Strong Prognosticator Research Articles

Imaging Assessment of Endothelial Function: An Index of Cardiovascular Health.

Endothelial dysfunction is a key early mechanism in a variety of cardiovascular diseases and can be observed in larger conduit arteries as well as smaller resistance vessels (microvascular dysfunction). The presence of endothelial dysfunction is a strong prognosticator for cardiovascular events and mortality, and assessment of endothelial function can aid in selecting therapies and testing their response. While the gold standard method of measuring coronary endothelial function remains invasive angiography, several non-invasive imaging techniques have emerged for investigating both coronary and peripheral endothelial function. In this review, we will explore and summarize the current invasive and non-invasive modalities available for endothelial function assessment for clinical and research use, and discuss the strengths, limitations and future applications of each technique.

Mitigation of Blood Load Impact in Patients with Subarachnoid Hemorrhage by Cisternal Lavage

Object: The initial amount of subarachnoid and ventricular blood is an important prognostic factor for outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). In this comparative study of an unselected aSAH-population, we assess the modifiability of these factors by implementation of blood clearance by cisternal lavage. Methods: All patients with aSAH treated in our department between October 2011 and October 2019 (8 years, n = 458) were included in our study. In the first 4-year period (BEFORE, n = 237), patients were treated according to international guidelines. In the second 4-year period (AFTER, n = 221), cisternal lavage methods were available and applied in 72 high-risk patients (32.5%). The cisternal and ventricular blood load was recorded by the Hijdra score. Multivariable regression models were used to assess the prognostic significance of risk factors, including blood load, in relation to common aSAH characteristics in both study groups. Results: Worse neurological outcomes (mRS > 3) occurred in the BEFORE population with 41.45% versus 30.77% in the AFTER cohort, 6 months after aSAH (HR: 1.59, 95% CI 1.08–2.34, p = 0.01). Admission WFNS grade, comorbidities (Charlson Comorbidity Index), herniation signs, concomitant intracerebral hemorrhage, and the development of delayed cerebral infarction were strongly associated with poor outcome in both study groups. Intraventricular and cisternal blood load and, particularly, a cast fourth ventricle (Cast 4) represented strong prognosticators of poor neurological outcome in the BEFORE cohort. This effect was lost after implementation of cisternal lavage (AFTER cohort). Conclusion: Cisternal and ventricular blood load – in particular: a Cast 4 – represent important prognosticators in patients with aSAH. They are, however, amenable to modification by blood clearing therapies.

Characteristics and prognosis of patients hospitalized for acute myocarditis

Few data are available on the outcome and prognostic factors in acute myocarditis (AM) diagnosed by CMR. We aimed to determine the characteristics and identify the factors associated with in-hospital and 5-year prognosis in patients hospitalized at Amiens University Hospital for AM between 2010 and 2020. 185 patients hospitalized with an initial CMR-based diagnosis of AM were enrolled between January 2010 and June 2020. Analysis of clinical, biological, and imaging data were performed to identify predictors of in-hospital and long term outcomes. Mean age was 33 years old with 80% of men. Men were significantly younger than women ( P < 0.001). The most frequent symptom at presentation was chest pain (92% of patients). Mean Left Ventricular Ejection Fraction (LVEF) measured by CMR at admission was 55% and left ventricular dysfunction was present in 24% of patients at baseline (LVEF < 50%). A total of 27 patients (14.6%) presented at least one event during hospitalization. On multivariable regression analysis, only the absence of chest pain (OR = 0.10; 95% CI [0.015-0.074]; P = 0.023) and reduced LVEF (OR = 0.87; 95% CI [0.79-0.96] P = 0.007) were identified as independent predictive factors of in-hospital outcome. During follow-up, 15 patients experienced at least one cardiovascular event. In multivariable analysis, very extensive (≥ 20%) late gadolinium enhancement (LGE) was found to be a strong prognosticator (HR = 10.65; 95% CI [1.44-78.60]; P = 0.020; Fig. 1 ) in addition to troponin, LV end-diastolic and end-systolic volumes, and reduced LVEF (all P < 0.05). The 5-year event-free survival rate was 95 ± 2% in the LGE < 20% group versus 62 ± 1% in the LGE ≥ 20% group ( p Log Rank = 0.001). During hospitalization, absence of chest pain and reduced LVEF were identified as predictive factors of presenting a cardiovascular event. A very extensive LGE was a powerful long-term prognostic marker.

85 Diuretics trajectories in dilated cardiomyopathy

Abstract Aims Diuretics in heart failure (HF) are commended to relieve symptoms at lowest dosage effective. Dilated cardiomyopathy (DCM) is a particular HF setting with several variables that may influence disease trajectory. We aimed to assess the long-term use of diuretics in DCM, the possibility of withdrawal and to explore the prognostic correlations. Methods and results All consecutive DCM patients enrolled from 1990 to 2018 were considered eligible. All the patients had available the information about the furosemide-equivalent dose at baseline and at follow-up evaluation within 24 months. Patients were categorized in stable (diuretic dose variation &amp;lt;50%), increasers (diuretics dose increase ≥50% or initiation of diuretic therapy), and decreasers (diuretics dose decrease ≥50% or never prescribed diuretics in the 24-months observation period). The prognostic role of the diuretics trajectory group was assessed with Kaplan Meier analysis and with a time-dependent multivariable model. The outcome measure was a composite of all-cause death/heart transplantation/HF hospitalization (ACD/HTx/HFH). 908 patients were included [mean age 50 ± 16, 70% male sex, 24% NYHA class III or IV, mean left ventricular ejection fraction (LVEF) 31 ± 9%, 66% treated with diuretics at baseline]. The furosemide-equivalent dose at enrolment had a linear association with the risk of outcome. Compared to other groups, decreaser patients were younger, had less HF symptoms, higher LVEF and more dilated left atrium. Decreasers had a lower prescription rate of diuretics and less frequent indication to renin-angiotensin inhibitors and mineralocorticoid receptors antagonists. Over a median follow-up of 122 (62–195) months decreasers had the lowest incidence of outcome, followed by stable, while increasers had the worst outcome (P &amp;lt; 0.001). After adjustment for other prognosticators, compared to stable patients, decreasers had a reduced risk of ACD/HTx/HFH [HR: 0.497 (95% CI: 0.337–0.731)] while increasers had the highest risk of adverse outcome [HR: 2.027 (95% CI: 1.254–3.276)]. Similarly, amongst patients taking diuretics at baseline, the diuretics withdrawal was in independent outcome predictor. The only multivariable predictors of diuretics withdrawal were younger age and lower furosemide-equivalent dose at enrolment. Conclusions In DCM patients the diuretics dose at baseline is a strong prognosticator. Diuretics dose reduction or its withdrawal provides a prognostic benefit on hard outcome. Diuretics tapering in selected patients should be considered in the short-term follow-up to improve DCM prognosis.

Loss of SATB2 Occurs More Frequently Than CDX2 Loss in Colorectal Carcinoma and Identifies Particularly Aggressive Cancers in High-Risk Subgroups

Simple SummaryThe immunohistochemical analysis of Special AT-rich sequence-binding protein 2 (SATB2) is increasingly being used to detect colorectal differentiation. Our study aimed to investigate SATB2 expression levels and the prognostic relevance of SATB2 loss in colorectal carcinoma (CRC), especially in comparison with CDX2, the standard marker of colorectal differentiation. We tested SATB2 expression in 1039 CRCs and identified SATB2 as a strong prognosticator in the overall cohort as well as in specific subcohorts, including high-risk subgroups. Compared to CDX2, SATB2 showed a higher prognostic power but was lost at a much higher frequency, generally rendering SATB2 as the less sensitive marker for colorectal differentiation compared to CDX2.Background: Special AT-rich sequence-binding protein 2 (SATB2) has emerged as an alternative immunohistochemical marker to CDX2 for colorectal differentiation. However, the distribution and prognostic relevance of SATB2 expression in colorectal carcinoma (CRC) have to be further elucidated. Methods: SATB2 expression was analysed in 1039 CRCs and correlated with clinicopathological and morphological factors, CDX2 expression as well as survival parameters within the overall cohort and in clinicopathological subgroups. Results: SATB2 loss was a strong prognosticator in univariate analyses of the overall cohort (p < 0.001 for all survival comparisons) and in numerous subcohorts including high-risk scenarios (UICC stage III/high tumour budding). SATB2 retained its prognostic relevance in multivariate analyses of these high-risk scenarios (e.g., UICC stage III: DSS: p = 0.007, HR: 1.95), but not in the overall cohort (DSS: p = 0.1, HR: 1.25). SATB2 loss was more frequent than CDX2 loss (22.2% vs. 10.2%, p < 0.001) and of higher prognostic relevance with only moderate overlap between SATB2/CDX2 expression groups. Conclusions: SATB2 loss is able to identify especially aggressive CRCs in high-risk subgroups. While SATB2 is the prognostically superior immunohistochemical parameter compared to CDX2 in univariate analyses, it appears to be the less sensitive marker for colorectal differentiation as it is lost more frequently.

Impact of Underlying Congestive Heart Failure on In-Hospital Outcomes in Patients with Septic Shock.

Purpose: Septic shock (SS) manifests with profound circulatory and cellular metabolism abnormalities and has a high in-hospital mortality (25%-50%). Congestive heart failure (CHF) patients have underlying circulatory dysfunction and compromised cardiac reserve that may place them at increased risk if they develop sepsis. Outcomes in patients with CHF who are admitted with SS have not been well studied. Materials and Method: Retrospective cross sectional secondary analysis of the Nationwide Readmission Database (NRD) for 2016 and 2017. ICD-10 codes were used to identify patients with SS during hospitalization, and then the cohort was dichotomized into those with and without an underlying diagnosis of CHF. Results: Propensity match analyses were performed to evaluate in-hospital mortality and clinical cardiovascular outcomes in the 2 groups. Cardiogenic shock patients were excluded from the study. A total of 578,629 patients with hospitalization for SS were identified, of whom 19.1% had a coexisting diagnosis of CHF. After propensity matching, 81,699 individuals were included in the comparative groups of SS with CHF and SS with no CHF. In-hospital mortality (35.28% vs 32.50%, P < .001), incidence of ischemic stroke (2.71% vs 2.53%, P = .0032), and acute kidney injury (69.9% vs 63.9%, P = .001) were significantly higher in patients with SS and CHF when compared to those with SS and no CHF. Conclusions: This study identified CHF as a strong adverse prognosticator for inpatient mortality and several major adverse clinical outcomes. Study findings suggest the need for further investigation into these findings' mechanisms to improve outcomes in patients with SS and underlying CHF.

Prognostic Value of Baseline PET/CT Imaging in Diffuse Large B-Cell Lymphoma: Does the Largest Distance between Two Lesions Play a Role in Prognosis?

Background: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) has become the international standard for diffuse large B-cell lymphoma (DLBCL) staging and is widely used for response assessment. In the past few years, the prognostic value of a variety of imaging-derived quantitative parameters has been investigated. One of these parameters is the distance between the 2 lesions that are farthest apart (Dmax). Dmax is a simple feature that captures lymphoma dissemination and has been reported to be a strong prognosticator of shorter progression-free survival (PFS) and overall survival (OS) in DLBCL patients (pts).Methods: Retrospective analysis of 146 pts with newly diagnosed Ann Arbor stage III-IV DLBCL, NOS, treated with R-CHOP(-like) regimens, between January 2010 and December 2019 in a tertiary center. Dmax was normalized with the body surface area [standardized Dmax (SDmax)]. The receiver operating characteristic curve (ROC) method was applied in resetting the optimal cut-off point for predicting prognosis and treatment outcome. The Kaplan-Meier method was used to describe time-to-event end points. A p-value of 0,05 was used as cut-off for significance.Results: Dmax was available for 40 pts. The median age at diagnosis was 63 years (24-78); 58% of pts were male. Most pts (69%) presented lactate dehydrogenase (LDH) above the upper limit of normal (ULN); 40% presented lymphopenia (lymphocyte count below 1000/μL), and 26% had albumin levels below 3.2 g/dL. Bone marrow (BM) infiltration occurred in 41% of pts, and 5% had central nervous system (CNS) involvement at diagnosis. According to the international prognostic index (IPI), 74% of pts were high-intermediate (HI) and high (H) risk; according to National Comprehensive Cancer Network (NCCN)-IPI, 68% of pts were HI and H risk. According to the cell of origin (COO) 63% of pts presented non-germinal center DLBCL. A complete metabolic response (CMR) on interim PET/CT was observed in 65% of pts, and 71% presented a CMR on end-of-treatment (EOT) PET/CT. At EOT the overall response rate was 80%. Seven percent of pts presented CNS relapse. The 5-year PFS was 58.5% and the 5-year overall survival (OS) was 69.4%.Higher SDmax was significantly associated with BM and CNS involvement at diagnosis (p=0.034 and p=0.049, respectively), as well as with CNS relapse (p=0.048). No statistically significant association was found between SDmax and the following features: lymphocyte count of < 1000/μL (p=0.505), albumin levels < 3.2 g/dL (p=0.140), LDH > ULN (p=0.501), IPI risk ≥ HI risk (p=0.719), NCCN-IPI ≥ HI risk (p=0.239) and COO (p=0.493).There was a tendency, although not significant, towards a lower rate of CMR on interim and EOT PET/CT in pts with higher SDmax (p=0.072 and p=0.077, respectively). A higher SDmax had no statistically significant impact on either PFS (HR 0.456; p=0.500) or OS (HR 0.339; p=0.561).The combination of NCCN-IPI and SDmax allowed to identify a subgroup of pts with low (L) risk and low-intermediate (LI) risk NCCN-IPI and higher (≥ 4.1cm) SDmax with inferior 5-year OS (87.5% vs 50%; HR 4.64; p=0.031) and with a trend towards an inferior 5-year PFS (75% vs 50%; HR 1.92; p=0.166).Conclusions: In our cohort, a higher SDmax was associated with some high-risk features, as well as with a trend towards an inferior response to treatment. Additionally, the combination of SDmax and NCCN-IPI allowed to identify a subgroup of L risk and LI risk pts with inferior OS and a trend towards an inferior PFS. Interpretation of these results may be limited by the small sample size. The role of Dmax in DLBCL prognostication may therefore require further validation before widespread clinical use. DisclosuresGomes: Takeda: Consultancy; Gilead: Consultancy; Janssen: Consultancy.

High Pregnane X Receptor (PXR) Expression Is Correlated with Poor Prognosis in Invasive Breast Carcinoma.

Pregnane X Receptor (PXR) is involved in human cancer, either by directly affecting carcinogenesis or by inducing drug-drug interactions and chemotherapy resistance. The clinical significance of PXR expression in invasive breast carcinoma was evaluated in the present study. PXR protein expression was assessed immunohistochemically on formalin fixed paraffin-embedded breast invasive carcinoma tissue sections, obtained from 148 patients, and was correlated with clinicopathological parameters, molecular phenotypes, tumor cells’ proliferative capacity, and overall disease-free patients’ survival. Additionally, the expression of PXR was examined on human breast carcinoma cell lines of different histological grade, hormonal status, and metastatic potential. PXR positivity was noted in 79 (53.4%) and high PXR expression in 48 (32.4%), out of 148 breast carcinoma cases. High PXR expression was positively associated with nuclear grade (p = 0.0112) and histological grade of differentiation (p = 0.0305), as well as with tumor cells’ proliferative capacity (p = 0.0051), and negatively with luminal A subtype (p = 0.0295). Associations between high PXR expression, estrogen, and progesterone receptor negative status were also recorded (p = 0.0314 and p = 0.0208, respectively). High PXR expression was associated with shorter overall patients’ survival times (log-rank test, p = 0.0009). In multivariate analysis, high PXR expression was identified as an independent prognostic factor of overall patients’ survival (Cox-regression analysis, p = 0.0082). PXR expression alterations were also noted in breast cancer cell lines of different hormonal status. The present data supported evidence that PXR was related to a more aggressive invasive breast carcinoma phenotype, being a strong and independent poor prognosticator.

1225P The progression-free survival of the first-line EGFR-TKI is a strong prognosticator of the second-line osimertinib in non-small cell lung cancer (NSCLC) patients with EGFR-T790M mutation: A real-world study

As a third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), osimertinib is recommended as standardized treatment for advanced or metastatic non-small cell lung cancer (NSCLC) patients with EGFR-T790M mutation after progressed on first-line EGFR-TKI. Our study aims to investigate the prognostic value of first-line EGFR-TKI on the second-line osimertinib in the real-world practice.

Prognostic value of right ventricular echocardiographic measures in patients with heart failure with reduced ejection fraction.

Right ventricular (RV) dysfunction is associated with poor outcome in patients with heart failure. In order to better predict mortality in this patient group we wanted to compare the prognostic value of conventional and advanced RV echocardiographic measures. Echocardiographic examinations were retrieved from 701 patients. End point was all-cause mortality and follow-up 100%. RV parameters were measured offline in accordance with current guidelines. Speckle tracking was derived using the algorithm originally designed for the left ventricle. During follow-up (median: 39 months) 118 patients (16.8%) died. RV global longitudinal strain (GLS) and RV free wall strain (FWS) remained associated with mortality after multivariable adjustment independent of Tricuspid annular plane systolic excursion (TAPSE) (RV GLS: HR 1.07, 95%CI 1.02-1.13, p=0.010, per 1% decrease) (RV FWS: HR 1.05, 95%CI 1.01-1.09, p=0.010, per 1% decrease). This seemed to be caused by significant associations in men. All RV estimates provided prognostic information incremental to established risk factors and significantly increased C-statistics. RV GLS and FWS were associated with mortality in HFrEF patients after multivariable adjustment independent of TAPSE. TAPSE, however, remained as the strongest prognosticator in women. More research is needed to identify whether speckle tracking could be superior to conventional RV measures in identifying HFrEF patients with poor outcome.

Abstract 1609: Peripheral NK-cell immunophenotypes predict progression in nasopharyngeal carcinoma patients

Abstract Objective: The tumorigenesis is closely associated with the alteration in the expression of cell-surface proteins. As NK cells play a vital role in cancer immunotherapy, we thus conducted this study to characterize the immunophenotypes of circulating NK cells and to explore the association between NK phenotypes and disease prognosis. Methods: 249 nasopharyngeal carcinoma (NPC) patients and 11 healthy individuals were recruited in the study, whose peripheral blood samples were collected before treatment. Multi-color flow cytometry analysis was performed. The expression of four inhibitory receptors, PD-1, TIGIT, LAG-3, TIM-3, and four stimulatory receptors, NKp46, NKp30, CD226, NKG2D, were measured in three NK subsets, identified by the co-expression of CD56 and CD16 when gated on CD3-. The LASSO (least absolute shrinkage and selection operator) logistic regression model was used to screen out potential prognostic NK subtypes and calculate the NK-function index. Results: NPC patients exhibited distinct peripheral NK-cell distribution and altered expression of key receptors, as characterized by increased expression of PD-1 and TIGIT on CD56+CD16- cells and decreased expression of NKp46 on CD56+CD16- and CD56-CD16- cells. Four markers were selected from the LASSO model to calculate the NK-function index: PD1 and NKp46 on CD56-CD16+ NK cells, NKp46 on CD56+CD16- cells and NKG2D on CD56+CD16+ cells. Patients with low NK index had significantly shorter progression-free survival (PFS) and distant metastasis-free survival (DMFS), and the NK-function index was an independent prognostic factor for NPC patients. Conclusions: The immunophenotype of peripheral NK cells and its association with survival outcomes of NPC patients revealed its potential as a strong prognosticator for PFS and DMFS, and highlighted the important role of circulating immune environment, especially for the application of immunotherapy. Citation Format: Xiao-Yun Li, Zi-Jian Lu, Hai-Qiang Mai. Peripheral NK-cell immunophenotypes predict progression in nasopharyngeal carcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1609.

8-Oxoguanine DNA Glycosylase (OGG1) Cys326 Variant: Increased Risk for Worse Outcome of Patients with Locally Advanced Rectal Cancer after Multimodal Therapy.

Simple SummaryIn Western countries, the lifetime risk for rectal cancer is around 1.5%. Most patients are diagnosed with locally advanced stages. For these patients, multimodal treatment comprising radiotherapy, chemotherapy, and surgery has become the standard of care. Whereas excellent local control is achieved, still about one out of three dies from this disease. Cytotoxicity of radiochemotherapy substantially involves reactive oxygen species (ROS). In ROS-related genes, we selected eight inherited variants, for which the literature reports functional or medical effects and which occur frequently in the general population. These variants were assessed whether they impact the clinical outcome of patients with rectal cancer. We found that the OGG1 Cys326 variant, which affected 37% of the 287 patients in the sample, was strongly linked with a worse outcome, in particular cancer-specific survival. Screening for this variant may identify a particular risk subgroup of patients who may be considered for more intensified therapy and aftercare.Despite excellent loco-regional control by multimodal treatment of locally advanced rectal cancer, a substantial portion of patients succumb to this disease. As many treatment effects are mediated via reactive oxygen species (ROS), we evaluated the effect of single nucleotide polymorphisms (SNPs) in ROS-related genes on clinical outcome. Based on the literature, eight SNPs in seven ROS-related genes were assayed. Eligible patients (n = 287) diagnosed with UICC stage II/III rectal cancer were treated multimodally starting with neoadjuvant radiochemotherapy (N-RCT) according to the clinical trial protocols of CAO/ARO/AIO-94, CAO/ARO/AIO-04, TransValid-A, and TransValid-B. The median follow-up was 64.4 months. The Ser326Cys polymorphism in the human OGG1 gene affected clinical outcome, in particular cancer-specific survival (CSS). This effect was comparable in extent to the ypN status, an already established strong prognosticator for patient outcome. Homozygous and heterozygous carriers of the Cys326 variant (n = 105) encountered a significantly worse CSS (p = 0.0004 according to the log-rank test, p = 0.01 upon multiple testing adjustment). Cox regression elicited a hazard ratio for CSS of 3.64 (95% confidence interval 1.70–7.78) for patients harboring the Cys326 allele. In a multivariable analysis, the effect of Cys326 on CSS was preserved. We propose the genetic polymorphism Ser326Cys as a promising biomarker for outcome in rectal cancer.

Tumour-stroma ratio is associated with Miller-Payne grading system and pathological response to neoadjuvant chemotherapy in HER2-negative breast cancer

Background: In breast cancer, the tumour-stroma ratio (TSR) has shown to be a strong prognosticator, portraying that patients with stroma-low tumours have better survival outcomes than patients with stroma-high tumours. However, the precise role of the TSR as a predictive marker for neoadjuvant chemotherapy outcome is yet unknown. Therefore, we evaluated this association for HER2-negative breast cancer in the prospective, randomized, multicenter DIRECT and NEOZOTAC trials.

Prognostic Value of 18F–FDG–PET Parameters in Patients with Small Cell Lung Cancer: A Meta-Analysis and Review of Current Literature

Many studies have suggested a prognostic value of one or several positron emission tomography (PET) parameters in patients with small cell lung cancer (SCLC). However, studies are often small, and there is a considerable interstudy disagreement about which PET parameters have a prognostic value. The objective of this study was to perform a review and meta-analysis to identify the most promising PET parameter for prognostication. PubMed®, Cochrane, and Embase® were searched for papers addressing the prognostic value of any PET parameter at any treatment phase with any endpoint in patients with SCLC. Pooled hazard ratios (HRs) were calculated by a random effects model for the prognostic value of the baseline maximum standardized uptake value (SUVmax) and metabolic tumor volume (MTV). The qualitative analysis included 38 studies, of these, 19 studies were included in the meta-analyses. The pooled results showed that high baseline MTV was prognostic for overall survival (OS) (HR: 2.83 (95% confidence interval [CI]: 2.00–4.01) and progression-free survival (PFS) (HR: 3.11 (95% CI: 1.99–4.90)). The prognostic value of SUVmax was less pronounced (OS: HR: 1.50 (95% CI: 1.17–1.91); PFS: HR: 1.24 (95% CI: 0.94–1.63)). Baseline MTV is a strong prognosticator for OS and PFS in patients with SCLC. MTV has a prognostic value superior to those of other PET parameters, but whether MTV is superior to other prognosticators of tumor burden needs further investigation.

Large-scale tumor-associated collagen signatures identify high-risk breast cancer patients.

The notion of personalized medicine demands proper prognostic biomarkers to guide the optimal therapy for an invasive breast cancer patient. However, various risk prediction models based on conventional clinicopathological factors and emergent molecular assays have been frequently limited by either a low strength of prognosis or restricted applicability to specific types of patients. Therefore, there is a critical need to develop a strong and general prognosticator.Methods: We observed five large-scale tumor-associated collagen signatures (TACS4-8) obtained by multiphoton microscopy at the invasion front of the breast primary tumor, which contrasted with the three tumor-associated collagen signatures (TACS1-3) discovered by Keely and coworkers at a smaller scale. Highly concordant TACS1-8 classifications were obtained by three independent observers. Using the ridge regression analysis, we obtained a TACS-score for each patient based on the combined TACS1-8 and established a risk prediction model based on the TACS-score. In a blind fashion, consistent retrospective prognosis was obtained from 995 breast cancer patients in both a training cohort (n= 431) and an internal validation cohort (n = 300) collected from one clinical center, and in an external validation cohort (n = 264) collected from a different clinical center.Results: TACS1-8 model alone competed favorably with all reported models in predicting disease-free survival (AUC: 0.838, [0.800-0.872]; 0.827, [0.779-0.868]; 0.807, [0.754-0.853] in the three cohorts) and stratifying low- and high-risk patients (HR 7.032, [4.869-10.158]; 6.846, [4.370-10.726], 4.423, [2.917-6.708]). The combination of these factors with the TACS-score into a nomogram model further improved the prognosis (AUC: 0.865, [0.829-0.896]; 0.861, [0.816-0.898]; 0.854, [0.805-0.894]; HR 7.882, [5.487-11.323]; 9.176, [5.683-14.816], and 5.548, [3.705-8.307]). The nomogram identified 72 of 357 (~20%) patients with unsuccessful 5-year disease-free survival that might have been undertreated postoperatively.Conclusions: The risk prediction model based on TACS1-8 considerably outperforms the contextual clinical model and may thus convince pathologists to pursue a TACS-based breast cancer prognosis. Our methodology identifies a significant portion of patients susceptible to undertreatment (high-risk patients), in contrast to the multigene assays that often strive to mitigate overtreatment. The compatibility of our methodology with standard histology using traditional (non-tissue-microarray) formalin-fixed paraffin-embedded (FFPE) tissue sections could simplify subsequent clinical translation.

Real-world outcomes in non-endemic hereditary transthyretin amyloidosis with polyneuropathy: a 20-year German single-referral centre experience

Background Hereditary transthyretin amyloidosis is caused by pathogenic variants in the TTR gene and typically manifests, alongside cardiac and other organ dysfunctions, with a rapidly progressive sensorimotor and autonomic polyneuropathy (ATTRv-PN) leading to severe disability. While most prospective studies have focussed on endemic ATTRv-PN, real-world data on non-endemic, mostly late-onset ATTRv-PN are limited. Methods This retrospective study investigated ATTRv-PN patients treated at the Amyloidosis Centre of Heidelberg University Hospital between November 1999 and July 2020. Clinical symptoms, survival, prognostic factors and efficacy of treatment with tafamidis were analysed. Neurologic outcome was assessed using the Coutinho ATTRv-PN stages, and the Peripheral Neuropathy Disability (PND) score. Results Of 346 subjects with genetic TTR variants, 168 patients had symptomatic ATTRv-PN with 32 different TTR variants identified. Of these, 81.6% had the late-onset type of ATTRv-PN. Within a mean follow-up period of 4.1 ± 2.8 years, 40.5% of patients died. Baseline plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) ≥900 ng/l (HR 3.259 [1.421–7.476]; p = .005) was the main predictor of mortality in multivariable analysis. 64 patients were treated with tafamidis and presented for regular follow-up examinations. The therapeutic benefit of tafamidis was more pronounced when treatment was started early in ATTRv-PN stage 1 (PND scores II vs. I; HR 2.718 [1.258–5.873]; p = .011). Conclusions In non-endemic, mostly late-onset ATTRv-PN, cardiac involvement assessed by NT-proBNP is a strong prognosticator for overall survival. Long-term treatment with tafamidis is safe and efficacious. Neurologic disease severity at the start of treatment is the main predictor for ATTRv-PN progression on tafamidis.

Right ventricular speckle tracking in patients with heart failure – a comparison of right ventricular measures

Abstract Background RV dysfunction is associated with increased mortality and morbidity in patients with heart failure. Due to the complex shape and position of the RV, assessing RV function from echocardiographic images remains a challenge. Purpose We have previously found that global longitudinal strain from 2DSTE is superior to left ventricular ejection fraction (LVEF) in identifying HFrEF patients with high risk of mortality. In this study we wanted to examine RV 2DSTE in patients with HFrEF and compare its prognostic value to conventional RV measures. Methods and results Echocardiographic examinations were retrieved from 701 patients with HFrEF. RV estimates were analysed offline, and end point was all-cause mortality. During follow-up (median 39 months) 118 patients (16.8%) died. RV GLS and RV FWS remained associated with mortality after multivariable adjustment, independent of TAPSE (RV GLS: HR 1.07, 95% CI 1.02–1.13, p=0.010, per 1% decrease) (RV FWS: HR 1.05, 95% CI 1.01–1.09, p=0.010, per 1% decrease). This seemed to be caused by significant associations in men as TAPSE remained as the only independent prognosticator in women. All RV estimates provided prognostic information incremental to established risk factors and significantly increased C-statistics (TAPSE: 0.74 to 0.75; RVFAC: 0.74 to 0.75; RVFWS: 0.74 to 0.77; RVGLS: 0.74 to 0.77). Conclusions RV strain from 2DSTE was associated with mortality in patients with HFrEF, independent of TAPSE and established risk factors. Our results indicate that RV strain is particularly valuable in male patients, whereas in women TAPSE remains a stronger prognosticator. RV GLS and the risk of mortality Funding Acknowledgement Type of funding source: Private company. Main funding source(s): PGJ reports receiving lecture fee from Novo Nordisk.

Tumor budding (TB) in Colorectal Cancer (CRC), The Best Slide To Count On!

Abstract Introduction/Objective TB is a strong prognosticator in CRC. The international TB consensus conference (ITBCC, 2016) proposed a “hot spot” approach for TB grading. We aimed to identify the characteristics of sections with the highest TB grade utilizing ITBCC’s method. Methods Resected CRC cases, excluding treated cases, were retrieved. All tumor sections were examined. Section TB grade(sTB) was noted. The highest sTB was deemed the final TB grade(fTB) of each case. The following categories were assessed: 1) maximum T stage; 2) presence of benign mucosa; 3) presence of a precursor lesion; 4) highest tumor volume; 5) presence of lymphovascular invasion(LVI). In cases where a given category was demonstrated in &amp;gt;1 section, the section with the highest sTB was used. High risk features (HFR) included T4, &amp;lt;12 lymph nodes, positive margin, high grade tumor, perineural invasion and LVI. Pearson’s correlation was performed to compare two groups using a p-value of &amp;lt;0.05. Results 147 cases were examined. fTB was 1=25.2%, 2=40.8% and 3=34%. 63 tumors involved the left colon and 62 had nodal disease. Of 119 cases with known MMR status 44 were MMR deficient. sTB was uniform across the categories in 101(68.7%) and uneven in 46(32.3%) cases. 12(24.5%) of 49 stage II CRC without HRF showed uneven sTB, with 2 showing 2-tier discrepancy (sTB1, fTB3). sTB was highest for category 3 (94.1%, P&amp;lt;.001), followed by category 2 (91.8%, P&amp;lt;.001), and lowest for category 1 (82.3%, P&amp;lt;.001), which remained true after subgrouping by MMR status and tumor location. Conclusion While about 70% of cases showed uniform TB grading across categories, choosing the slide(s) with a precursor lesion or benign mucosa increases the probability of correctly grading TB. Given the management implication, it may be prudent to scan all tumor slides in stage II CRC without HRF to avoid under-grading of TB.

Characterization of Extracapsular Lymph Node Involvement and Its Clinicopathological Characteristics in Stage II–IIIA Lung Adenocarcinoma

The prognostic impact and clinicopathological characteristics of extracapsular lymph node involvement (ECLNI) in patients with surgically resected lung adenocarcinoma (LUAD) remain unknown in the context of the eighth edition N classification. We retrospectively reviewed 279 patients with stage II-IIIA LUAD who underwent lobectomy and lymphadenectomy. The correlations of ECLNI presence and clinicopathological profiles were analyzed. We also assessed the impact of ECLNI on the postoperative survival of pN1 and pN2 LUAD patients. ECLNI-positive status was more common in patients with high lymph node yield and in patients with multiple stations involved. The logistic regression model identified tumor spread through air spaces, micropapillary component, cribriform component, and nodal stage as predictive factors for ECLNI presence. LUAD patients with ECLNI presence had an increased risk of locoregional recurrence compared with those without (p < 0.001). Presence of ECLNI was confirmed as an independent risk factor for worse recurrence-free survival (RFS) (p < 0.001) and overall survival (OS) (p < 0.001) in the entire cohort. Among the 61 patients with ECLNI(+)pN2 disease, our analysis revealed that adjuvant radiation was a significant predictor of improved RFS and OS. In addition, ECLNI status provides additional precision in stratifying pN1 and pN2 patients with significantly different RFS and OS. Our data suggest that ECLNI remains a strong prognosticator of unfavorable OS and RFS for LUADs in the context of the eighth edition N classification. Adjuvant radiation should be actively considered for pN1b and pN2 LUAD patients with ECLNI presence.

Concordance of tumour characteristics and survival clustering among pairs of first-degree relatives with breast cancer.

Family history is a known risk factor for breast cancer, but its prognostic value and the prognostic value of tumour characteristics in relation to family history has not been clearly established. In addition, studies of intra-familial tumour characteristics and prognosis in population-based settings are very rare. Two previous studies have suggested that breast cancer prognosis clusters within families. However, both studies lack information on HER2 expression status, which is a strong prognostic factor and could contribute to the observed results. We conducted a population-based study on 145 mother-daughter and sister-sister affected pairs using data extracted from the Geneva Cancer Registry. Histopathological characteristics were determined in archived tumour blocks by immunochemistry techniques. Breast cancer survival among family members was studied according to patient and tumour characteristics. No significant intra-familial agreement of pathological characteristic features was observed. We found that relatives of breast cancer patients experienced a much higher risk of breast cancer death compared to the general population. However, we did not find significant concordance in good and poor breast cancer-specific survival between pairs. The small number of family pairs and deaths from breast cancer may partly explain our results. Large-scale studies with accurate data on strong prognosticators are still needed to confirm the possibility of familial inheritance of breast cancer prognosis. &nbsp.