Inferior Patient Outcomes Research Articles

The impact of mental health disorders on outcomes following total ankle arthroplasty: A systematic review.

The purpose of this systematic review was to evaluate the impact of mental health disorders (MHDs) on the clinical and functional outcomes following total ankle arthroplasty (TAA) for the treatment of end-stage ankle arthritis. A systematic review of the EMBASE, MEDLINE, and Cochrane Library databases was conducted in April 2024 following PRISMA guidelines. Data collected included patient demographics, clinical outcomes, complications, and failures. Six studies published between 2019 and 2023 were included, involving a total of 8772 patients who underwent TAA. Among these, 1076 patients (12.3 %) had a pre-operative MHD. The weighted mean age was 64.1 ± 4.9 years, and the mean postoperative follow-up was 4.6 ± 7.2 months. There were inferior subjective clinical outcomes in patients with an associated MHD, as demonstrated by lower scores in the Self-Administered Foot Evaluation Questionnaire (SAFE-Q), Visual Analogue Scale (VAS), and American Orthopaedic Foot and Ankle Society (AOFAS) scores compared to patients without a MHD. Additionally, patients with MHDs had high complication rates (23.7 %), including 76 prosthetic complications (6.1 %) and 15 cases (1.2 %) requiring revision procedures. However, no significant differences in objective outcomes such as joint mobility or implant failure rates were found between those with and without MHDs. MHDs adversely affect subjective outcomes and complications following TAA, highlighting the need for integrated mental health management in preoperative and postoperative care. Further research is needed to understand the precise role of mental health in TAA outcomes.

Low-Frequency PPM1D Gene Mutations Associated with Inferior Treatment Response to CD19 Targeted CAR-T Cell Therapy in Mantle Cell Lymphoma

Background/Objectives: Mantle cell lymphoma (MCL) represents a rare B-cell lymphoma subtype with rather high relapse rates. Somatic mutations in the PPM1D gene were shown to be associated with adverse outcomes in patients with diffuse large B-cell lymphoma (DLBCL) who received CD19 CAR-T-cell therapy with tisa-cel, which may also apply to mantle cell lymphoma receiving brexu-cel CAR-T-cells. Methods: In this study, we determined the prevalence of PPM1D mutations in peripheral blood cells of MCL patients before CAR-T-cell infusion and analyzed the impact of low-frequency PPM1D mutations on efficacy and safety aspects of brexu-cel CAR-T-cell treatment in the first 16 r/r MCL patients enrolled at Inselspital Bern. Results: The prevalence of low-frequency PPM1D gene mutations was 25%, with variant allele frequencies (VAF) of 0.011 to 0.099. Clinical response was analyzed in the PPM1D mutated (PPM1Dmut) vs. PPM1D wild-type (PPM1Dwt) groups with median progression-free survival of 1 versus 32 months (p = 0.07) and median overall survival of 1.5 vs. 27 months (p = 0.001). Conclusions: Our data suggest that low-frequency PPM1D gene mutations in peripheral blood cells may predict inferior outcomes in patients with mantle cell lymphoma treated with CAR-T-cell therapy.

Inferior short-term survivorship and patient outcomes for cementless compared to hybrid fixation with a cemented femoral implant in a novel blade-anchored medial unicompartmental knee arthroplasty design: An analysis of 132 cases

PurposeFor younger, more active patients, a cementless unicompartmental knee arthroplasty (UKA) might be more advantageous than cemented fixation. Therefore, this study aimed to compare implant survivorship and patient-reported outcome measures (PROMs) between cementless and hybrid fixation (cemented femur and cementless tibial fixation) in a novel tibial blade-anchored, medial UKA design. MethodsTwo surgeon’s registries were reviewed for patients who underwent primary cementless or hybrid medial UKA for medial osteoarthritis between 2019 and 2022. Patients were included if implant survivorship and one-year postoperative PROMs (UCLA-activity score, Oxford Knee Score (OKS), Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS-JR), pain (VAS) and satisfaction) were registered. Variables were compared using independent two-sample t-tests or the Chi-square test. Survival rates were determined using the Kaplan-Meier models and compared using the Log-rank test. ResultsA total of 132 knees were included (cementless 58.3%; cemented 41.7%; mean follow-up 3.1 ± 0.6 years). Three-year all-cause revision survival rate was significantly superior for the hybrid fixation (hybrid: 100%; cementless 88.5%[84.7%–92.3%], p = 0.026). However, the difference in three-year conversion rate to total knee arthroplasty (TKA) did not reach statistical significance. The one-year postoperative OKS (hybrid: 42.9 ± 4.8; cementless: 39.8 ± 6.4, p = 0.003) and KOOS-JR (hybrid:81.5 ± 13.7; cementless: 74.4 ± 12.1, p = 0.002) were significantly superior for the hybrid fixation. Three-year conversion rate to TKA and two-year postoperative PROMs did not significantly differ. ConclusionThe cementless medial UKA demonstrated a significantly inferior short-term all-cause survival rate and inferior postoperative one-year OKS and KOOS-JR compared to the hybrid medial UKA design with a cemented femoral component.

GPR68 supports AML cells through the calcium/calcineurin pro-survival pathway and confers chemoresistance by mediating glucose metabolic symbiosis

Accumulating evidence demonstrates that the “Warburg effect” that glycolysis is enhanced even in the presence of oxygen existed in hematopoietic malignancies, contributing to extracellular acidosis. G-protein coupled receptor 68 (GPR68), as a proton sensing GPCR responding to extracellular acidosis, is expected to play a critical role in hematopoietic malignancies. In the present study, we found that GPR68 was overexpressed in acute myeloid leukemia (AML) cells, and GPR68 deficiency impaired AML cell survival in vitro and cell engraftment in vivo. Mechanistic studies revealed that unlike GPR68 regulates Calpain1 in myelodysplastic syndromes (MDS) cells, GPR68 deficiency reduced cytosolic Ca2+ levels and calcineurin (CaN) activity in AML cells through an NFAT-independent mechanism. Moreover, the decreased Ca2+ levels disturbed cellular respiration (i.e., oxidative phosphorylation, OxPhos) by inhibiting isocitrate dehydrogenase (IDH) activity; this was more pronounced when BCL2 was inhibited simultaneously. Interestingly, GPR68 inhibition also decreased aerobic glycolysis in AML cells in a Ca2+-independent manner, suggesting that GPR68 mediated glucose metabolic symbiosis. As glucose metabolic symbiosis and the heterogeneous dependencies on aerobic glycolysis and cellular respiration tremendously impact chemosensitivity, the inhibition of GPR68 potentiated the tumoricidal effect of first-line chemotherapeutic agents, including BCL-2 inhibitors targeting OxPhos and cytarabine (Ara-C) targeting glycolysis. Consistent with these in vitro observations, higher levels of GPR68 were associated with inferior clinical outcomes in AML patients who received chemotherapies. In short, GPR68 drives the Ca2+/CaN pro-survival pathway and mediates glucose metabolic pathways in AML cells. Targeting GPR68 eradicates AML cells and alleviates chemoresistance, which could be exploited as a therapeutic target.

Myelodysplasia-Related Mutations in Adults and End-of-Induction Measurable Residual Disease Are Associated with Inferior Outcome in Patients with Acute Leukemia of Ambiguous Lineage

Myelodysplasia-Related Mutations in Adults and End-of-Induction Measurable Residual Disease Are Associated with Inferior Outcome in Patients with Acute Leukemia of Ambiguous Lineage

Inferior Clinical Outcomes Following Endoscopic Proximal Hamstring Repair in Patients with Chronic Degenerative Tears Despite the use of Dermal Allograft Augmentation

PurposeTo compare clinical outcomes in patients undergoing endoscopic proximal hamstring repair with and without dermal allograft augmentation. MethodsA retrospective review of prospectively collected data was performed on patients undergoing endoscopic proximal hamstring repair (PHR) and proximal hamstring repair with dermal allograft augmentation (PHR-A) by a single surgeon between 2016 and 2023. Augmentation was utilized for cases of chronic degenerative tears (> 6 weeks from the time of initial injury) where hamstring tissue quality was deemed poor intraoperatively. A survey of patient-reported outcome measures (PROMs) was completed at a minimum of 1 year postoperatively. PROMs included a Visual Analogue Scale (VAS) for pain; University of California, Los Angeles (UCLA) Activity Scale; modified Harris Hip Score (mHHS); Hip Outcome Score-Sports-Specific Subscale (HOS-SSS); and a Single Assessment Numeric Evaluation (SANE). The proportion of patients achieving the minimal clinically important difference (MCID), patient acceptable symptom state (PASS), and substantial clinical benefit (SCB) for PROMs were compared between groups. ResultsSixty-four patients were included (42 PHR, 22 PHR-A). No differences were seen between the PHR and PHR-A groups in terms of age at surgery (49 ± 12 vs. 54 ± 9, p=0.08), sex, or body-mass index (BMI). There was a significantly longer time to follow-up (41.5±23.4 vs. 20.1±10.2 months, p<0.001) in the PHR group. There were significantly greater postoperative mHHS (82.7±15.1 vs. 72.0±18.0, p=0.02) and SANE (89.6±9.9 vs. 73.6±22.5, p=0.002) scores in the PHR group. There were no significant differences in postoperative VAS, UCLA, or HOS-SSS between groups. A greater proportion of patients in the PHR group achieved a SCB for mHHS (71% vs. 36%, p=0.008). ConclusionsOur study demonstrates inferior clinical outcomes in patients undergoing endoscopic proximal hamstring repair with dermal allograft augmentation compared to patients undergoing endoscopic proximal hamstring repair without augmentation. Level of EvidenceIII, retrospective comparative case series

Does performing cardiac surgery after hours impact postoperative outcomes? A systematic review and meta-analysis.

There has been concern regarding the safety of cardiac surgical intervention during off-hours. Sleep deprivation, resource limitations, and an increased case urgency have been postulated to increase off-hours surgical risk, although outcomes are inconsistent in the existing literature. In this systematic review and meta-analysis, we review the literature comparing patients undergoing cardiac surgery during on and off-hours. PubMed and Embase were systematically searched for literature published from January 2000-September 2023, comparing outcomes of patients undergoing cardiac surgery during on and off-hours. Overall, 3540 manuscript titles and abstracts were screened and 11 articles were included. Overall aggregate analysis indicated no significant differences in rates of in-hospital mortality(OR 1.04; 95% CI, 0.41-2.63; P=0.93) and perioperative morbidity, including stroke (P=0.52), reoperation (P=0.92), major bleeding (P=0.10), and renal complications (P=0.55). Composite rates of sternal wound infection favored on-hours surgery (P=0.01). Although inferior outcomes in patients undergoing cardiac surgery during off-hours have been noted, aggregate analysis largely revealed equivalent perioperative morbidity and mortality during on and off-hours surgery, although with the exclusion of one outlier study in-hospital mortality and reoperation favored on-hours surgery. Heterogeneity in outcomes is likely multifactorial, with surgical staff fatigue, patient preoperative risk, clinical setting, and resource limitations all contributing. Further investigation is required directly comparing emergent cardiac surgical intervention during on-hours and off-hours controlling for baseline surgical risk to elucidate the true impact of timing of surgery on postoperative outcomes.

Comparing oncological outcomes of robotic versus open surgery in the treatment of endometrial cancer.

Robotic surgery has been incorporated in the treatment of endometrial cancer, with evidence suggesting that minimal access surgery offers advantages over laparotomy including less blood loss, lower rate of perioperative complications, and accelerated postoperative recovery. The laparoscopic approach to cervical cancer (LACC) study has recently demonstrated inferior survival outcomes in cervical cancer patients treated with minimal access surgery including robotic surgery. It is, therefore, imperative that further evaluation of the latter in endometrial cancer is performed. A retrospective analysis of clinical data was performed. We compared two different types of surgery performed for the treatment of FIGO stage 1 to 3 endometrial cancer; open surgery performed in the years 2013-2015 vs robotic surgery performed in 2017-2019, after the implementation of the robotic program in our institution. Main outcome measures were recurrence-free survival and overall survival, with secondary outcomes including surgical morbidity and postoperative recovery. We compared 123 patients who had open surgery with 104 patients who underwent robotic surgery. One case from the second group was converted to open surgery due to the inability to complete it robotically. After a median follow-up of 68months, there was no difference in recurrence-free survival or overall survival between the two groups. Length of stay after an operation was significantly different with mean hospital stay of 1.6days after robotic surgery and 5days after open surgery (p = 0.001). No significant difference was identified in the rate of complications (p = 0.304). Our analysis has demonstrated that robotic surgery offers better perioperative outcomes without compromising the oncological safety.

Multidisciplinary Team Discussions and the Inclusion of Individualized Patient Factors May Improve Informed Consent in Sports Medicine

Informed consent allows for the maintenance of patient autonomy and is essential in establishing trusting relationships between physicians and their patients. This process involves thorough discussion of the risks and alternatives, as well as the short- and long-term outcomes, of proposed treatment options. Inadequacies with informed consent can lead to inferior patient outcomes and may be subject to severe legal consequences. Individualized discussions are warranted to address the questions of these patients, whether it be the high-level athlete or the weekend warrior. This review highlights factors, identifies barriers, and proposes potential solutions to improve informed consent within orthopaedic sports medicine.

Genomic correlates of the response to first-line PD-1 blockade plus chemotherapy in patients with advanced non-small-cell lung cancer.

Programmed death 1 (PD-1) blockade plus chemotherapy has become the new first-line standard of care for patients with advanced non-small-cell lung cancer (NSCLC). Yet not all NSCLC patients benefit from this regimen. This study aimed to investigate the predictors of PD-1 blockade plus chemotherapy in untreated advanced NSCLC. We integrated clinical, genomic, and survival data from 287 patients with untreated advanced NSCLC who were enrolled in one of five registered phase 3 trials and received PD-1 blockade plus chemotherapy or chemotherapy alone. We randomly assigned these patients into a discovery cohort (n=125), a validation cohort (n=82), and a control cohort (n=80). The candidate genes that could predict the response to PD-1 blockade plus chemotherapy were identified using data from the discovery cohort and their predictive values were then evaluated in the three cohorts. Immune deconvolution was conducted using transcriptome data of 1014 NSCLC patients from The Cancer Genome Atlas dataset. A genomic variation signature, in which one or more of the 15 candidate genes were altered, was correlated with significantly inferior response rates and survival outcomes in patients treated with first-line PD-1 blockade plus chemotherapy in both discovery and validation cohorts. Its predictive value held in multivariate analyses when adjusted for baseline parameters, programmed cell death ligand 1 (PD-L1) expression level, and tumor mutation burden. Moreover, applying both the 15-gene panel and PD-L1 expression level produced better performance than either alone in predicting benefit from this treatment combination. Immune landscape analyses revealed that tumors with one or more variation in the 15-gene panel were associated with few immune infiltrates, indicating an immune-desert tumor microenvironment. These findings indicate that a 15-gene panel can serve as a negative prediction biomarker for first-line PD-1 blockade plus chemotherapy in patients with advanced NSCLC.

Transcriptional Phenocopies of Deleterious KEAP1 Mutations Correlate with Survival Outcomes in Lung Cancer Treated with Immunotherapy.

Co-occurring mutations in KEAP1 and STK11/KRAS have emerged as determinants of survival outcomes in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy. However, these mutational contexts identify a fraction of nonresponders to immune checkpoint inhibitors. We hypothesized that KEAP1 wild-type tumors recapitulate the transcriptional footprint of KEAP1 mutations and that this KEAPness phenotype can determine immune responsiveness with higher precision compared to mutation-based models. The Cancer Genome Atlas was used to infer the KEAPness phenotype and explore its immunological correlates at the pan-cancer level. The association between KEAPness and survival outcomes was tested in two independent cohorts of patients with advanced NSCLC treated with immunotherapy and profiled by RNA sequencing (SU2C n = 153; OAK/POPLAR n = 439). The NSCLC TRACERx421 multiregion sequencing study (tumor regions, n = 947) was used to investigate evolutionary trajectories. KEAPness-dominant tumors represented 50% of all NSCLCs and were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAPness-free cases in independent cohorts of patients with NSCLC treated with immunotherapy (SU2C PFS P = 0.042, OS P = 0.008; OAK/POPLAR PFS P = 0.0014, OS P < 0.001). Patients with KEAPness tumors had survival outcomes comparable to those with KEAP1-mutant tumors. In the TRACERx421, KEAPness exhibited limited transcriptional intratumoral heterogeneity and immune exclusion, resembling the KEAP1-mutant disease. This phenotypic state occurred across genetically divergent tumors, exhibiting shared and private cancer genes under positive selection when compared to KEAP1-mutant tumors. We identified a KEAPness phenotype across evolutionary divergent tumors. KEAPness outperforms mutation-based classifiers as a biomarker of inferior survival outcomes in patients with NSCLC treated with immunotherapy.

GCT-07. CONTRIBUTORS TO DELAYED TREATMENT OF NON-GERMINOMATOUS GERM CELL TUMORS IN CHINA: A TERTIARY-CENTER REVIEW

Abstract BACKGROUND Non-Germinomatous Germ Cell Tumors (NGGCT) are rare malignancies with potential for treatment delays. This study aims to identify risk factors and systemic challenges contributing to delayed management of NGGCT in China. METHODS We reviewed the clinical features and referral pattern of 56 consecutively diagnosed NGGCT patients at Shanghai Children’s Medical Center (SCMC) from 9/2018-2/2023. Patients were diagnosed by pathology (n=42), or by elevated markers alone (n=14, AFP&amp;gt;10ng/ml, and/or β-HCG&amp;gt;50mIU/ml). Patients were treated per COG ACNS0122. Delay of treatment was defined as chemotherapy initiated more than 6 months after symptom onset. RESULTS Forty-three males and 13 females were included. Median age at diagnosis was 9.17year (4month-16year). Primary tumor locations included the pineal region (n=31), sellar region (n=19), basal ganglia (n=5), and posterior fossa (n=1). Presenting symptoms included features of increased intracranial pressure (ICP, n=29), endocrine symptoms (n=21), blurred vision or squint (n=7), and hemiplegia (n=4). Delayed treatment occurred in 16 cases (29%), and was more likely in patients with non-pineal region primary (Chi-square p=0.003), and absence of symptoms pertaining to increased ICP (Chi-square p&amp;lt;0.001). Reasons for delay included lack of parental recognition on symptoms (n=7), misdiagnosis (n=3), and inappropriate/incomplete workup (n=6). As a national referral center, patients commuted a median of 483 km (range: 12-2943km) to SCMC (median 2 hospitals (1,5) before SCMC), including 10 patients with obvious hydrocephalus travelling before any CSF diversion procedure. Three-year Event-Free Survival (EFS) was 76.9% and Overall Survival was 86.0%. There was a trend to inferior outcome in patients with delay in treatment (3y EFS 69.6%) compared with those without (3year EFS 80.6%, p=0.112). CONCLUSIONS Delay in treatment is common for children with NGGCT managed at a tertiary referral center in China. Improving public awareness, training for primary-care clinicians, and establishing a national referral network are potential strategies to enhancing the outcome.

Association of elevated ctDNA burden following one cycle of chemotherapy with inferior outcomes for patients with metastatic Ewing sarcoma: A report from the Children’s Oncology Group (COG).

10018 Background: All patients with Ewing sarcoma (EWS) currently receive the same intensive chemotherapy and novel risk-adapted approaches to therapy are needed. We have previously shown that elevated baseline ctDNA burden is prognostic among patients with EWS. Here we investigate the prognostic impact of on-treatment ctDNA burden in patients with metastatic EWS treated on COG AEWS1221. Methods: AEWS1221 was a randomized phase 3 trial evaluating ganitumab plus interval compressed chemotherapy (vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide given every 2 weeks) for patients with newly diagnosed metastatic EWS. We evaluated 680 serial blood samples and data from 273 patients enrolled to AEWS1221. We utilized a custom NGS hybrid-capture assay for ctDNA quantification that detects EWSR1 and FUSfusions. We used log rank tests to compare event-free survival (EFS) from the designated timepoint according to ctDNA burden post cycle 1 of VDC (planned day 14) and post cycle 2 VDC+IE (planned day 28) of chemotherapy. We dichotomized patients by ≥0.5% ctDNA at each timepoint. A P-value of ≤0.05 was considered evidence of a significant association. Results: Of 298 eligible patients with metastatic EWS, 273 provided blood samples for ctDNA analysis. Three patients had non-FET-ETS family fusions ( CIC::DUX4, EWSR1::WT1 and EWSR1::GTDC1) and were excluded from further analysis. Eighty-five percent of patients were &lt; 21, 56% were male, 33% had pelvic bone primary tumors, and 40% had lung only metastatic disease. ctDNA was ≥0.5% in 86% of patients at baseline (median 25%, range 0-113%, n = 264), in 53% (median 0.53%, range 0-15%, n = 34) after 1 cycle (median day 14, range 11-20), and in 14% (median 0, range 0-53%, n = 130) after 2 cycles (median day 29, range 25-36). Baseline ctDNA burden ≥0.5% was associated with an increased risk of EFS-event (3-year EFS 35% [95% CI 29-41%] vs. 61% [95% CI 43-76%], HR = 2.2, P= 0.002). ctDNA ≥0.5% after cycle 1 was also associated with an increased risk of EFS-event (3-year EFS 6% [95% CI 0.4-22%] vs. 56% [95% CI 29-76%], HR = 6.0, P&lt; 0.0001). ctDNA ≥0.5% after cycle 2 was not associated with an increased risk of EFS-event (28% [95% CI 10-49%] vs. 34% [95% CI 25-43%], HR = 1.2, P= 0.55). Conclusions: ctDNA burden ≥0.5% following one cycle of chemotherapy identifies patients highly likely to relapse, albeit in a small cohort with available data at that timepoint. Conversely, ctDNA at a cutpoint of ≥0.5% after two cycles of chemotherapy was not prognostic, suggesting either more sensitive assays are needed or the prognostic value of ctDNA burden is diminished following additional therapy. These findings will enable novel trials of risk-adapted therapy focused on baseline and early ctDNA burden.

Influence of TP53 mutation on efficacy and survival in advanced EGFR-mutant non-small cell lung cancer patients treated with third-generation EGFR tyrosine kinase inhibitors.

TP53 comutation is related to poor prognosis of non-small cell lung cancer. However, there is limited study focusing on the structural influence of TP53 mutation on third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. We retrospectively analyzed the clinical and molecular data of patients treated with third-generation EGFR-TKIs in two independent cohorts. A total of 117 patients from the Sun Yat-sen University Cancer Center (SYSUCC) and 141 patients from the American Association for Cancer Research Project GENIE database were included. In the SYSUCC cohort, TP53 comutations were found in 59 patients (50.4%) and were associated with poor median progress-free survival (mPFS) and median overall survival (mOS). The additional subtype analysis found that TP53 mutation in the alpha-helix region had shorter mOS compared with those with TP53 mutations in other regions in the SYSUCC cohort (mOS, 12.2 vs. 21.7 months; p=0.027). Similar findings were confirmed in the GENIE cohort. Specifically, the presence of TP53 mutation in the alpha-helix region was an independent negative predictive factor for PFS [hazard ratio (HR) 2.05(1.01-4.18), p=0.048] and OS [HR 3.62(1.60-8.17), p=0.002] in the SYSUCC cohort. TP53 mutation in alpha-helix region was related to inferior clinical outcomes in patients treated with third-generation EGFR-TKIs.

Clinical Impact of Contouring Variability for Prostate Cancer Tumor Boost

PurposeThe focal radiotherapy (RT) boost technique was shown in a phase III randomized controlled trial (RCT) to improve prostate cancer outcomes without increasing toxicity. This technique relies on the accurate delineation of prostate tumors on MRI. A recent prospective study evaluated radiation oncologists’ accuracy when asked to delineate prostate tumors on MRI and demonstrated high variability in tumor contours. We sought to evaluate the impact of contour variability and inaccuracy on predicted clinical outcomes. We hypothesized that radiation oncologists' contour inaccuracies would yield meaningfully worse clinical outcomes. Materials & Methods45 radiation oncologists and 2 expert radiologists contoured prostate tumors on 30 patient cases. Of these cases, those with CT simulation or diagnostic CT available were selected for analysis. A knowledge-based planning model was developed to generate focal RT boost plans for each contour per the RCT protocol. Probability of biochemical failure (BF) was determined using a model from the RCT. The primary metric evaluated was delta BF (ΔBF = Participant BF – Expert BF). An absolute increase in BF ≥5% was considered clinically meaningful. Results8 patient cases and 394 target volumes for focal RT boost planning were included in this analysis. In general, participant plans were associated with worse predicted clinical outcomes compared to the expert plan, with an average absolute increase in BF of 4.3%. 37% of participant plans were noted to have an absolute increase in BF of 5% or more. ConclusionRadiation oncologists’ attempts to contour tumor targets for focal RT boost are frequently inaccurate enough to yield meaningfully inferior clinical outcomes for patients.

METTL8 links mt-tRNA m3C modification to the HIF1α/RTK/Akt axis to sustain GBM stemness and tumorigenicity

Epitranscriptomic RNA modifications are crucial for the maintenance of glioma stem cells (GSCs), the most malignant cells in glioblastoma (GBM). 3-methylcytosine (m3C) is a new epitranscriptomic mark on RNAs and METTL8 represents an m3C writer that is dysregulated in cancer. Although METTL8 has an established function in mitochondrial tRNA (mt-tRNA) m3C modification, alternative splicing of METTL8 can also generate isoforms that localize to the nucleolus where they may regulate R-loop formation. The molecular basis for METTL8 dysregulation in GBM, and which METTL8 isoform(s) may influence GBM cell fate and malignancy remain elusive. Here, we investigated the role of METTL8 in regulating GBM stemness and tumorigenicity. In GSC, METTL8 is exclusively localized to the mitochondrial matrix where it installs m3C on mt-tRNAThr/Ser(UCN) for mitochondrial translation and respiration. High expression of METTL8 in GBM is attributed to histone variant H2AZ-mediated chromatin accessibility of HIF1α and portends inferior glioma patient outcome. METTL8 depletion impairs the ability of GSC to self-renew and differentiate, thus retarding tumor growth in an intracranial GBM xenograft model. Interestingly, METTL8 depletion decreases protein levels of HIF1α, which serves as a transcription factor for several receptor tyrosine kinase (RTK) genes, in GSC. Accordingly, METTL8 loss inactivates the RTK/Akt axis leading to heightened sensitivity to Akt inhibitor treatment. These mechanistic findings, along with the intimate link between METTL8 levels and the HIF1α/RTK/Akt axis in glioma patients, guided us to propose a HIF1α/Akt inhibitor combination which potently compromises GSC proliferation/self-renewal in vitro. Thus, METTL8 represents a new GBM dependency that is therapeutically targetable.

Abstract PO3-03-09: Clinical Significance of Grade in Triple Negative Breast Cancer

Abstract Triple negative breast cancer (TNBC) is a heterogeneous cancer type that lacks receptors for estrogen (ER), progesterone (PR), and human epidermal growth factor receptor-2 proteins (HER-2). An important prognostic factor for breast cancer patients is the tumour grade, which is the degree of cell proliferation or differentiation of the tumour cells from normal cells. In our initial study involving 305 TNBC patients from 2004-2017 at Windsor Regional Hospital Cancer Centre, we found a statistically significant difference between grade 2 and grade 3 patients, with grade 2 predicting significantly inferior progression-free and overall survival. In our initial study, the overall survival rates for grade 1, 2, and 3 tumours were 90.12%, 64.4%, and 77.2% respectively (p = 0.019) with relapse rates of 70%, 55.6%, and 75.6% respectively (p = 0.04). Our current study is an attempt to validate these initial findings by expanding our data set to include data from the London Health Sciences Centre. A literature review on TNBC and grade was conducted, followed by a retrospective chart review for 305 TNBC patients from the Windsor Regional Hospital and 515 TNBC patients from the London Health Sciences Centre. The parameters for data collection included patient demographics, tumour demographics, therapies, and patient outcomes. We calculated all patient stages using both American Joint Committee on Cancer 7th edition (AJCC7) and the updated AJCC8 staging systems. Initial review of the data supports our earlier findings with a relapse rate of 12.5% in patients with grade 3 tumours and 17% in patients with grade 1 and grade 2 tumours. The completed data set will be analyzed and presented at the conference. Validating our previous findings of significantly inferior patient outcomes for grade 2 compared to grade 3 patients may alter the staging system used for TNBC patients. Citation Format: Mah-noor Malik, Neya Ramanan, Sarang Upneja, Muriel Brackstone, Lisa Porter, Bre-Anne Fifield, Caroline Hamm. Clinical Significance of Grade in Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-03-09.

ECMO as a bridge to heart transplantation: Insights into stratification by heart failure etiology

PurposeRevisions to the heart allocation criteria in 2018 motivated an increased use of extracorporeal membrane oxygenation (ECMO) as a bridge to transplantation. Studies have demonstrated inferior post-transplant outcomes in patients bridged with ECMO but do not account for underlying diagnosis. Our objective was to elucidate the differential impact of ECMO on outcomes by heart failure (HF) etiology. MethodsThe United Network of Organ Sharing (UNOS) database was queried for adults who underwent isolated heart transplantation after October 2018. Patients were stratified by ECMO utilization at time of transplantation, and then by HF etiology. After baseline statistical comparisons, survival analysis relied on Kaplan-Meier estimates and Cox proportional models. Results13,203 patients were included, of whom 761 (5.8%) were supported with ECMO. ECMO patients were younger (48 vs. 54 years, p<0.001), less likely to have diabetes (24% vs 30%, p<0.001), smoke cigarettes (31% vs 41%, p<0.001) or have prior cardiac surgery (29% vs. 36%, p<0.001), more likely to require dialysis (20% vs. 5%, p<0.001), and spent fewer days on the waitlist (59 vs. 190, p<0.001). After adjustment, ECMO was associated with increased mortality (HR 1.85, p<0.001) in the full cohort. After incorporating HF etiology, this increased mortality risk persisted in all subgroups except restrictive cardiomyopathy and congenital heart disease (CHD). ConclusionsOur findings illustrate that HF etiology is associated with differing outcomes when bridging with ECMO. ECMO patients with restrictive cardiomyopathy or CHD did not have increased mortality risk. With ECMO utilization increasing, these data are hypothesis-generating and serve as a basis for further studies.

P065 Patient-initiated follow up in rheumatoid arthritis: a systematic review and meta-analysis

Abstract Background/Aims Inflammatory arthritides including rheumatoid arthritis (RA) typically require lifelong outpatient care. Patient-initiated follow up (PIFU) has been employed to alleviate burdens on over-stretched rheumatology clinics, aiming to eliminate unnecessary clinic visits and reduce waiting times. There is a paucity of robust data to establish whether clinical outcomes differ under PIFU compared to clinician-mandated follow up. We examined the effect of PIFU on key outcomes in patients with inflammatory arthritis. Methods We searched MEDLINE, Embase, PsycInfo and CENTRAL for randomised controlled trials comparing PIFU (and similar patient-directed strategies) with clinician-mandated follow up in patients with inflammatory arthritis. Publications were screened in accordance with PRISMA guidelines and included based on pre-specified criteria. Risk of bias was assessed using the Cochrane ROB2 tool. Outcome measures analysed were disease activity, serum C-reactive protein, disability, service use and satisfaction with care. Standardised mean differences (SMD) were used to account for variable use of outcome measures between papers. Results Six studies were included with a total of 1,059 patients, all of whom had RA, followed up for between one and six years. Two trials were conducted in Denmark, two in the UK and one each in Sweden and the Netherlands. Two involved two sites; four were single centre. Three studies were deemed to be at high risk of bias, two at moderate risk and one at low risk. The data demonstrated a reduced burden of clinic visits for patients under PIFU (all studies; SMD -0.56, [95% CI -0.85 to -0.28]) equivalent to a reduction in approximately one clinic visit for every two patients over the course of the study period. This was balanced by an increased number of telephone consultations (4 studies, 817 patients; SMD 0.40 [0.13 to 0.66]) equating to an extra consultation per 2.5 patients under PIFU. Non-significant trends were seen towards higher patient satisfaction (all studies; SMD 0.28 [-0.12 to 0.68]) for patients under PIFU. However, there were also trends towards higher CRP (three studies, 490 patients; SMD 0.22 [-0.08, 0.52]) and DAS28 score (4 studies, 658 patients; SMD 0.08[-0.20, 0.36]. No significant difference was seen in patient-reported disability. There was substantial statistical heterogeneity between studies. Conclusion PIFU is associated with a reduction in outpatient clinic appointments but increased numbers of telephone consultations, while maintaining patient satisfaction. Current data do not exclude the possibility of inferior long-term clinical outcomes for patients receiving PIFU. Transition to PIFU risks reducing services’ capacity to assess and modify clinically important parameters (e.g. cardiovascular risk) through regular scheduled review. These studies highlight the challenges in conducting meaningful trials on this question due to the heterogeneity of interventions and outcomes and the already-widespread use of some aspects of PIFU in routine care. Disclosure E. Alveyn: Other; Educational support from UCB. R. Crowder: None. M. Perry: None. S. Norton: None. J. Galloway: Honoraria; from AbbVie, Celgene, Chugai, Gilead, Janssen, Eli Lilly, Pfizer, Roche and UCB.

BCLAF1 drives esophageal squamous cell carcinoma progression through regulation of YTHDF2-dependent SIX1 mRNA degradation

Esophageal cancer ranks among the most prevalent malignant tumors, and esophageal squamous cell carcinoma (ESCC) constitutes its predominant histological form. Despite its impact, a thorough insight into the molecular intricacies of ESCC's development is still incomplete, which hampers the advancement of targeted molecular diagnostics and treatments. Recently, B-cell lymphoma-2-associated transcription factor 1 (BCLAF1) has come under investigation for its potential involvement in tumor biology, yet its specific role and mechanism in ESCC remain unclear. In this study, we observed a marked increase in BCLAF1 expression in ESCC tissues, correlating with advanced tumor stages and inferior patient outcomes. Our comprehensive in vitro and in vivo studies show that BCLAF1 augments glycolytic activity and the proliferation, invasion, and spread of ESCC cells. By employing mass spectrometry, we identified YTHDF2 as a key protein interacting with BCLAF1 in ESCC, with further validation provided by colocalization, co-immunoprecipitation, and GST pull-down assay. Further investigations involving MeRIP-seq and RIP-seq, alongside transcriptomic analysis, highlighted SIX1 mRNA as a molecule significantly upregulated and modified by N6-methyladenosine (m6A) in BCLAF1 overexpressing cells. BCLAF1 was found to reduce the tumor-suppressive activities of YTHDF2, and its effects on promoting glycolysis and cancer progression were shown to hinge on SIX1 expression. This research establishes that BCLAF1 fosters glycolysis and tumor progression in ESCC through the YTHDF2-SIX1 pathway in an m6A-specific manner, suggesting a potential target for future therapeutic intervention.