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Discrete lifetime data are very common in engineering and medical researches. In many cases the lifetime is censored at a random or predetermined time and we do not know the complete survival time. There are many situations that the lifetime variable could be dependent on the time of censoring. In this paper we propose the dependent right censoring scheme in discrete setup when the lifetime and censoring variables have a bivariate geometric distribution. We obtain the maximum likelihood estimators of the unknown parameters with their risks in closed forms. The Bayes estimators as well as the constrained Bayes estimates of the unknown parameters under the squared error loss function are also obtained. We considered an extension to the case where covariates are present along with the data. Finally we provided a simulation study and an illustrative example with a real data. [ABSTRACT FROM AUTHOR]

In this paper, we introduce classical and Bayesian approaches for the Basu–Dhar bivariate geometric distribution in the presence of covariates and censored data. This distribution is considered for the analysis of bivariate lifetime as an alternative to some existing bivariate lifetime distributions assuming continuous lifetimes as the Block and Basu or Marshall and Olkin bivariate distributions. Maximum likelihood and Bayesian estimators are presented. Two examples are considered to illustrate the proposed methodology: an example with simulated data and an example with medical bivariate lifetime data. [ABSTRACT FROM PUBLISHER]

Background: Only a subset of gastric cancer (GC) patients with stage II-III benefits from chemotherapy after surgery. Tumour infiltrating lymphocytes per area (TIL density) has been suggested as a potential predictive biomarker of chemotherapy benefit., Methods: We quantified TIL density in digital images of haematoxylin-eosin (HE) stained tissue using deep learning in 307 GC patients of the Yonsei Cancer Center (YCC) (193 surgery+adjuvant chemotherapy [S + C], 114 surgery alone [S]) and 629 CLASSIC trial GC patients (325 S + C and 304 S). The relationship between TIL density, disease-free survival (DFS) and clinicopathological variables was analysed., Results: YCC S patients and CLASSIC S patients with high TIL density had longer DFS than S patients with low TIL density (P = 0.007 and P = 0.013, respectively). Furthermore, CLASSIC patients with low TIL density had longer DFS if treated with S + C compared to S (P = 0.003). No significant relationship of TIL density with other clinicopathological variables was found., Conclusion: This is the first study to suggest TIL density automatically quantified in routine HE stained tissue sections as a novel, clinically useful biomarker to identify stage II-III GC patients deriving benefit from adjuvant chemotherapy. Validation of our results in a prospective study is warranted., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Introduction: The relationship between the chemical composition of food products and their sensory profile is a complex association confronting many challenges. However, new untargeted methodologies are helping correlate metabolites with sensory characteristics in a simpler manner. Nevertheless, in the pilot phase of a project, where only a small set of products are used to explore the relationships, choices have to be made about the most appropriate untargeted metabolomics methodology., Objective: To provide a framework for selecting a metabolite-sensory methodology based on: the quality of measurements, the relevance of the detected metabolites in terms of distinguishing between products or in terms of whether they can be related to the sensory attributes of the products., Methods: In this paper we introduce a systematic approach to explore all these different aspects driving the choice for the most appropriate metabolomics method., Results: As an example we have used a tomato soup project where the choice between two sampling methods (SPME and SBSE) had to be made. The results are not always consistently pointing to the same method as being the best. SPME was able to detect metabolites with a better precision, SBSE seemed to be able to provide a better distinction between the soups., Conclusion: The three levels of comparison provide information on how the methods could perform in a follow up study and will help the researcher to make a final selection for the most appropriate method based on their strengths and weaknesses., (© 2021. The Author(s).)

Background: Gastric and gastro-esophageal junction cancers (GCs) frequently recur after resection, but markers to predict recurrence risk are missing. T-cell infiltrates have been validated as prognostic markers in other cancer types, but not in GC because of methodological limitations of past studies. We aimed to define and validate the prognostic role of major T-cell subtypes in GC by objective computational quantification., Methods: Surgically resected chemotherapy-naïve GCs were split into discovery (n = 327) and validation (n = 147) cohorts. CD8 (cytotoxic), CD45RO (memory), and FOXP3 (regulatory) T-cell densities were measured through multicolor immunofluorescence and computational image analysis. Cancer-specific survival (CSS) was assessed. All statistical tests were two-sided., Results: CD45RO-cell and FOXP3-cell densities statistically significantly predicted CSS in both cohorts. Stage, CD45RO-cell, and FOXP3-cell densities were independent predictors of CSS in multivariable analysis; mismatch repair (MMR) and Epstein-Barr virus (EBV) status were not statistically significant. Combining CD45RO-cell and FOXP3-cell densities into the Stomach Cancer Immune Score showed highly statistically significant (all P ≤ .002) CSS differences (0.9 years median CSS to not reached). T-cell infiltrates were highest in EBV-positive GCs and similar in MMR-deficient and MMR-proficient GCs., Conclusion: The validation of CD45RO-cell and FOXP3-cell densities as prognostic markers in GC may guide personalized follow-up or (neo)adjuvant treatment strategies. Only those 20% of GCs with the highest T-cell infiltrates showed particularly good CSS, suggesting that a small subgroup of GCs is highly immunogenic. The potential for T-cell densities to predict immunotherapy responses should be assessed. The association of high FOXP3-cell densities with longer CSS warrants studies into the biology of regulatory T cells in GC., (© The Author(s) 2020. Published by Oxford University Press.)

Despite the use of multimodal treatment, survival of esophageal cancer (EC) patients remains poor. One proposed explanation for the relatively poor response to cytotoxic chemotherapy is intratumor heterogeneity. The aim was to establish a statistical model to objectively measure intratumor heterogeneity of the proportion of tumor (IHPoT) and to use this newly developed method to measure IHPoT in the pretreatment biopsies from from EC patients recruited to the OE02 trial. A statistical mixed effect model (MEM) was established for estimating IHPoT based on variation in hematoxylin/eosin (HE) stained pretreatment biopsy pieces from the same individual in 218 OE02 trial patients (103 treated by chemotherapy and surgery (chemo+surgery); 115 patients treated by surgery alone). The relationship between IHPoT, prognosis, chemotherapy survival benefit, and clinicopathological variables was assessed. About 97 (44.5%) and 121 (55.5%) ECs showed high and low IHPoT, respectively. There was no significant difference in IHPoT between surgery (median [range], 0.1637 [0-3.17]) and chemo+surgery (median [range], 0.1692 [0-2.69]) patients (P = 0.43). Chemo+surgery patients with low IHPoT had a significantly longer survival than surgery patients (HR = 1.81, 95% CI: 1.20-2.75, P = 0.005). There was no survival difference between chemo+surgery and surgery patients with high IHPoT (HR = 1.15, 95% CI: 0.72-1.81, P = 0.566). This is the first study suggesting that IHPoT measured in the pretreatment biopsy can predict chemotherapy survival benefit in EC patients. IHPoT may represent a clinically useful biomarker for patient treatment stratification. Future studies should determine if pathologists can reliably estimate IHPoT., (© The Author(s) 2020. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Neoadjuvant chemotherapy (NAC) remains an important therapeutic option for advanced oesophageal cancer (OC). Pathological tumour regression grade (TRG) may offer additional information by directing adjuvant treatment and/or follow-up but its clinical value remains unclear. We analysed the prognostic value of TRG and associated pathological factors in OC patients enrolled in the Medical Research Council (MRC) OE02 trial., Methods and Results: Histopathology was reviewed in 497 resections from OE02 trial participants randomised to surgery (S group; n = 244) or NAC followed by surgery [chemotherapy plus surgery (CS) group; n = 253]. The association between TRG groups [responders (TRG1-3) versus non-responders (TRG4-5)], pathological lymph node (LN) status and overall survival (OS) was analysed. One hundred and ninety-five of 253 (77%) CS patients were classified as 'non-responders', with a significantly higher mortality risk compared to responders [hazard ratio (HR) = 1.53, 95% confidence interval (CI) = 1.05-2.24, P = 0.026]. OS was significantly better in patients without LN metastases irrespective of TRG [non-responders HR = 1.87, 95% CI = 1.33-2.63, P < 0.001 versus responders HR = 2.21, 95% CI = 1.11-4.10, P = 0.024]. In multivariate analyses, LN status was the only independent factor predictive of OS in CS patients (HR = 1.93, 95% CI = 1.42-2.62, P < 0.001). Exploratory subgroup analyses excluding radiotherapy-exposed patients (n = 48) showed similar prognostic outcomes., Conclusion: Lymph node status post-NAC is the most important prognostic factor in patients with resectable oesophageal cancer, irrespective of TRG. Potential clinical implications, e.g. adjuvant treatment or intensified follow-up, reinforce the importance of LN dissection for staging and prognostication., (© 2018 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background: It is uncertain whether repeated measurements of a multi-target biomarker panel may help to personalize medical heart failure (HF) therapy to improve outcome in chronic HF., Methods: This analysis included 499 patients from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF), aged ≥ 60 years, LVEF ≤ 45%, and NYHA ≥ II, who had repeated clinical visits within 19 months follow-up. The interaction between repeated measurements of biomarkers and treatment effects of loop diuretics, spironolactone, β-blockers, and renin-angiotensin system (RAS) inhibitors on risk of HF hospitalization or death was investigated in a hypothesis-generating analysis. Generalized estimating equation (GEE) models were used to account for the correlation between recurrences of events in a patient., Results: One hundred patients (20%) had just one event (HF hospitalization or death) and 87 (17.4%) had at least two events. Loop diuretic up-titration had a beneficial effect for patients with high interleukin-6 (IL6) or high high-sensitivity C-reactive protein (hsCRP) (interaction, P  = 0.013 and P  = 0.001), whereas the opposite was the case with low hsCRP (interaction, P  = 0.013). Higher dosage of loop diuretics was associated with poor outcome in patients with high blood urea nitrogen (BUN) or prealbumin (interaction, P  = 0.006 and P  = 0.001), but not in those with low levels of these biomarkers. Spironolactone up-titration was associated with lower risk of HF hospitalization or death in patients with high cystatin C (CysC) (interaction, P  = 0.021). β-Blockers up-titration might have a beneficial effect in patients with low soluble fms-like tyrosine kinase-1 (sFlt) (interaction, P  = 0.021). No treatment biomarker interactions were found for RAS inhibition., Conclusion: The data of this post hoc analysis suggest that decision-making using repeated biomarker measurements may be very promising in bringing treatment of heart failure to a new level in the context of predictive, preventive, and personalized medicine. Clearly, prospective testing is needed before this novel concept can be adopted., Clinical Trial Registration: isrctn.org, identifier: ISRCTN43596477., Competing Interests: Compliance with ethical standardsThe study was approved by the ethics committees of each center, and each patient gave written informed consent before entering the study.Biomarker measurement was done by Roche Diagnostics. Hans-Peter Brunner-La Rocca received unrestricted research grants from Roche Diagnostics. The other authors report no conflicts of interest related to this topic. The other authors have declared that no competing interests exist.

Background: Although heart failure (HF) patients are known to experience repeated hospitalizations, most studies evaluated only time to first event. N-Terminal B-type natriuretic peptide (NT-proBNP)-guided therapy has not convincingly been shown to improve HF-specific outcomes, and effects on recurrent all-cause hospitalization are uncertain. Therefore, we investigated the effect of NT-proBNP-guided therapy on recurrent events in HF with the use of a time-between-events approach in a hypothesis-generating analysis., Methods and Results: The Trial of Intensified Versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized 499 HF patients, aged ≥60 years, left ventricular ejection fraction ≤45%, New York Heart Association functional class ≥I,I to NT-proBNP-guided versus symptom-guided therapy for 18 months, with further follow-up for 5.5 years. The effect of NT-proBNP-guided therapy on recurrent HF-related and all-cause hospitalizations and/or all-cause death was explored. One hundred four patients (49 NT-proBNP-guided, 55 symptom-guided) experienced 1 and 275 patients (133 NT-proBNP-guided, 142 symptom-guided) experienced ≥2 all-cause hospitalization events. Regarding HF hospitalization, 132 patients (57 NT-proBNP-guided, 75 symptom-guided) experienced 1 and 122 patients (57 NT-proBNP-guided, 65 symptom-guided) experienced ≥2 events. NT-proBNP-guided therapy was significant in preventing 2nd all-cause hospitalizations (hazard ratio [HR] 0.83; P = .01), in contrast to nonsignificant results in preventing 1st all-cause hospitalization events (HR 0.91; P = .35). This was not the case regarding HF hospitalization events (HR 0.85 [P = .14] vs HR 0.73 [P = .01]) The beneficial effect of NT-proBNP-guided therapy was seen only in patients aged <75 years, and not in those aged ≥75 years (interaction terms with P = .01 and P = .03 for all-cause hospitalization and HF hospitalization events, respectively)., Conclusion: NT-proBNP-guided therapy reduces the risk of recurrent events in patients <75 years of age. This included all-cause hospitalization by mainly reducing later events, adding knowledge to the neutral effect on this end point when shown using time-to-first-event analysis only., Clinical Trial Registration: isrctn.org, identifier: ISRCTN43596477., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)