termed "hazardous" because it is estimated from groups that increasingly differ in their (unobserved or omitted) baseline characteristics, yielding biased treatment estimates. We therefore adapt the Landmarking approach to assess the effect of ignoring a gradually increasing proportion of early events on the estimated hazard ratio. We propose an extension called "Dynamic Landmarking". This approach is based on successive deletion of observations, refitting Cox models and balance checking of omitted but observed prognostic factors, to obtain a visualization that can indicate built-in selection bias. In a small proof-of-concept simulation, we show that our approach is valid under the given assumptions. We further use "Dynamic Landmarking" to assess the suspected selection bias in the individual patient data sets of 27 large randomized clinical trials (RCTs). Surprisingly, we find no empirical evidence of selection bias in these RCTs and thus conclude that the supposed bias of the hazard ratio is of little practical relevance in most cases. This is mainly due to treatment effects in RCTs being small and the patient populations being homogeneous, e.g., due to inclusion and exclusion criteria.

Cranial variation between coastal and offshore bottlenose dolphins, Tursiops truncatus (Cetacea: Delphinidae) in Ecuador and the Mediterranean: a three-dimensional geometric morphometric study

Abstract Skull shape analysis provides useful information on wildlife ecology and potential local adaptations. Common bottlenose dolphins (Tursiops truncatus) often differentiate between coastal and offshore populations worldwide, and skull shape analyses can be particularly useful in this context. Here we quantify skull shape variation between coastal populations from the Gulf of Guayaquil (Ecuador) and the Mediterranean Sea, compared to offshore specimens from multiple oceans. We analysed skull shape differences using 3D models from museum specimens through geometric morphometrics (3DGM). Two complementary landmark approaches included single-point semi-landmarks in homologous features, as well as pseudo-landmarks placed automatically. Results show skull shape distinction between both coastal populations and offshore specimens. Offshore specimens showed little differentiation between distinct locations. Skull shape patterns mostly diverged in the shape and length of rostrum, as well as the shape of the ascending processes of the maxilla, pterygoids, and occipital bones. However, both coastal populations differed in the patterns and direction of change of those features and were also morphologically distinct. Our results are consistent with local data on site fidelity and social structure in the coastal populations. Skull shape changes suggest divergent feeding and sound production patterns are potential drivers, probably specific to the local environment of each community.

Comparison of Landmark-Guided Versus Fluoroscopy-Guided Cerebrospinal Fluid Drain-Related Complications After Aortic Repairs

Cerebrospinal fluid drains (CSFDs) are efficacious in preventing spinal cord injury after thoracic or thoracoabdominal aortic repair with extensive coverage. Increasingly, fluoroscopy is used to guide placement instead of the traditional landmark-based approach, but it is unknown which approach is associated with fewer complications. A retrospective cohort study. In the operating room. Patients having undergone thoracic or thoracoabdominal aortic repair with a CSFD over a 7-year period at a single center. No intervention. Groups were reviewed and statistically compared with respect to baseline characteristics, ease of CSFD placement, and major and minor complications directly related to placement. A total of 150 CSFDs were placed with landmark guidance as opposed to 95 with fluoroscopy guidance. Compared to the landmark group, patients with fluoroscopy-guided CSFDs were older (p < 0.008), had lower American Society of Anesthesiologists physical status scores (p=0.008), required fewer CSFD placement attempts (p=0.011), had the CSFD in place for longer duration (p < 0.001), and had a similar incidence of CSFD-related complications (p > 0.999). Composites of both major (4.5% of cases) and minor CSFD-related complications (6.1% of cases), the primary outcomes of the study, occurred with similar incidences between the 2 groups (p > 0.999 for both comparisons) after adjusting potential confounders. In patients undergoing thoracic or thoracoabdominal aortic repairs, there were no significant differences in the risk of major and minor CSFD-related complications between fluoroscopic guidance and the landmark approach. Although the authors' institution is a high-volume center for this type of procedure, the study was limited by a small sample size. Hence, regardless of the technique used for the placement of CSFD, the risks related to the placement should be balanced carefully against the potential benefits resulting from spinal cord injury prevention. Fluoroscopy-aided insertion of CSFD requires fewer attempts and, hence, may be better tolerated by patients.

Analysis of Real‐World Treatment Patterns and Outcomes Among Patients With Relapsed/Refractory Follicular Lymphoma Including POD24 Patients

Introduction: Although follicular lymphoma (FL) is an indolent disease, there is much heterogeneity in outcomes. Patients with early relapsed disease within 24 months (POD24) have been reported to be a poor prognostic subgroup, although this finding has not been confirmed in several recent real-world studies. This study describes treatment patterns, prognostic factors, and outcomes in patients with relapsed/refractory (R/R) FL, including those who progress through multiple lines of therapy (LOTs). Methods: This study was conducted using the COTA database, which is comprised of electronic health records drawn from academic centers (50%) and community practices (50%) in the US. Patients included in this study had a confirmed diagnosis of FL (index date) between 1 January 1990 and 31 December 2022, were ≥18 y of age at index date, were administered treatment for FL, and were followed >3 months after first-line (L) treatment initiation. The utilization of novel treatment options was captured progressively throughout the study period. Patients who progressed from 1L chemoimmunotherapy (CIT) within 24 months were identified as POD24 patients. A landmark approach was taken to assess the overall survival (OS) of the POD24 patients who had at least 24 months of follow-up from 1L CIT versus non-POD24 patients as described in previous studies (Casulo et al., Blood 2022). Patient demographics, treatment patterns, and OS were also assessed by LOT. Results: Overall, 3568 FL patients met inclusion criteria. Among these, 2465 received 1L CIT, with 459 (18.6%) identified as POD24. Of these POD24 patients, 264 had ≥24 months of follow-up from 1L CIT and were included in the landmark analysis. This sub-group of POD24 patients had a median age of 64 y at diagnosis and 86.6% had stage III/IV disease. Non-POD24 patients (n = 2006) had a median age of 61 y at diagnosis and 81.4% had stage III/IV disease. POD24 patients had worse OS (hazard ratio [HR] 2.24; 95% confidence interval [CI] 1.79, 2.80) versus non-POD24 patients. Of the 3568 1L FL patients, 862 continued to 2L, 328 continued to 3L, 146 continued to 4L, and 59 continued to 5L+ treatment. Across all LOTs, the most common therapy was rituximab or obinutuzumab + chemotherapy. The utilization of novel treatments (ie, kinase inhibitors, CAR T-cell therapy, tazemetostat) increased through LOTs, with 6.4% utilization at 3L, 9.6% at 4L, and 20.7% at 5L. Patients who progressed through successive LOTs experienced worsening OS (Figure 1). The research was funded by: This study was funded by Genmab A/S and AbbVie Inc. Keywords: Cancer Health Disparities, Late Effects in Lymphoma Survivors Conflicts of interests pertinent to the abstract. L. H. Sehn Consultant or advisory role: AbbVie, Bayer, BeiGene, BMS/Celgene, Epizyme, Genentech/Roche, Genmab, Incyte, Janssen, Kite/Gilead, Loxo, Miltenyi, MorphoSys, Novartis, Rapt, Regeneron, Takeda A. Wang Employment or leadership position: AbbVie Stock ownership: AbbVie J. Yu Employment or leadership position: AbbVie R. Kamalakar Employment or leadership position: AbbVie K. Sail Employment or leadership position: AbbVie Stock ownership: AbbVie W. Sinai Employment or leadership position: AbbVie Stock ownership: AbbVie D. Arnette Employment or leadership position: AbbVie S. Yang Employment or leadership position: Genmab A. Mutebi Employment or leadership position: Genmab Stock ownership: Genmab F. R. Navarro Employment or leadership position: Genmab G. Salles Consultant or advisory role: AbbVie, Bayer, BeiGene, BMS/Celgene, Epizyme, Genentech/Roche, Genmab, Incyte, Janssen, Kite/Gilead, Loxo, Miltenyi, MorphoSys, Novartis, Rapt, Regeneron, Takeda

Association of ctDNA tumor fraction with survival in advanced non-small cell lung cancer (NSCLC) treated with maintenance durvalumab in the UNICANCER SAFIR02-Lung/IFCT1301 trial.

2516 Background: ctDNA shed is a promising biomarker for cancer immunotherapy, with patients (pts) having higher concentration of plasma ctDNA being reported to have poorer outcome. Its role in the maintenance setting with immune checkpoint inhibitors remains unexplored. In SAFIR02-Lung, advanced NSCLC pts were enrolled to receive a platinum-based chemotherapy. After 4 cycles, if stable or in response, pts with no targetable alterations were oriented to the immunotherapy sub-study and randomized between maintenance durvalumab or Standard of Care (SoC) (PMID 35802649). Durvalumab prolonged survival only in the PD-L1 ≥ 1% subgroup. Here we explored Tumor Fraction (TF) as determined by Low-Pass Whole Genome Sequencing as a biomarker for immunotherapy irrespective of PD-L1. Methods: SAFIR02-Lung (NCT02117167) is a multicentric, randomized phase 2 clinical trial. Plasma samples were obtained at randomization, just before maintenance treatment initiation. DNA was extracted using the Maxwell RSC ccfDNA Plasma Kit (Promega, AS1840). Sequencing libraries were prepared using the Low Input SureSelectXT protocol (Agilent, G9916A). Pooled libraries were sequenced on a NovaSeq 6000 platform (Illumina) as 2 × 150 bp paired-end reads (NovaSeq 6000 SP Reagent Kit v1.5). Genomic copy number aberrations and TF were investigated using the ichorCNA (V0.2.0) tool. TF ≥ 2% was considered positive. For the survival analyses, a landmark approach was performed, by considering the randomization date as the landmark time. Progression Free Survival (PFS) was the primary endpoint, defined as the time from randomization until the date of objective radiological disease progression, clinical progression or death. The secondary endpoint was Overall Survival (OS). Results: 50 out of 121 plasma samples from pts randomized to durvalumab were analyzed for the feasibility part. 34 pts (68%) were &lt; 65 years, 33 (66%) were male. PD-L1 expression was available for 18 pts and 39% of them had PD-L1 ≥ 1%. Median TF was 1.1%, 8 pts (16%) had a TF ≥ 2%, ranging from 2.2% to 23.3%. TF at randomization was marginally correlated with the presence of liver metastases (p 0.063) and with the sum of target lesions (p 0.081). No significant correlation was observed with PD-L1 positivity. Pts with TF ≥ 2% had lower median PFS 1.7months (m) (95% CI 1.2 – 4.2) vs 5.8m (95% CI 2.9 – 7.5) for those with TF &lt; 2%, p 0.0003. Similarly, median OS was lower for pts with TF &gt; 2% 10.4m (95% CI 4.2 – 18.7) vs 25.9m (95% CI 18.2 – NR) for those with TF &lt; 2%, p 0.0002. Data will be presented on the whole cohort, including control group receiving SoC, to discriminate between a prognostic or a predictive value of TF. Conclusions: TF was positive in 16% of pts randomized to durvalumab in the SAFIR02-Lung trial. This population seems to have a limited benefit from maintenance durvalumab after induction chemotherapy. Clinical trial information: NCT02117167 .

MOOD PLAYER: EMOTION BASED MUSICRECOMMENDATION SYSTEM

Music can create, change and lighten one’s mood, and when technologies of artificial intelligence meet with music it can be a great combination. Selecting appropriate songs according to our emotion from such a wide range is a very tedious and timeconsuming task. It takes a lot of time and effort to manually group songs on a playlist and annotate them according to the user’s emotional condition at the moment. To automate this process, many algorithms have been proposed. However, the current algorithms are inefficient, use more hardware, which raises the system’s overall cost, and are less accurate. This paper aims at recognition of human facial expressions through a model based on 68 landmarks approach of the training dataset, further selecting the appropriate playlist for the user. The Emotion Based Music Recommendation System has the potential to enhance the music listening experience by providing users with music that not only matches their preferences but also their emotional state, thereby increasinguser engagement and satisfaction.

Dynamic effects of prognostic factors and individual survival prediction for amyotrophic lateral sclerosis disease.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons, with broad heterogeneity in disease progression and survival in different patients. Therefore, an accurate prediction model will be crucial to implement timely interventions and prolong patient survival time. A total of 1260 ALS patients from the PRO-ACT database were included in the analysis. Their demographics, clinical variables, and death reports were included. We constructed an ALS dynamic Cox model through the landmarking approach. The predictive performance of the model at different landmark time points was evaluated by calculating the area under the curve (AUC) and Brier score. Three baseline covariates and seven time-dependent covariates were selected to construct the ALS dynamic Cox model. For better prognostic analysis, this model identified dynamic effects of treatment, albumin, creatinine, calcium, hematocrit, and hemoglobin. Its prediction performance (at all landmark time points, AUC ≥ 0.70 and Brier score ≤ 0.12) was better than that of the traditional Cox model, and it predicted the dynamic 6-month survival probability according to the longitudinal information of individual patients. We developed an ALS dynamic Cox model with ALS longitudinal clinical trial datasets as the inputs. This model can not only capture the dynamic prognostic effect of both baseline and longitudinal covariates but also make individual survival predictions in real time, which are valuable for improving the prognosis of ALS patients and providing a reference for clinicians to make clinical decisions.

Construction of Soft Prep Cadaver Pericardiocentesis Training Model and Implementation Among Emergency Medicine Residents.

This procedure training model is designed for all levels of emergency medicine residents. Pericardiocentesis is a relatively uncommon but potentially life-saving procedure within the scope of Emergency Medicine practice. As such, the Accreditation Council for Graduate Medical Education (ACGME) designates its competency as a requirement within emergency medicine residency programs. Because of its relative rarity, simulation-based training is often utilized to fill the gaps in clinical experience during emergency medicine residency training. There have been several models of pericardiocentesis training, including gel-based models that can be purchased or constructed,1-3 non-gel models,4 and cadaveric models.5 In this paper, we describe the fabrication of a high-fidelity cadaveric model and report emergency medicine resident experience with this model. Training programs can use this model to increase trainee competence and confidence with this high-acuity, low-frequency procedure. By the end of this session, residents will gain increased procedural competence and confidence with pericardiocentesis. Residents will be able to identify necessary supplies for the procedure, identify relevant surface anatomy and ultrasound views, and successfully aspirate fluid from model effusion. We created a pericardial effusion in a soft prep cadaver by placing a catheter into the pericardial sac and then infusing normal saline via intravenous fluid tubing. Learners were then able to practice aspiration of pericardial fluid via landmark and ultrasound-guided approaches under observation by facilitators able to offer real-time feedback. Learners were asked to complete a survey assessing pre-intervention and post-intervention subjective confidence in their ability to perform pericardiocentesis and were asked for qualitative feedback on the experience of using the training model. All residents were able to successfully visualize the pericardial effusion and perform needle aspiration via parasternal and subxiphoid approaches under dynamic ultrasound guidance, allowing needle visualization. All residents reported a subjective increase in procedural confidence and competence after practicing with this training model. Overall, the primary benefit of this training model cited by emergency medicine residents was that it closely approximates reality. This model is re-usable, relatively durable, and reproducible. Emergency medicine residencies associated with academic medical centers that already utilize cadavers for education may relatively easily incorporate this training model into their procedure training curriculum. Pericardiocentesis, simulation, task trainer.

An efficient landmark model for prediction of suicide attempts in multiple clinical settings

Growing evidence has shown that applying machine learning models to large clinical data sources may exceed clinician performance in suicide risk stratification. However, many existing prediction models either suffer from “temporal bias” (a bias that stems from using case-control sampling) or require training on all available patient visit data. Here, we adopt a “landmark model” framework that aligns with clinical practice for prediction of suicide-related behaviors (SRBs) using a large electronic health record database. Using the landmark approach, we developed models for SRB prediction (regularized Cox regression and random survival forest) that establish a time-point (e.g., clinical visit) from which predictions are made over user-specified prediction windows using historical information up to that point. We applied this approach to cohorts from three clinical settings: general outpatient, psychiatric emergency department, and psychiatric inpatients, for varying prediction windows and lengths of historical data. Models achieved high discriminative performance (area under the Receiver Operating Characteristic curve 0.74–0.93 for the Cox model) across different prediction windows and settings, even with relatively short periods of historical data. In short, we developed accurate, dynamic SRB risk prediction models with the landmark approach that reduce bias and enhance the reliability and portability of suicide risk prediction models.

Real-Time Ultrasound Guidance as Compared With Landmark Technique for Subclavian Central Venous Cannulation: A Systematic Review and Meta-Analysis With Trial Sequential Analysis.

We conducted a systematic review and meta-analysis to assess the effectiveness of real-time dynamic ultrasound-guided subclavian vein cannulation as compared to landmark technique in adult patients. PubMed and EMBASE until June 1, 2022, with the EMBASE search restricted to the last 5 years. We included randomized controlled trials (RCTs) comparing the two techniques (real-time ultrasound-guided vs landmark) for subclavian vein cannulation. The primary outcomes were overall success rate and complication rate, whereas secondary outcomes included success at first attempt, number of attempts, and access time. Independent extraction by two authors according to prespecified criteria. After screening, six RCTs were included. Two further RCTs using a static ultrasound-guided approach and one prospective study were included in the sensitivity analyses. The results are presented in the form of risk ratio (RR) or mean difference (MD) with 95% CI. Real-time ultrasound guidance increased the overall success rate for subclavian vein cannulation as compared to landmark technique (RR = 1.14; [95% CI 1.06-1.23]; p = 0.0007; I2 = 55%; low certainty) and complication rates (RR = 0.32; [95% CI 0.22-0.47]; p < 0.00001; I2 = 0%; low certainty). Furthermore, ultrasound guidance increased the success rate at first attempt (RR = 1.32; [95% CI 1.14-1.54]; p = 0.0003; I2 = 0%; low certainty), reduced the total number of attempts (MD = -0.45 [95% CI -0.57 to -0.34]; p < 0.00001; I2 = 0%; low certainty), and access time (MD = -10.14 s; [95% CI -17.34 to -2.94]; p = 0.006; I2 = 77%; low certainty). The Trial Sequential Analyses on the investigated outcomes showed that the results were robust. The evidence for all outcomes was considered to be of low certainty. Real-time ultrasound-guided subclavian vein cannulation is safer and more efficient than a landmark approach. The findings seem robust although the evidence of low certainty.

The Journal of Urology® Home Study Course 2023 Volume 209/210.

The Journal of Urology® Home Study Course 2023 Volume 209/210.

An automated landmark method to describe geometric changes in the human mandible during growth

ObjectiveThe principal aim of this study was to assess an automatic landmarking approach to human mandibles based on the atlas method. The secondary aim was to identify the areas of greatest variation in the mandibles of middle-aged to older adults. DesignOur sample consisted of 160 mandibles from computed tomography scans of 80 men and 80 women aged between 40 and 79 years. Eleven anatomical landmarks were placed manually on mandibles. The automated landmarking through point cloud alignment and correspondence (ALPACA) method implemented in 3D Slicer was used to automatically place landmarks to all meshes. Euclidean distances, normalized centroid size, and Procrustes ANOVA were calculated for both methods. A pseudo-landmarks approach was followed using ALPACA to identify areas of changes among our sample. ResultsThe ALPACA method showed significant differences in Euclidean distances for all landmarks compared to the manual method. A mean Euclidean distance of 1.7 mm was found for the ALPACA method and 0.99 mm for the manual method. Both methods found that sex, age, and size had a significant effect on mandibular shape. The greatest variations were observed in the condyle, ramus, and symphysis regions. ConclusionThe results obtained using the ALPACA method are acceptable and promising. This approach can automatically place landmarks with an average accuracy of less than 2 mm, which may be sufficient in most anthropometric analyses. In the light of our results, however, odontological application such as occlusal analysis is not recommended.