A Bayesian method to estimate the optimal threshold of a marker used to select patients' treatment

2019 ◽  
Vol 29 (1) ◽  
pp. 29-43
Author(s):  
Yoann Blangero ◽  
Muriel Rabilloud ◽  
René Ecochard ◽  
Fabien Subtil
Keyword(s):  
Utility Function ◽  
Expected Utility ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Credible Interval ◽  
Optimal Threshold ◽  
Selection Marker ◽  
Large Sample Size ◽  
Marker Distribution ◽  
Definition Of

The use of a quantitative treatment selection marker to choose between two treatment options requires the estimate of an optimal threshold above which one of these two treatments is preferred. Herein, the optimal threshold expression is based on the definition of a utility function which aims to quantify the expected utility of the population (e.g. life expectancy, quality of life) by taking into account both efficacy (success or failure) and toxicity of each treatment option. Therefore, the optimal threshold is the marker value that maximizes the expected utility of the population. A method modelling the marker distribution in patient subgroups defined by the received treatment and the outcome is proposed to calculate the parameters of the utility function so as to estimate the optimal threshold and its 95% credible interval using the Bayesian inference. The simulation study found that the method had low bias and coverage probability close to 95% in multiple settings, but also the need of large sample size to estimate the optimal threshold in some settings. The method is then applied to the PETACC-8 trial that compares the efficacy of chemotherapy with a combined chemotherapy + anti-epidermal growth factor receptor in stage III colorectal cancer.

scholarly journals Optimal threshold estimator of a prognostic marker by maximizing a time-dependent expected utility function for a patient-centered stratified medicine

2016 ◽  
Vol 27 (6) ◽  
pp. 1847-1859 ◽  
Author(s):  
Etienne Dantan ◽  
Yohann Foucher ◽  
Marine Lorent ◽  
Magali Giral ◽  
Philippe Tessier
Keyword(s):  
Utility Function ◽  
Kidney Transplant ◽  
Expected Utility ◽  
Time Dependent ◽  
Optimal Threshold ◽  
Stratified Medicine ◽  
Quality Adjusted Life Years ◽  
Patient Centered ◽  
Life Years ◽  
Quality Adjusted Life

Defining thresholds of prognostic markers is essential for stratified medicine. Such thresholds are mostly estimated from purely statistical measures regardless of patient preferences potentially leading to unacceptable medical decisions. Quality-Adjusted Life-Years are a widely used preferences-based measure of health outcomes. We develop a time-dependent Quality-Adjusted Life-Years-based expected utility function for censored data that should be maximized to estimate an optimal threshold. We performed a simulation study to compare estimated thresholds when using the proposed expected utility approach and purely statistical estimators. Two applications illustrate the usefulness of the proposed methodology which was implemented in the R package ROCt ( www.divat.fr ). First, by reanalysing data of a randomized clinical trial comparing the efficacy of prednisone vs. placebo in patients with chronic liver cirrhosis, we demonstrate the utility of treating patients with a prothrombin level higher than 89%. Second, we reanalyze the data of an observational cohort of kidney transplant recipients: we conclude to the uselessness of the Kidney Transplant Failure Score to adapt the frequency of clinical visits. Applying such a patient-centered methodology may improve future transfer of novel prognostic scoring systems or markers in clinical practice.

scholarly journals Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3807
Author(s):  
Pierangela Sepe ◽  
Arianna Ottini ◽  
Chiara Carlotta Pircher ◽  
Andrea Franza ◽  
Melanie Claps ◽  
...  
Keyword(s):  
Renal Cell ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Case Reports ◽  
Treatment Options ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Mtor Inhibitors ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described diseases, often characterized by bad prognosis and with no standard treatments available. The gap in their clinical management is linked to the poor molecular characterization in handling the treatment of non clear-cell RCC with untailored therapies. Due to their rarity, non-clear RCC are in fact under-represented in prospective randomized trials. Thus, treatment choices are based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. Over the last two decades, various options have been considered as the mainstay for the treatment of metastatic RCC (mRCC), including angiogenesis inhibitors, vascular endothelial growth factor receptor inhibitors, other tyrosine kinase inhibitors (TKIs), as well as MET inhibitors and mammalian targeting of rapamycin (mTOR) inhibitors. More recently, the therapeutic armamentarium has been enriched with immunotherapy, alone or in combination with targeted agents that have been shown to significantly improve outcomes of mRCC patients, if compared to TKI single-agent. It has been widely proven that non-clear cell RCC is a morphologically and clinically distinct entity from its clear cell counterpart but more knowledge about its biology is certainly needed. Histology-specific collaborative trials are in fact now emerging to investigate different treatments for non-clear cell RCC. This review summarizes pathogenetic mechanisms of non-clear cell RCC, the evolution of treatment paradigms over the last few decades, with a focus on immunotherapy-based trials, and future potential treatment options.

scholarly journals Molecular Subtypes and Precision Oncology in Intrahepatic Cholangiocarcinoma

2021 ◽  
Vol 10 (13) ◽  
pp. 2803
Author(s):  
Carolin Czauderna ◽  
Martha M. Kirstein ◽  
Hauke C. Tews ◽  
Arndt Vogel ◽  
Jens U. Marquardt
Keyword(s):  
Clinical Care ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Specific Treatment ◽  
Growth Factor Receptor ◽  
Treatment Modalities ◽  
Precision Oncology ◽  
Recurrence Rates ◽  
Isocitrate Dehydrogenase 1 ◽  
Liver Cancers

Cholangiocarcinomas (CCAs) are the second-most common primary liver cancers. CCAs represent a group of highly heterogeneous tumors classified based on anatomical localization into intra- (iCCA) and extrahepatic CCA (eCCA). In contrast to eCCA, the incidence of iCCA is increasing worldwide. Curative treatment strategies for all CCAs involve oncological resection followed by adjuvant chemotherapy in early stages, whereas chemotherapy is administered at advanced stages of disease. Due to late diagnosis, high recurrence rates, and limited treatment options, the prognosis of patients remains poor. Comprehensive molecular characterization has further revealed considerable heterogeneity and distinct prognostic and therapeutic traits for iCCA and eCCA, indicating that specific treatment modalities are required for different subclasses. Several druggable alterations and oncogenic drivers such as fibroblast growth factor receptor 2 gene fusions and hotspot mutations in isocitrate dehydrogenase 1 and 2 mutations have been identified. Specific inhibitors have demonstrated striking antitumor activity in affected subgroups of patients in phase II and III clinical trials. Thus, improved understanding of the molecular complexity has paved the way for precision oncological approaches. Here, we outline current advances in targeted treatments and immunotherapeutic approaches. In addition, we delineate future perspectives for different molecular subclasses that will improve the clinical care of iCCA patients.

scholarly journals The APAC Score: A Novel and Highly Performant Serological Tool for Early Diagnosis of Hepatocellular Carcinoma in Patients with Liver Cirrhosis

2021 ◽  
Vol 10 (15) ◽  
pp. 3392
Author(s):  
Joeri Lambrecht ◽  
Mustafa Porsch-Özçürümez ◽  
Jan Best ◽  
Fabian Jost-Brinkmann ◽  
Christoph Roderburg ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
At Risk ◽  
Liver Cirrhosis ◽  
Early Stage ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Serum Samples ◽  
Disease Etiology ◽  
Risk Patients ◽  
Scoring Tool

(1) Background: Surveillance of at-risk patients for hepatocellular carcinoma (HCC) is highly necessary, as curative treatment options are only feasible in early disease stages. However, to date, screening of patients with liver cirrhosis for HCC mostly relies on suboptimal ultrasound-mediated evaluation and α-fetoprotein (AFP) measurement. Therefore, we sought to develop a novel and blood-based scoring tool for the identification of early-stage HCC. (2) Methods: Serum samples from 267 patients with liver cirrhosis, including 122 patients with HCC and 145 without, were collected. Expression levels of soluble platelet-derived growth factor receptor beta (sPDGFRβ) and routine clinical parameters were evaluated, and then utilized in logistic regression analysis. (3) Results: We developed a novel serological scoring tool, the APAC score, consisting of the parameters age, sPDGFRβ, AFP, and creatinine, which identified patients with HCC in a cirrhotic population with an AUC of 0.9503, which was significantly better than the GALAD score (AUC: 0.9000, p = 0.0031). Moreover, the diagnostic accuracy of the APAC score was independent of disease etiology, including alcohol (AUC: 0.9317), viral infection (AUC: 0.9561), and NAFLD (AUC: 0.9545). For the detection of patients with (very) early (BCLC 0/A) HCC stage or within Milan criteria, the APAC score achieved an AUC of 0.9317 (sensitivity: 85.2%, specificity: 89.2%) and 0.9488 (sensitivity: 91.1%, specificity 85.3%), respectively. (4) Conclusions: The APAC score is a novel and highly accurate serological tool for the identification of HCC, especially for early stages. It is superior to the currently proposed blood-based algorithms, and has the potential to improve surveillance of the at-risk population.

scholarly journals Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 184
Author(s):  
Kalpana K. Bhanumathy ◽  
Amrutha Balagopal ◽  
Frederick S. Vizeacoumar ◽  
Franco J. Vizeacoumar ◽  
Andrew Freywald ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Tyrosine Protein Kinase ◽  
Mesenchymal Epithelial Transition Factor ◽  
The Impact

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

Re-use of erlotinib in a patient using osimertinib after erlotinib, case report

2021 ◽  
pp. 107815522110191
Author(s):  
Pinar Gursoy
Keyword(s):  
Lung Cancer ◽  
Case Report ◽  
Treatment Options ◽  
Resistance Mutation ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Development Of Resistance ◽  
Exon 19

Introduction Most patients with non-small-cell lung cancer tumors that have epidermal growth factor receptor (EGFR) mutations have deletion mutations in exon 19 or exon 21, or both.In recent years, targeted therapies in lung cancer have increased survival, but the development of resistance to these drugs poses a major problem. Thesubstitution of methionineforthreonine at position 790 (T790M) mutation,is primarily responsible for this resistance. However, after osimertinib used in T790M positivepatients treatment options are generally limited to chemotherapy. Case report We reported the efficacy of erlotinib, which we reapplied due to the disappearance of the resistance mutation after osimertinib in a 68-year-old patient using osimertinib after erlotinib. Management and outcome: In the patient using erlotinib due to exon 19 deletion when progression was observed and T790M positivity was detected, osimertinib treatment was initiated. However, when T790M was found to be negative with rebiopsy in progression after osimertinib, a complete response was achieved by restarting erlotinib. Discussion The strategy of restarting erlotinib treatment with negative T790M mutation detected in biopsies of patients with osimertinib resistance may be an acceptable treatment option.

Rash and Mucositis Associated With Mycoplasma pneumoniae and Chlamydophila pneumoniae: A Recurrence of MIRM?

2020 ◽  
Author(s):  
Danielle Brazel ◽  
Brooke Kulp ◽  
Geoanna Bautista ◽  
Andrew Bonwit
Keyword(s):  
Mycoplasma Pneumoniae ◽  
Treatment Options ◽  
Specific Treatment ◽  
Corticosteroid Treatment ◽  
Stevens Johnson Syndrome ◽  
First Case ◽  
Johnson Syndrome ◽  
Vesicular Rash ◽  
Recurrent Aphthous Ulcers ◽  
Definition Of

Abstract Introduction A new concept has come to light recently, that is, Mycoplasma-induced rash and mucositis (MIRM). Here, we report the first case of recurrent rash, mucositis, and conjunctivitis involving Mycoplasma pneumoniae and C. pneumoniae that fits under the criteria of what is currently defined as MIRM. Case Presentation A patient aged 12 years with a history of recurrent aphthous ulcers presented in 2013 with worsening oral lesions, conjunctivitis, and vesicular rash. Her respiratory polymerase chain reaction (PCR) panel was positive for M. pneumoniae. She was diagnosed with Stevens-Johnson syndrome (SJS) secondary to M. pneumoniae and treated with a macrolide, acyclovir, and intravenous immunoglobulin (IVIG). The same patient returned 3 years later with an identical constellation of symptoms, at which time her PCR was positive for C. pneumoniae. In addition to IVIG and a macrolide, a corticosteroid treatment was administered. Discussion Here, we present the case of a pediatric patient with a recurrence of mucocutaneous disease that is more consistent with MIRM than the proposed SJS or erythema multiforme (EM) documented via histology. Our patient’s symptoms were controlled with azithromycin and IVIG and, in the second episode, with corticosteroids as well. This case adds to that of Mayor-Ibarguren et al, providing further evidence that C. pneumonia may also be a trigger for MIRM. Patients will benefit from expanding the definition of MIRM, as the pathogenesis differs from SJS and EM and could result in more specific treatment options.

ORAL CANCER BIOCHEMICAL RESEARCH: CURRENT STATUS AND EMERGING FRONTIERS

2021 ◽  
Vol 1 (1) ◽  
pp. 10-16
Author(s):  
Radu Radulescu ◽  
Alexandra Totan ◽  
Daniela Miricescu ◽  
Maria Greabu
Keyword(s):  
Oral Cancer ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
B Cell Lymphoma ◽  
Current Status ◽  
Inflammatory Factors ◽  
Ki 67 ◽  
Proliferation Markers ◽  
Genomic Markers ◽  
Biochemical Research

Cancer represents one of the leading causes or mortality worldwide, oral cancer accounting for almost 9% of deaths, early diagnosis playing a crucial role. Salivary biomarkers analysis is proving to be an alternative diagnosis method. Oral cancer biomarkers can be compounds that play role in every aspect of malignancy from triggering factors to markers of progression, inflammation or invasiveness. There are numerous genomic markers, ranging from well known ones such as p16, p21, p27 and p53 genes, cyclin D1, EGFR gene (epidermal growth factor receptor), C-kit gene (KIT proto-oncogene, receptor tyrosine kinase), bcl-6(B-cell lymphoma 6 protein gene) to least studied ones such as OXSR1(oxidative stress-responsive kinase-1gene). Proteomic markers range from inflammatory factors such as interleukins IL-8 and Il-6, transcription factors such as FOXO3 (forkhead box O3) protein and S100B protein, matrix metalloproteinases (MMP) involved in extracellular matrix degradation and their inhibitors (TIMP - tissue inhibitor of metalloproteinases), specific proliferation markers such as Ki-67 protein and many more. Developing saliva based oral cancer screening and prognosis tests may lead to better treatment options.

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