Inferior Survival Research Articles

Trends in survival after heart transplantation based on Social Vulnerability Index in the United States

IntroductionThe association of social vulnerability (SV) and cardiac transplant survival remains poorly defined, particularly related to long-term outcomes. The purpose of this study was to define the impact of SV on survival among heart transplant recipients with at least 1-year of survival post-transplant. MethodsHeart transplant recipients were identified using the United Network for Organ Sharing database between 6/1/06-12/31/20. The Center for Disease Control’s Social Vulnerability Index (SVI) database was used to stratify patients based on SVI into three groups: Low: <25; Average: 26-74; High: 75+. The groups were analyzed with comparative statistics, and unadjusted survival was assessed using Kaplan-Meier methods. To determine the independent association between SVI and survival, a multivariable Cox proportional hazard model was created. ResultsThere were 27,740 recipients identified. High SVI patients more commonly identified as Black individuals and had a higher incidence of diabetes, pre-transplant intensive care unit admission and need for concomitant kidney transplant (p<0.05 for all). Additionally, High SVI patients had the longest length of stay post-transplant (21.4 days) (p<0.05). High and Average SVI patients had inferior 3-year, 5-year, and 10-year survival versus Low SVI patients (p<0.05). After adjustment, Average (hazard ratio [HR]:1.12) and High (HR:1.16) SVI were independently associated with an increased risk of mortality on multivariable analysis (both p<0.001). ConclusionHigh or average SVI is independently associated with increased mortality following heart transplantation in patients with 1-year conditional survival. These findings demonstrate that disparities persist among heart transplant recipients during long-term follow up.

MET overexpression correlated with prognosis of EGFR-mutant treatment‑naïve advanced lung adenocarcinoma: a real‑world retrospective study.

About 50-60% treatment-naïve advanced non-small-cell lung cancers were coexistence of epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition (MET) overexpression. However, few studies demonstrated the prognostic value of MET protein expression in untreated EGFR-mutant lung adenocarcinoma (LUAD). A total of 235 EGFR-mutant untreated advanced LUAD patients were retrospectively enrolled. MET expression was determined using immunohistochemistry, and MET positivity was defined as 2 + or 3 + using the METmab scoring algorithm. Progression-free survival (PFS) and overall survival (OS) were analysed according to MET expression status. Independent factors predicting prognosis were identified using multivariate Cox regression analyses. Of the 235 patients, 113 (48.1%) harboured exon 19 deletion (19_del), 103 (43.8%) had exon 21 L858R mutations, and 19 (8.1%) had other mutation types, including exon 21 L861Q, exon 18 G719A/C, exon 20 S768I, and L858R/19_del double mutations. MET-positive expression was observed in 192 (81.7%) cases. There was no significant difference in baseline clinicopathological characteristics between MET positivity and MET negativity groups. Patients were stratified by different EGFR mutation subtypes. MET-positive patients in the L858R mutation subgroup had markedly shorter PFS and OS than MET-negative patients (median PFS: 13 versus 27.5months, p < 0.001; median OS: 29 versus not reached, p = 0.008), but no significant difference was observed in the 19_del subgroup. Multivariate Cox regression analyses indicated that MET positivity was an independent predictor for poor PFS and OS in L858R subgroup (PFS: HR = 3.059, 95% CI 1.552-6.029, p = 0.001; OS: HR = 3.511, 95% CI 1.346-9.160, p = 0.010). Additionally, an inferior survival outcome of MET positivity was observed in the L858R mutation subgroup when treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy as the first-line regimen (median PFS: 13 versus 36.5months, p < 0.001; median OS: 29 versus not reached, p = 0.012) but not with EGFR-TKI plus platinum doublet chemotherapy. MET positive expression was an independent predictor of poor outcomes in untreated EGFR L858R mutation advanced LUAD patients treated with first-line EGFR-TKI monotherapy.

Protocol liver biopsy predicts graft survival after liver transplantation.

The use of protocol liver biopsy to monitor liver allograft status remains controversial. There is limited data from modern transplantation populations that includes protocol biopsies to evaluate its value in predicting clinical outcomes. All protocol liver biopsies were identified from 875 patients who underwent liver transplantation at Helsinki University Hospital between 2000 and 2019. Each histologic component was analyzed for its ability to predict long-term outcomes, especially graft survival. We determined the frequency of significant biopsy findings based on the Banff working group definition. Liver function tests (LFTs) and clinical markers were evaluated for their ability to predict significant biopsy findings. In total, 867 protocol liver biopsies were analyzed. Significant findings were identified in 20.1% of the biopsies. In the first protocol biopsy, steatohepatitis (hazard ratio [HR] 3.504, p=.03) and moderate or severe congestion (HR 3.338, p=.04) predicted graft loss. The presence of cholangitis (HR 2.563, p=.04), necrosis (HR 7.635, p<.001), mild congestion (HR 4.291, p=.009), and significant biopsy finding (HR 2.540, p=.02) predicted inferior death-censored graft survival. While the degree of elevation of LFTs was positively associated with significant biopsy findings, the discrimination was poor (AUC.572-.622). Combined LFTs and clinical risk factors remained suboptimal for discriminating significant biopsy findings (AUC.696). Our findings support the use of protocol liver biopsies after liver transplantation since they frequently revealed changes associated with long-term outcomes, even when LFTs were normal.

Abstract B031: High risk no specific molecular profile (HR-NSMP) endometrial cancer can be stratified into three subgroups based on tumor grade and estrogen receptor status with differing clinicopathologic characteristics and outcomes

Abstract Introduction: Recent publications have identified ‘low risk’ (LR-NSMP) and ‘high risk’ no specific molecular profile (HR-NSMP) endometrial cancers (ECs). Although LR-NSMP (low grade (G1/2) estrogen receptor (ER) positive tumors have extremely low rates (&amp;lt;2%) of death from disease and are considered candidates for de-escalation of adjuvant therapy, little is known about the newly defined entity of HR-NSMP (G3 and/or ER-negative), including optimal management, with 27% of HR-NSMP patients dying from their disease We aimed to perform in-depth characterization of a cohort of HR-NSMP ECs to identify additional prognostic or predictive features that may inform management. Methods: Clinicopathologic data collection, immunohistochemistry (IHC), and next generation sequencing was performed on a cohort of 148 HR-NSMP ECs testing for associations with outcomes. Three subgroups of HR-NSMP were assessed: i) low grade without any ER expression (G1/2ER-, n=40), ii) high grade with ER (G3ER+, n=67), and iii) high grade without ER expression (G3ER-, n=41). Results: In a univariate analysis, advanced stage (III/IV), positive lymph node (LN) status, no LN assessment, and PIK3CA mutations were associated with inferior progression-free survival (PFS), disease specific survival (DSS), and overall survival (OS). HR-NSMP patients with positive LNs had a hazard ratio (HR) of death of 7.55 (95% CI: 3.41−16.73) compared to node negative. Additionally, patients with no LN assessment had an increased risk of death with a HR of 2.33 (95% CI: 1.12−4.85) compared to node negative. Within the three HR-NSMP subgroups, the worst OS (HR 7.06, CI 4.12-12.09, p&amp;lt; 0.001), DSS (HR 20.43, CI 10.14-41.19, p&amp;lt; 0.001), and PFS (HR 3.69, CI 1.59-8.63, p&amp;lt;0.001) were observed in patients with both adverse features (G3ER-). PIK3CA mutations were found in 32.7% of all HR-NSMP tumors tested (G1/2ER- 45.5%, G3ER+ 42.3%, G3ER- 6.7%) and associated with inferior OS (HR 4.84, CI 1.21-19.41, p=0.014), DSS (HR 4.84, CI 1.21-19.41, p=0.014), and PFS (HR 3.22, CI=1.08-9.66, p=0.028). There was a trend towards decreased OS and DSS in HR-NSMP patients with overexpression of HER2 IHC. L1CAM IHC overexpression and CTNNB1 mutation status were not associated with outcomes when assessed across all HR-NSMP or within subgroups. Conclusion: Among HR-NSMP ECs, the worst clinical outcomes were observed in patients harboring both high grade and ER negative tumors. In contrast to LR-NSMP ECs where patients who had no lymph node assessment had excellent outcomes mirroring node negative status, HR-NSMP patients who had no nodal assessment had a high rate of recurrence and death from disease suggesting the importance of comprehensive staging in this cohort. PIK3CA appears to be a prognostic stratification feature within HR-NSMP and represents a potential therapeutic pathway. More work is needed to understand the association of HER2 expression and ER status and whether HER2 -targeted therapies represent actionable opportunities for these patients. Citation Format: Andrea Neilson, Amy Jamieson, Derek Chiu, Samuel Leung, Amy Lum, Jennifer Pors, Stefan Kommoss, Aline Talhouk, David G. Huntsman, Naveena Singh, C. Blake Gilks, Jessica N. McAlpine. High risk no specific molecular profile (HR-NSMP) endometrial cancer can be stratified into three subgroups based on tumor grade and estrogen receptor status with differing clinicopathologic characteristics and outcomes [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B031.

Dynamic monitoring of circulating tumor DNA reveals outcomes and genomic alterations in patients with relapsed or refractory large B-cell lymphoma undergoing CAR T-cell therapy

BackgroundOver 50% of patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) receiving CD19-targeted chimeric antigen receptor (CAR19) T-cell therapy fail to achieve durable remission. Early identification of relapse...

Survival impact of variant histology in patients with upper tract urothelial carcinoma after radical nephroureterectomy

ObjectiveTo investigate the prognostic impact of variant histology (VH) on survival outcomes in upper tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy (RNU). Materials and methodsData from 635 UTUC patients who underwent RNU at our institution from May 2003 to June 2019 were retrospectively acquired and analyzed. After propensity score matching (PSM), we investigated the impact of VH on overall survival (OS) and cancer-specific survival (CSS) by using cumulative incidence plots with the log-rank test, Cox regression models, and competing risk regression models. ResultsOverall, 121 (19.1%) patients were diagnosed with VH, including 68 (10.7%) with squamous cell differentiation (SCD) and 28 (4.4%) with adenocarcinoma differentiation (AD). After PSM, the presence of VH was significantly associated with worse OS (HR 1.70, 95% CI 1.25–2.32) and CSS (HR 1.64, 95% CI 1.17–2.31) only in locally advanced UTUC patients (pT>2). In the subgroup analysis, SCD revealed inferior outcomes (OS: HR 1.81, 95% CI 1.28–2.57; CSS: HR 1.73, 95% CI 1.18–2.54) compared with pure urothelial carcinoma (pUC), whereas AD conferred comparable outcomes. In addition, compared with pUC patients, SCD patients with extensive squamous components had significantly decreased OS (HR 4.17, 95% CI 1.84–9.44) and CSS (HR 1.10, 95% CI 0.61–1.99), whereas those with regional squamous components had similar survival outcomes. ConclusionFor UTUC patients after RNU, the presence of VH is associated with aggressive clinicopathological features and inferior survival outcomes. However, the survival outcomes of localized UTUC patients (pT≤2) with VH, and patients with the AD or regional SCD subtype are comparable to those of patients with pUC.

An overview of childhood cancer care and outcomes in Egypt: a narrative review.

Childhood cancer is an urgent priority in Egypt, owing to a large number of children with cancer, the great need and demand for paediatric oncology services, limited resources/funds and inferior survival outcomes. Therefore, an overview of the status of childhood cancer care in Egypt and an evidence-based approach towards optimal utilisation of resources/funds to improve this care are needed. This paper summarises key evidence about childhood cancer care and outcomes in Egypt. We conducted a narrative literature review using a structured search strategy of the MEDLINE database through the PubMed interface. All relevant evidence was summarised under five main sub-topics: (1) burden of childhood cancer in Egypt; (2) treatment approaches; (3) health outcomes; (4) costs and cost-effectiveness of treatment; and (5) barriers and facilitators to optimal childhood cancer care. We found high estimates of disease burden of childhood cancer in Egypt. Furthermore, childhood cancer treatment in Egypt is based on either implementing intensity-regulated protocols or adopting international protocols with or without adaptations to local contexts, leading to varying standards of care among the different treating centres. Limited data about the survival outcomes, costs and cost-effectiveness of treatment exist, although high-quality data from retrospective cohort studies were published from a large paediatric oncology centre (Children's Cancer Hospital Egypt-57357). As Egypt joins the WHO Global Initiative for Childhood Cancers as a focus country, it is prepared to move towards streamlining national efforts to implement a national childhood cancer plan to advance care, improve health outcomes and optimise resource use. Through these efforts, Egypt could become a beacon of hope and a role model to other low- and middle-income countries seeking to improve their childhood cancer care.

Exploration and machine learning model development for T2 NSCLC with bronchus infiltration and obstructive pneumonia/atelectasis

In the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for Non-Small Cell Lung Cancer (NSCLC), tumors exhibiting main bronchial infiltration (MBI) near the carina and those presenting with complete lung obstructive pneumonia/atelectasis (P/ATL) have been reclassified from T3 to T2. Our investigation into the Surveillance, Epidemiology, and End Results (SEER) database, spanning from 2007 to 2015 and adjusted via Propensity Score Matching (PSM) for additional variables, disclosed a notably inferior overall survival (OS) for patients afflicted with these conditions. Specifically, individuals with P/ATL experienced a median OS of 12 months compared to 15 months (p < 0.001). In contrast, MBI patients demonstrated a slightly worse prognosis with a median OS of 22 months versus 23 months (p = 0.037), with both conditions significantly correlated with lymph node metastasis (All p < 0.001). Upon evaluating different treatment approaches for these particular T2 NSCLC variants, while adjusting for other factors, surgery emerged as the optimal therapeutic strategy. We counted those who underwent surgery and found that compared to surgery alone, the MBI/(P/ATL) group experienced a much higher proportion of preoperative induction therapy or postoperative adjuvant therapy than the non-MBI/(P/ATL) group (41.3%/54.7% vs. 36.6%). However, for MBI patients, initial surgery followed by adjuvant treatment or induction therapy succeeded in significantly enhancing prognosis, a benefit that was not replicated for P/ATL patients. Leveraging the XGBoost model for a 5-year survival forecast and treatment determination for P/ATL and MBI patients yielded Area Under the Curve (AUC) scores of 0.853 for P/ATL and 0.814 for MBI, affirming the model's efficacy in prognostication and treatment allocation for these distinct T2 NSCLC categories.

The impact of Karnofsky performance status on prognosis of patients with hepatocellular carcinoma in liver transplantation

BackgroundFunctional performance as measured by the Karnofsky Performance Status (KPS) scale has been linked to the outcomes of liver transplant patients; however, the effect of KPS on the outcomes of the hepatocellular carcinoma (HCC) liver transplant population has not been fully elucidated. We aimed to investigate the association between pre-transplant KPS score and long-term outcomes in HCC patients listed for liver transplantation.MethodsAdult HCC candidates listed on the Scientific Registry of Transplant Recipients (SRTR) database from January 1, 2011 to December 31, 2017 were grouped into group I (KPS 80–100%, n = 8,379), group II (KPS 50–70%, n = 8,091), and group III (KPS 10–40%, n = 1,256) based on percentage KPS score at listing. Survival was compared and multivariable analysis was performed to identify independent predictors.ResultsPatients with low KPS score had a higher risk of removal from the waiting list. The 5-year intent-to-treat survival was 57.7% in group I, 53.2% in group II and 46.7% in group III (P < 0.001). The corresponding overall survival was 77.6%, 73.7% and 66.3% in three groups, respectively (P < 0.001). Multivariable analysis demonstrated that KPS was an independent predictor of intent-to-treat survival (P < 0.001, reference group I; HR 1.19 [95%CI 1.07–1.31] for group II, P = 0.001; HR 1.63 [95%CI 1.34–1.99] for group III, P < 0.001) and overall survival(P < 0.001, reference group I; HR 1.16 [95%CI 1.05–1.28] for group II, P = 0.004; HR 1.53 [95%CI 1.26–1.87] for group III, P < 0.001). The cumulative 5-year recurrence rates was higher in group III patients (7.4%), compared with 5.2% in group I and 5.5% in group II (P = 0.037). However, this was not significant in the competing regression analysis.ConclusionsLow pre-transplant KPS score is associated with inferior long-term survival in liver transplant HCC patients, but is not significantly associated with post-transplant tumor recurrence.

A multicenter study: predicting KRAS mutation and prognosis in colorectal cancer through a CT-based radiomics nomogram.

To establish a CT-based radiomics nomogram for preoperative prediction of KRAS mutation and prognostic stratification in colorectal cancer (CRC) patients. In a retrospective analysis, 408 patients with confirmed CRC were included, comprising 168 cases in the training set, 111 cases in the internal validation set, and 129 cases in the external validation set. Radiomics features extracted from the primary tumors were meticulously screened to identify those closely associated with KRAS mutation. Subsequently, a radiomics nomogram was constructed by integrating these radiomics features with clinically significant parameters. The diagnostic performance was assessed through the area under the receiver operating characteristic curve (AUC). Lastly, the prognostic significance of the nomogram was explored, and Kaplan-Meier analysis was employed to depict survival curves for the high-risk and low-risk groups. A radiomics model was constructed using 19 radiomics features significantly associated with KRAS mutation. Furthermore, a nomogram was developed by integrating these radiomics features with two clinically significant parameters (age, tumor location). The nomogram achieved AUCs of 0.834, 0.813, and 0.811 in the training set, internal validation set, and external validation set, respectively. Additionally, the nomogram effectively stratified patients into high-risk (KRAS mutation) and low-risk (KRAS wild-type) groups, demonstrating a significant difference in overall survival (P < 0.001). Patients categorized in the high-risk group exhibited inferior overall survival in contrast to those classified in the low-risk group. The CT-based radiomics nomogram demonstrates the capability to effectively predict KRAS mutation in CRC patients and stratify their prognosis preoperatively.

Venetoclax with decitabine or azacitidine in relapsed or refractory acute myeloid leukemia.

Relapsed or refractory acute myeloid leukemia (AML) is associated with poor outcomes and resistance to therapy. The addition of venetoclax, a BCL-2 antagonist, to lower-intensity therapies results in improved survival in the first-line setting compared to monotherapy with a hypomethylating agent or low-dose cytarabine. Despite this, much remains unknown about the performance of venetoclax with a hypomethylating agent following the first-line setting. Additionally, while the ELN 2022 guidelines appear to improve the prognostication of AML, clarification is needed to determine how the revision applies to lower-intensity strategies. To investigate this, we retrospectively analyzed the performance of venetoclax with decitabine or azacitidine in relapsed or refractory AML under the ELN 2022 guidelines. We demonstrated that the ELN 2022 revision is not optimized for lower-intensity venetoclax-based strategies. To refine the prognostication schema, we showed significantly improved response and survival benefits for patients with mutated NPM1 and IDH. Relatively, patients with mutated NRAS, KRAS, and FLT3-ITD were associated with inferior response and survival. Furthermore, there is an unmet clinical need for tools to improve the selection of lower-intensity therapy candidates with borderline functional status. Using an incremental survival computation method, we discovered that a CCI score threshold of 5 distinguishes patients at an elevated risk of death. Together, these novel findings highlight areas of refinement to improve survival in relapsed or refractory AML.

Infection-Related Hospitalizations After Simultaneous Pancreas-Kidney Transplantation Compared to Kidney Transplantation Alone.

The total burden of infections after transplantation has not been compared in detail between recipients of simultaneous pancreas-kidney transplantation (SPK) and kidney transplantation alone (KTA). We compared infection-related hospitalizations and bacteremias after transplantation during 1- and 5-year follow-up among 162 patients undergoing SPK. The control group consisted of 153 type 1 diabetics undergoing KTA with the inclusion criteria of donor and recipient age < 60, and BMI < 30. During the first year, SPK patients had more infection-related hospitalizations (0.54 vs. 0.31 PPY, IRR 1.76, p = <0.001) and bacteremias (0.11 vs. 0.01 PPY, IRR 17.12, p = <0.001) compared to KTA patients. The first infection-related hospitalizations and bacteremias occurred later during follow-up in KTA patients. SPK was an independent risk factor for infection-related hospitalization and bacteremia during the first year after transplantation, but not during the 5-year follow-up. Patient survival did not differ between groups, however, KTA patients had inferior kidney graft survival. SPK patients are at greater risk for infection-related hospitalizations and bacteremias during the first year after transplantation compared to KTA patients, however, at the end of the follow-up the risk of infection was similar between groups.

Current analysis of the survival implications for minimally invasive surgery in the treatment of early-stage cervix cancer.

Early-stage cervical cancer (ESCC) is managed with radical hysterectomy, a procedure that can be performed either via open surgery or minimally invasive surgery (MIS), the latter of which is accomplished via traditional laparoscopy or robotic-assisted surgery. Previously, MIS was routinely incorporated into the management of ESCC due to the approach's reduced operative morbidity and truncated hospital stay duration, but more recent clinical evidence has since impugned the efficacy of MIS because of the reportedly inferior disease-free survival and overall survival outcomes compared to open surgery. However, additional studies have documented equivalent outcomes among the various surgical modalities, suggesting further exploration of clinical factors as we endeavor to conclusively determine the standard of care for patients diagnosed with ESCC.

Clinical characteristics and prognosis of acute myeloid leukemia patients with Runt-related transcription factor 1 mutation: A single-center retrospective analysis.

This study aimed to investigate the clinical characteristics and prognosis of Runt-related transcription factor 1 (RUNX1) mutant acute myeloid leukemia (AML) patients by comparing the features of AML patients with or without RUNX1 mutation. We retrospectively analyzed 180 AML patients including 36 AML patients with mutant RUNX1(AML-RUNX1mut ) and 144 AML patients with wild-type RUNX1(AML-RUNX1wt ) were selected using the case-pair method(1:4). Compared to AML-RUNX1wt , AML-RUNX1mut showed higher frequency of ASXL1 (p<0.001), SRSF2 (p<0.001), BCORL1 (p<0.001), RAS (p=0.010) mutations, and absent NPM1 mutations (p=0.022). The 3-year overall survival (OS) and disease-free survival (DFS) of AML-RUNX1mut and AML-RUNX1wt were 73.1% versus 68.0% (p=0.64) and 80.7% versus 71.6% (p=0.37), respectively. AML-RUNX1mut receiving allogeneic hematopoietic cell transplantation (allo-HSCT) showed better survival than those who did not receive allo-HSCT (3-year OS, 84.3% vs. 52.7%; p=0.006). Multivariate analysis showed that EZH2 mutation (p=0.003), white blood cell (WBC) ≥30×109 /L (p=0.036) and age ≥60years (p=0.038) were significant independent risk factors for inferior OS of AML-RUNX1mut ; WBC ≥30×109 /L (p=0.013) and DNMT3A mutation (p=0.045) were significant independent risk factors for shorter DFS of AML-RUNX1mut . In conclusion, AML-RUNX1mut showed unique clinical characteristics, but the survival between AML-RUNX1mut and AML-RUNX1wt were comparable. EZH2 co-mutation, DNMT3A co-mutation, old age and high WBC count were associated with inferior survival of AML-RUNX1mut . Allo-HSCT can significantly improve the prognosis of AML-RUNX1mut .

Assessment of IgM DSAs in Transplant Recipients: Relationship to De Novo IgG DSAs and Risk for Antibody Rejection.

The presence of anti-HLA donor-specific antibodies (DSAs) is associated with antibody-mediated rejection (AMR) and inferior graft survival. However, recent data suggest that ~50% of AMR episodes are IgG DSA negative and possibly related to non-HLA DSAs. After the initial activation of B cells to alloantigen, IgM is the first immunoglobulin produced. In addition, both IgM and IgG isotopes can activate the classic complement pathway and induce complement-dependent cytotoxicity to allograft targets. Current practices focus on the assessment of IgG DSAs with little concern for the assessment of IgM DSAs. Here, we examined anti-HLA IgM in a cohort of 22 patients who developed de novo IgG DSAs by a modified single-antigen bead-based test. We found IgM HLA DSAs developed before IgG DSAs. The median time from the detection of IgM DSAs to the appearance of de novo IgG DSAs was 461 d. Most patients had IgM DSAs against the same HLA-DQ antigens, for which IgG de novo DSAs were also later detected. IgM DSAs were detected in patients with biopsies suspected of AMR. The detection of IgM DSAs could be an early indicator of alloimmune responses to allografts before IgG de novo DSAs appear.

Analysis of the effect of baseline detection and early clearance of ct-DNA, on survival outcomes among patients with advanced EGFR-mutant non-small cell lung cancer.

To determine if circulating tumor DNA (ct-DNA) dynamics of epidermal growth factor receptor (EGFR) mutation in plasma can identify asubset of patients with EGFR-mutant (EGFR- m) non-small cell lung cancer (NSCLC) with inferior survival outcomes, we analyzed and compared survival outcomes among patients with and without baseline presence and early clearance of EGFR ct-DNA in plasma. For 66patients newly dia-gnosed with EGFR- m NSCLC, plasma samples were collected at baseline and 1st response assessment at 12-24weeks for extraction of ct-DNA. Estimation of ct-DNA (EGFR exons 18, 19, 20and 21) was done using droplet digital polymerase chain reaction (dd-PCR) on the QX200ddPCR system (BioRad, USA). Patients with detectable EGFR ct-DNA at baseline (sample 1), with either undetectable or persistent detectable ct-DNA in sample 2were classified as clearers and non-clearers, respectively. Fifty-three patients received 1st/ 2nd generation EGFR tyrosine kinase inhibitors (TKIs) and 13received either 3rd generation TKI (osimertinib) or chemotherapy plus gefitinib. The baseline ct-DNA-positive group had more patients with extra thoracic disease (60.4vs. 48.5%). For the entire cohort, there was no difference in median progression-free survival (PFS) among baseline ct-DNA-negative (13.57months) vs. ct-DNA-positive patients (12.32months) (HR 0.74). There was asignificant improvement of PFS among early ct-DNA clearers vs. non-clearers (12.32vs. 9.92months; HR 0.57). For those treated with 1st/ 2nd generation EGFR TKIs, this improvement in median PFS among early ct-DNA clearers vs. non-clearers was more apparent (11.76vs. 6.8months; HR 0.34). Baseline detection of the presence of ct-DNA of EGFR mutation in plasma was not predictive of first-line PFS, but is associated with extra thoracic disease. Patients with EGFR mutation and persistence of ct-DNA at first follow-up have worse PFS and overall survival (OS) in comparison to those clearing the same in plasma, especially among those treated with 1st/ 2nd generation EGFR TKIs.

[Translated article] Closing wedge high tibial osteotomy: An old-fashioned technique? Survival, clinical and radiological outcomes of a case series analysis

IntroductionClosing wedge high tibial osteotomy (CW-HTO) is a surgical option for active patients with medial knee pain and mild–moderate osteoarthritis with varus limb deformity. Despite its good reported results, this technique has been losing popularity. The aim of this study was to analyse the survival rate, clinical functional outcomes and radiological results of CW-HTO. MethodsIt is a retrospective case series study. Seventy patients with primary knee osteoarthritis, operated on between 2010 and 2020 in a single Spanish tertiary hospital using the CW-HTO technique and with a minimum follow-up of 2 years were analysed. ResultsSurvival rate was 87.6% and 75.5% after a follow-up of 5 and 10 years respectively. Functional outcomes were good-to-excellent (KSS 77.7/100 and OKS 35.6/48) and good pain control (VAS 3.9/10) and high satisfaction (7.2/10) were achieved. Limb varus malalignment was significantly corrected (mean postoperative HKA angle 177.6° and MPTA 90.7°). However, 30% of patients presented hypocorrection, which was associated with inferior survival, functionality and satisfaction. ConclusionCW-HTO technique can be useful for patients with knee osteoarthritis and varus limb. It allows to correct varus malalignment while achieving good-to-excellent functional outcomes, good pain control, high patient satisfaction and acceptable medium-long term survival rate. However, it is associated with a non-negligible risk of hypocorrection or medial hinge disruption.

Biomarker analysis of the ASPEN study comparing zanubrutinib with ibrutinib for patients with Waldenström macroglobulinemia

AbstractThe phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.

Correlation between choroid plexus carcinoma and Li-Fraumeni syndrome: implications of TP53 mutations and management strategies-a case-based narrative review.

Choroid plexus carcinomas (CPCs) are rare, aggressive grade 3 tumors of the central nervous system associated with Li-Fraumeni syndrome (LFS) in a notable percentage of cases due to TP53 germline mutations. Understanding the correlation between CPCs and LFS is crucial for tailored management strategies. However, distinguishing CPCs from benign choroid plexus papillomas (CPPs) remains challenging, relying largely on histologic features. This study aimed to explore the association between CPCs and LFS, emphasizing the impact of TP53 mutations on diagnosis, treatment, and clinical outcomes. Scientific databases such as PubMed, Scopus, and Web of Science were systematically searched up to January 2024 using keywords related to CPCs, LFS, TP53 mutation, and central nervous system tumors. Selection criteria included studies investigating the link between CPCs and LFS, their management approaches, and genetic implications of TP53 mutations. Ten relevant studies were selected for analysis after screening titles, abstracts, and full-text articles. Data extraction focused on clinical, genetic, and management factors related to CPCs associated with LFS. The review highlighted the strong association (36%) between CPCs and LFS, primarily due to TP53 germline mutations. Studies emphasized the need for genetic testing in patients with CPCs, especially in pediatric cases, to identify LFS implications. Furthermore, the impact of TP53 mutations on treatment strategies was emphasized, recommending irradiation-sparing therapies due to inferior survival rates associated with radiotherapy in LFS patients with CPCs. Cases illustrated the challenges in diagnosing CPCs and the importance of immunohistochemistry and genetic testing for TP53 mutations. CPCs pose challenges in diagnosis and management, particularly in distinguishing them from benign tumors. The association with LFS, often due to TP53 germline mutations, underscores the importance of genetic testing for early detection and tailored treatment strategies. Irradiation-sparing therapies are recommended for LFS-associated CPCs to mitigate the risk of secondary malignancies. Comprehensive profiling of CPC patients, especially in pediatric cases, is crucial for early detection and management of potential secondary cancers associated with LFS.

Abstract B054: Deciphering the normal-like molecular subtype of breast cancer

Abstract The normal-like molecular subtype of breast cancer has not been well characterized and is currently not included in the clinically approved PAM50 molecular subtype classification. Tumors classified as normal-like display high expression of basal epithelial genes and low expression of luminal epithelial genes, but also high expression of genes expressed by non-epithelial cell types including adipocytes [1]. The normal-like subtype has been suggested to represent tumors with low invasive tumor cell content, hence challenging its legitimacy as an intrinsic subtype. To clarify this issue we aimed to characterize the features of early breast cancers classified as normal-like using RNA sequencing and immunohistochemistry (IHC). Using a consecutive series of 14,000 early breast cancers from the population-based multi-center observational Sweden Cancerome Analysis Network – Breast (SCAN-B) and a recently published RNAseq-based single-sample molecular subtype predictor [2] the subtype distribution was: 39% luminal A, 25% luminal B, 12% HER2-enriched, 9% basal and 15% normal-like. The median tumor size did not differ significantly between the subtypes, while tumor cellularity assessed on H&amp;E slides was lower among normal-like breast cancers (median 20%) compared to the other subtypes (median range 40-70%). Using a version of the classifier that excludes the normal-like subtype, i.e. akin to clinical PAM50 subtyping, 67.5% of the tumors classified as normal-like were re-classified as luminal A, with the remaining cases re-classified as either basal (17.5%) or HER2-enriched (14.9%). The distribution of hallmark features among normal-like tumors was 75% ER+, 67% PR+, 20% Ki67 high and 10% HER2 positive by IHC/CISH. IHC further revealed loss of E-cadherin in 30% of normal-like breast cancers, in line with 30% lobular histology. Significantly differentially expressed genes between lobular and non-lobular normal-like breast cancers included CDH1, PGC, CPB1, SERPINA6, TRH, MSLN, MMP1 and AKR1B15. The lobular normal-like breast cancers were enriched for the ER+/HER2-/node negative clinical subgroup (58%). Mutation calling using the SCAN-B MutationExplorer application [3] revealed enrichment of PIK3CA (46% vs. 18%), CDH1 (37% vs. 18%), TP53 (7% vs 0%) and ESR1 (6% vs. 0%) mutations in normal-like lobular vs. luminal lobular breast cancers. Finally, overall survival within the normal-like group was significantly different from all other subtypes and was intermediate between the luminal A and B groups (p&amp;lt;0.05 for pairwise comparisons). To conclude, the normal-like subgroup is enriched for lobular breast cancers and displays downregulation of genes involved in cell adhesion and hormone regulation. Normal-like breast cancers are primarily classified as luminal A tumors with current clinical subtype classification algorithms, but the inferior survival and distinct features of these tumors do not preclude that this may be a true intrinsic subtype, thus warranting further investigation of the normal-like subtype. 1. PMID: 11553815 2. PMID: 35974007 3. PMID: 32926574 Citation Format: Srinivas Veerla, Siker Kimbung, Anna Ebbesson, Johan Vallon-Christersson, Ingrid Hedenfalk. Deciphering the normal-like molecular subtype of breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B054.