Automated digital TIL analysis (ADTA) adds prognostic value to standard assessment of depth and ulceration in primary melanoma

AbstractAccurate prognostic biomarkers in early-stage melanoma are urgently needed to stratify patients for clinical trials of adjuvant therapy. We applied a previously developed open source deep learning algorithm to detect tumor-infiltrating lymphocytes (TILs) in hematoxylin and eosin (H&E) images of early-stage melanomas. We tested whether automated digital (TIL) analysis (ADTA) improved accuracy of prediction of disease specific survival (DSS) based on current pathology standards. ADTA was applied to a training cohort (n = 80) and a cutoff value was defined based on a Receiver Operating Curve. ADTA was then applied to a validation cohort (n = 145) and the previously determined cutoff value was used to stratify high and low risk patients, as demonstrated by Kaplan–Meier analysis (p ≤ 0.001). Multivariable Cox proportional hazards analysis was performed using ADTA, depth, and ulceration as co-variables and showed that ADTA contributed to DSS prediction (HR: 4.18, CI 1.51–11.58, p = 0.006). ADTA provides an effective and attainable assessment of TILs and should be further evaluated in larger studies for inclusion in staging algorithms.

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Prognostic value of histopathology, stromal tumor infiltrating lymphocytes (sTILs) and adjuvant chemotherapy (AdjCT) in early stage triple negative breast cancer (TNBC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.533 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 533-533

Author(s):

Roberto Antonio Leon-Ferre ◽

Mei-Yin Polley ◽

Heshan Liu ◽

Judith A. Gilbert ◽

Victoria Cafourek ◽

...

Keyword(s):

Breast Cancer ◽

Proportional Hazards ◽

Multivariate Analyses ◽

Early Stage ◽

Tumor Infiltrating Lymphocytes ◽

Invasive Disease ◽

Cox Proportional Hazards ◽

Prognostic Impact ◽

N Stage ◽

The Impact

533 Background: Current guidelines define TNBC as complete absence of estrogen (ER) and progesterone receptor (PR), without HER2 amplification. However, the prognostic impact of clinical and histopathological factors, sTILs, and AdjCT in TNBC meeting these strict criteria is unknown. Methods: From a cohort of 9985 women who underwent upfront surgery for M0 breast cancer (BC) at Mayo Clinic Rochester from 1985-2012, 1159 pts with ER negative or low (≤10%) BC were identified for central ER/PR/HER2 staining and HER2 FISH (IHC2+ only) to select those with TNBC by modern definitions. Cox proportional hazards models were used to assess the impact of clinicopathological variables on invasive disease-free (IDFS) and overall survival (OS). Results: Tumors from 605 pts (median age 56.3 yrs) met criteria for TNBC (ER < 1%, PR < 1% and HER2 0, 1 or 2+ and FISH negative). 51% were T1, 65% N0, 88% grade 3, and 75% had Ki67 > 15%. Histologically, 39% were anaplastic, 26% invasive ductal, 16% medullary, 8% metaplastic, 6% apocrine and 5% others. Median sTILs was 20% (0-90%). 55% pts received AdjCT [21% anthracycline (A), 19% A + taxane, and 15% other]. Median follow-up for IDFS and OS were 7.4 and 10.6 yrs, respectively. Multivariate analyses demonstrated that higher N stage (p < 0.01), lower sTILs (p = 0.01) and no AdjCT (p < 0.01) were independently associated with worse IDFS and OS. Histology (medullary subtype) was associated with better IDFS in univariate (HR 0.56, 95% CI, 0.35-0.89) but not in multivariate analyses, once sTILs were accounted for. Among systemically untreated pts (n = 182), higher N (p < 0.01) and lower sTILs (p = 0.04) were associated with worse IDFS. For systemically untreated T1N0 pts (n = 111), the 5-yr IDFS was 70% (95% CI, 61-81) [T1a: 83% (95% CI, 63-100), T1b: 68% (95% CI, 52-88) and T1c: 67% (95% CI, 55-83)], compared to 78% (95% CI, 68-84) for T1N0 pts treated with AdjCT. Conclusions: In TNBC pts, N stage, sTILs and receipt of AdjCT were independently prognostic for IDFS and OS. sTILs remained prognostic for IDFS in systemically untreated TNBC. In N0 TNBC, the risk of recurrence or death was substantial in the absence of chemotherapy, even for those with T1 tumors.

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Prognostic impact of high stromal tumor-infiltrating lymphocytes (sTIL) in the absence of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in early stage triple negative breast cancer (TNBC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.583 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 583-583

Author(s):

Nour Abuhadra ◽

Ryan Sun ◽

Jennifer Keating Litton ◽

Gaiane M Rauch ◽

Alastair Mark Thompson ◽

...

Keyword(s):

Proportional Hazards ◽

Early Stage ◽

Pathologic Complete Response ◽

Disease Free Survival ◽

Tumor Infiltrating Lymphocytes ◽

Distant Metastases ◽

Complete Response ◽

Cox Proportional Hazards ◽

Prognostic Impact ◽

Significant Difference

583 Background: Pathologic complete response is an excellent surrogate for disease-free survival (DFS) and overall survival (OS) in TNBC. High sTIL is associated with improved pCR rates in TNBC. Recent data suggest that high sTIL is also associated with improved outcomes in patients who received no chemotherapy for early stage TNBC (Park, Annals of Oncology, 2019). Thus, we hypothesized that high sTIL may have prognostic impact in patients who do not achieve pCR to NAT. Methods: Pretreatment core biopsies from 182 patients with early-stage TNBC enrolled on the ARTEMIS trial (NCT02276443) were evaluated for sTIL by H&E. Patients were stratified according to sTIL (low < 30%, and high > 30%) and pCR (patients with pCR vs. no pCR). The primary outcome measure was DFS, defined from the date of diagnosis to the first local recurrence, distant metastases or death. Cox proportional hazards regression model was used. During follow-up 33 events for DFS were observed. Results: Among subjects who achieve pCR, DFS was excellent regardless of sTIL status and significantly better than those without pCR (p < 0.05). However, patients with high sTIL and no pCR demonstrated significantly worse DFS compared to all subjects having pCR (HR 0.18, 95% CI 0.04-0.76, p = 0.02). Additionally, we did not find a significant difference between high and low sTIL patients who did not achieve pCR. Conclusions: In early TNBC receiving NAT, for patients failing to achieve pCR, high sTIL was not associated with improved DFS; outcomes were comparable to those with low sTIL without pCR. Thus, high sTIL at baseline does not appear to confer an intrinsic prognostic benefit in the absence of pCR.

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PETCO2 gradient: a novel prognostic parameter in cardiopulmonary exercise testing

European Heart Journal ◽

10.1093/ehjci/ehaa946.1077 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

I.D Poveda Pinedo ◽

I Marco Clement ◽

O Gonzalez ◽

I Ponz ◽

A.M Iniesta ◽

...

Keyword(s):

Exercise Testing ◽

Proportional Hazards ◽

Cardiopulmonary Exercise Testing ◽

Cox Proportional Hazards ◽

Prognostic Parameter ◽

Cardiopulmonary Exercise ◽

Proportional Hazards Regression ◽

Kaplan Meier ◽

Baseline Characteristics ◽

The Difference

Abstract Background Previous parameters such as peak VO2, VE/VCO2 slope and OUES have been described to be prognostic in heart failure (HF). The aim of this study was to identify further prognostic factors of cardiopulmonary exercise testing (CPET) in HF patients. Methods A retrospective analysis of HF patients who underwent CPET from January to November 2019 in a single centre was performed. PETCO2 gradient was defined by the difference between final PETCO2 and baseline PETCO2. HF events were defined as decompensated HF requiring hospital admission or IV diuretics, or decompensated HF resulting in death. Results A total of 64 HF patients were assessed by CPET, HF events occurred in 8 (12.5%) patients. Baseline characteristics are shown in table 1. Patients having HF events had a negative PETCO2 gradient while patients not having events showed a positive PETCO2 gradient (−1.5 [IQR −4.8, 2.3] vs 3 [IQR 1, 5] mmHg; p=0.004). A multivariate Cox proportional-hazards regression analysis revealed that PETCO2 gradient was an independent predictor of HF events (HR 0.74, 95% CI [0.61–0.89]; p=0.002). Kaplan-Meier curves showed a significantly higher incidence of HF events in patients having negative gradients, p=0.002 (figure 1). Conclusion PETCO2 gradient was demonstrated to be a prognostic parameter of CPET in HF patients in our study. Patients having negative gradients had worse outcomes by having more HF events. Time to first event, decompensated heart Funding Acknowledgement Type of funding source: None

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The Efficacy of Etoposide-Based Therapy in Adult Secondary Hemophagocytic Lymphohistiocytosis

Acta Haematologica ◽

10.1159/000514920 ◽

2021 ◽

pp. 1-9

Author(s):

Leonard Naymagon ◽

Douglas Tremblay ◽

John Mascarenhas

Keyword(s):

Hemophagocytic Lymphohistiocytosis ◽

Proportional Hazards ◽

Multivariable Analysis ◽

Cox Proportional Hazards ◽

Rank Test ◽

Kaplan Meier ◽

Hazard Ratios ◽

Significant Difference ◽

The Impact

Data supporting the use of etoposide-based therapy in hemophagocytic lymphohistiocytosis (HLH) arise largely from pediatric studies. There is a lack of comparable data among adult patients with secondary HLH. We conducted a retrospective study to assess the impact of etoposide-based therapy on outcomes in adult secondary HLH. The primary outcome was overall survival. The log-rank test was used to compare Kaplan-Meier distributions of time-to-event outcomes. Multivariable Cox proportional hazards modeling was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Ninety adults with secondary HLH seen between January 1, 2009, and January 6, 2020, were included. Forty-two patients (47%) received etoposide-based therapy, while 48 (53%) received treatment only for their inciting proinflammatory condition. Thirty-three patients in the etoposide group (72%) and 32 in the no-etoposide group (67%) died during follow-up. Median survival in the etoposide and no-etoposide groups was 1.04 and 1.39 months, respectively. There was no significant difference in survival between the etoposide and no-etoposide groups (log-rank <i>p</i> = 0.4146). On multivariable analysis, there was no association between treatment with etoposide and survival (HR for death with etoposide = 1.067, 95% CI: 0.633–1.799, <i>p</i> = 0.8084). Use of etoposide-based therapy was not associated with improvement in outcomes in this large cohort of adult secondary HLH patients.

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Evaluation of Changes on World Stock Exchanges in Connection with the SARS-CoV-2 Pandemic. Survival Analysis Methods

Risks ◽

10.3390/risks9070121 ◽

2021 ◽

Vol 9 (7) ◽

pp. 121

Author(s):

Beata Bieszk-Stolorz ◽

Krzysztof Dmytrów

Keyword(s):

Survival Analysis ◽

Proportional Hazards ◽

Proportional Hazards Model ◽

Stock Exchange ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Stock Exchanges ◽

Analysis Methods ◽

Hazards Model ◽

Kaplan Meier

The aim of our research was to compare the intensity of decline and then increase in the value of basic stock indices during the SARS-CoV-2 coronavirus pandemic in 2020. The survival analysis methods used to assess the risk of decline and chance of rise of the indices were: Kaplan–Meier estimator, logit model, and the Cox proportional hazards model. We observed the highest intensity of decline in the European stock exchanges, followed by the American and Asian plus Australian ones (after the fourth and eighth week since the peak). The highest risk of decline was in America, then in Europe, followed by Asia and Australia. The lowest risk was in Africa. The intensity of increase was the highest in the fourth and eleventh week since the minimal value had been reached. The highest odds of increase were in the American stock exchanges, followed by the European and Asian (including Australia and Oceania), and the lowest in the African ones. The odds and intensity of increase in the stock exchange indices varied from continent to continent. The increase was faster than the initial decline.

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Association between milk and yogurt intake and mortality: a community-based cohort study (Yamagata study)

BMC Nutrition ◽

10.1186/s40795-021-00435-1 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Akiko Nakanishi ◽

Erika Homma ◽

Tsukasa Osaki ◽

Ri Sho ◽

Masayoshi Souri ◽

...

Keyword(s):

Proportional Hazards ◽

Proportional Hazards Model ◽

Hazard Analysis ◽

Total Mortality ◽

Cox Proportional Hazards ◽

Cox Proportional Hazards Model ◽

Milk Intake ◽

Community Based ◽

Hazards Model ◽

Kaplan Meier

Abstract Background Dairy products are known as health-promoting foods. This study prospectively examined the association between milk and yogurt intake and mortality in a community-based population. Methods The study population comprised of 14,264 subjects aged 40–74 years who participated in an annual health checkup. The frequency of yogurt and milk intake was categorized as none (< 1/month), low (< 1/week), moderate (1–6/week), and high (> 1/day) intake. The association between yogurt and milk intake and total, cardiovascular, and cancer-related mortalities was determined using the Cox proportional hazards model. Results During the follow-up period, there were 265 total deaths, 40 cardiovascular deaths and 90 cancer-related deaths. Kaplan–Meier analysis showed that the total mortality in high/moderate/low yogurt intake and moderate/low milk intake groups was lower than that in none group (log-rank, P < 0.01). In the multivariate Cox proportional hazard analysis adjusted for possible confounders, the hazard ratio (HR) for total mortality significantly decreased in high/moderate yogurt intake group (HR: 0.62, 95% confidence interval [CI]: 0.42–0.91 for high intake, HR: 0.70, 95%CI: 0.49–0.99 for moderate intake) and moderate milk intake group (HR: 0.67, 95% CI: 0.46–0.97) compared with the none yogurt and milk intake groups. A similar association was observed for cancer-related mortality, but not for cardiovascular mortality. Conclusions Our study showed that yogurt and milk intake was independently associated with a decrease in total and cancer-related mortalities in the Japanese population.

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Inter-pregnancy interval and later pediatric cardiovascular health of the offspring – a population-based cohort study

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174420001130 ◽

2020 ◽

pp. 1-5

Author(s):

Majdi Imterat ◽

Tamar Wainstock ◽

Eyal Sheiner ◽

Gali Pariente

Keyword(s):

Proportional Hazards ◽

Proportional Hazards Model ◽

Population Based ◽

Cox Proportional Hazards ◽

Cardiovascular Morbidity ◽

Cox Proportional Hazards Model ◽

Hazards Model ◽

Kaplan Meier ◽

Inter Pregnancy Interval

Abstract Recent evidence suggests that a long inter-pregnancy interval (IPI: time interval between live birth and estimated time of conception of subsequent pregnancy) poses a risk for adverse short-term perinatal outcome. We aimed to study the effect of short (<6 months) and long (>60 months) IPI on long-term cardiovascular morbidity of the offspring. A population-based cohort study was performed in which all singleton live births in parturients with at least one previous birth were included. Hospitalizations of the offspring up to the age of 18 years involving cardiovascular diseases and according to IPI length were evaluated. Intermediate interval, between 6 and 60 months, was considered the reference. Kaplan–Meier survival curves were used to compare the cumulative morbidity incidence between the groups. Cox proportional hazards model was used to control for confounders. During the study period, 161,793 deliveries met the inclusion criteria. Of them, 14.1% (n = 22,851) occurred in parturient following a short IPI, 78.6% (n = 127,146) following an intermediate IPI, and 7.3% (n = 11,796) following a long IPI. Total hospitalizations of the offspring, involving cardiovascular morbidity, were comparable between the groups. The Kaplan–Meier survival curves demonstrated similar cumulative incidences of cardiovascular morbidity in all groups. In a Cox proportional hazards model, short and long IPI did not appear as independent risk factors for later pediatric cardiovascular morbidity of the offspring (adjusted HR 0.97, 95% CI 0.80–1.18; adjusted HR 1.01, 95% CI 0.83–1.37, for short and long IPI, respectively). In our population, extreme IPIs do not appear to impact long-term cardiovascular hospitalizations of offspring.

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Effects of antiarrhythmic drugs on atrioventricular conduction in patients with preexisting bundle branch block

European Heart Journal ◽

10.1093/ehjci/ehaa946.3358 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

S Kochav ◽

R.C Chen ◽

J.M.D Dizon ◽

J.A.R Reiffel

Keyword(s):

Proportional Hazards ◽

Cox Proportional Hazards ◽

Class I ◽

Class Iii ◽

Bundle Branch Block ◽

Kaplan Meier ◽

Cox Proportional Hazards Models ◽

Hazard Ratios ◽

History Of ◽

Propensity Score Stratification

Abstract Background Theoretical concern exists regarding AV block (AVB) with class I antiarrhythmics (AADs) when bundle branch block (BBB) is present. Whether this is substantiated in real-world populations is unknown. Purpose To determine the relationship between type of AAD and incidence of AVB in patients with preexisting BBB. Methods We retrospectively studied all patients with BBB who received class I and III AADs between 1997–2019 to compare incidence of AVB. We defined index time as first exposure to either drug class and excluded patients with prior AVB or exposed to both classes. Time-at-risk window ended at first outcome occurrence or when patients were no longer observed in the database. We estimated hazard ratios for incident AVB using Cox proportional hazards models with propensity score stratification, adjusting for over 32,000 covariates from the electronic health record. Kaplan-Meier methods were used to determine treatment effects over time. Results Of 40,120 individuals with BBB, 148 were exposed to a class I AAD and 2401 to a class III AAD. Over nearly 4,200 person-years of follow up, there were 22 and 620 outcome events in the class I and class III cohorts, respectively (Figure). In adjusted analyses, AVB risk was markedly lower in patients exposed to class I AADs compared with class III (HR 0.48 [95% CI 0.30–0.75]). Conclusion Among patients with BBB, exposure to class III AADs was strongly associated with greater risk of incident AVB. This likely reflects differences in natural history of patients receiving class I vs class III AADs rather than adverse class III effects, however, the lack of worse outcomes acutely with class I AADs suggests that they may be safer in BBB than suspected. Funding Acknowledgement Type of funding source: None

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Impact of KRAS mutational status on outcomes in patients with pancreatic cancer (PDAC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4142 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4142-4142

Author(s):

Lucy Xiaolu Ma ◽

Gun Ho Jang ◽

Amy Zhang ◽

Robert Edward Denroche ◽

Anna Dodd ◽

...

Keyword(s):

Proportional Hazards ◽

Advanced Disease ◽

Cox Proportional Hazards ◽

Prognostic Impact ◽

First Line ◽

Kras Mutations ◽

Kaplan Meier ◽

Mutational Status ◽

Translational Research Program ◽

The Impact

4142 Background: KRAS mutations (m) (KRASm) are present in over 90% of pancreatic adenocarcinomas (PDAC) with a predominance of G12 substitutions. KRAS wildtype (WT) PDAC relies on alternate oncogenic drivers, and the prognostic impact of these remains unknown. We evaluated alterations in WT PDAC and explored the impact of specific KRASm and WT status on survival. Methods: WGS and RNAseq were performed on 570 patients (pts) ascertained through our translational research program from 2012-2021, of which 443 were included for overall survival (OS) analyses. This included 176 pts with resected and 267 pts with advanced PDAC enrolled on the COMPASS trial (NCT02750657). The latter cohort underwent biopsies prior to treatment with first line gemcitabine-nab-paclitaxel or mFOLFIRINOX as per physician choice. The Kaplan-Meier and Cox proportional hazards methods were used to estimate OS. Results: KRAS WT PDAC (n = 52) represented 9% of pts, and these cases trended to be younger than pts with KRASm (median age 61 vs 65 years p = 0.1). In resected cases, the most common alterations in WT PDAC (n = 23) included GNASm (n = 6) and BRAFm/fusions (n = 5). In advanced WT PDAC (n = 27), alterations in BRAF (n = 11) and ERBB2/3/4 (n = 6) were most prevalent. Oncogenic fusions (NTRK, NRG1, BRAF/RAF, ROS1, others) were identified in 9 pts. The BRAF in-frame deletion p.486_491del represented the most common single variant in WT PDAC, with organoid profiling revealing sensitivity to both 3rd generation BRAF inhibitors and MEK inhibition. In resected PDAC, multivariable analyses documented higher stage (p = 0.043), lack of adjuvant chemotherapy (p < 0.001), and the KRAS G12D variant (p = 0.004) as poor prognostic variables. In advanced disease, neither WT PDAC nor KRAS specific alleles had an impact on prognosis (median OS WT = 8.5 mths, G12D = 8.2, G12V = 10.0, G12R = 12.0, others = 9.2, p = 0.73); the basal-like RNA subtype conferred inferior OS (p < 0.001). A targeted therapeutic approach following first line chemotherapy was undertaken in 10% of pts with advanced PDAC: MMRd (n = 1), homologous recombination deficiency (HRD) (n = 19), KRASG12C (n = 1), CDK4/6 amplification (n = 3), ERBB family alterations (n = 2), BRAF variants (n = 2). OS in this group was superior (14.7 vs 8.8 mths, p = 0.04), mainly driven by HRD-PDAC where KRASm were present in 89%. Conclusions: In our dataset, KRAS G12D is associated with inferior OS in resected PDAC, however KRAS mutational status was not prognostic in advanced disease. This suggests that improved OS in the WT PDAC population can only be achieved if there is accelerated access to targeted drugs for pts.

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D-dimer as a biomarker for assessment of COVID-19 prognosis: D-dimer levels on admission and its role in predicting disease outcome in hospitalized patients with COVID-19

PLoS ONE ◽

10.1371/journal.pone.0256744 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0256744

Author(s):

Ayusha Poudel ◽

Yashasa Poudel ◽

Anurag Adhikari ◽

Barun Babu Aryal ◽

Debika Dangol ◽

...

Keyword(s):

Proportional Hazards ◽

Characteristic Curve ◽

Area Under The Curve ◽

Respiratory Illness ◽

Immunofluorescence Assay ◽

Cox Proportional Hazards ◽

Optimal Cutoff ◽

Cutoff Value ◽

Potential Biomarker ◽

D Dimer

Introduction Coronavirus Disease 2019 is a primarily respiratory illness that can cause thrombotic disorders. Elevation of D-dimer is a potential biomarker for poor prognosis in COVID-19, though optimal cutoff value for D-dimer to predict mortality has not yet been established. This study aims to assess the accuracy of admission D-dimer in the prognosis of COVID-19 and to establish the optimal cutoff D-dimer value to predict hospital mortality. Methods Clinical and laboratory parameters and outcomes of confirmed COVID-19 cases admitted to four hospitals in Kathmandu were retrospectively analyzed. Admitted COVID-19 cases with recorded D-dimer and definitive outcomes were included consecutively. D-dimer was measured using immunofluorescence assay and reported in Fibrinogen Equivalent Unit (μg/ml). The receiver operating characteristic curve was used to determine the accuracy of D-dimer in predicting mortality, and to calculate the optimal cutoff value, based on which patients were divided into two groups and predictive value of D-dimer for mortality was measured. Results 182 patients were included in the study out of which 34(18.7%) died during the hospital stay. The mean admission D-dimer among surviving patients was 1.067 μg/ml (±1.705 μg/ml), whereas that among patients who died was 3.208 μg/ml (±2.613 μg/ml). ROC curve for D-dimer and mortality gave an area under the curve of 0.807 (95% CI 0.728–0.886, p<0.001). Optimal cutoff value for D-dimer was 1.5 μg/ml (sensitivity 70.6%, specificity 78.4%). On Cox proportional hazards regression analysis, the unadjusted hazard ratio for high D-dimer was 6.809 (95% CI 3.249–14.268, p<0.001), and 5.862 (95% CI 2.751–12.489, p<0.001) when adjusted for age. Conclusion D-dimer value on admission is an accurate biomarker for predicting mortality in patients with COVID-19. 1.5 μg/ml is the optimal cutoff value of admission D-dimer for predicting mortality in COVID-19 patients.

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