Sentinel Lymph Node Biopsy (SLNB) for Early-Stage Head and Neck Squamous-Cell Carcinoma of the Tongue: Twenty Years of Experience at I.N.T. "G.Pascale".

Oral tongue squamous-cell carcinoma (OTSCC) is the most prevalent malignancy in the head and neck region. Lymphatic spread, particularly to cervical lymph nodes, significantly impacts 5-year survival rates, emphasizing the criticality of precise staging. Metastatic cervical lymph nodes can decrease survival rates by 50%. Yet, elective neck dissection (END) in T1-2 cN0 patients proves to be an overtreatment in around 80% of cases. To address this, sentinel lymph node biopsy (SLNB) was introduced, aiming to minimize postoperative morbidity. This study, conducted at the ENT and Maxillofacial Surgery department of the Istituto Nazionale Tumori in Naples, explores SLNB's efficacy in early-stage oral tongue squamous-cell carcinoma (OTSCC). From January 2020 to January 2022, 122 T1/T2 cN0 HNSCC patients were enrolled. Radioactive tracers and lymphoscintigraphy identified sentinel lymph nodes, aided by a gamma probe during surgery. Results revealed 24.6% SLN biopsy positivity, with 169 SLNs resected and a 21.9% positivity ratio. The study suggests SLNB's reliability for T1-2 cN0 OTSCC patient staging and early micrometastasis detection.

Translational Insights in the Landscape of Salivary Gland Cancers: Ready for a New Era?

Salivary gland carcinomas (SGCs) are rare neoplasms, representing less than 10% of all head and neck tumors, but they are extremely heterogeneous from the histological point of view, their clinical behavior, and their genetics. The guidelines regarding their treatment include surgery in most cases, which can also play an important role in oligometastatic disease. Where surgery cannot be used, systemic therapy comes into play. Systemic therapy for many years has been represented by polychemotherapy, but recently, with the affirmation of translational research, it can also count on targeted therapy, at least in some subtypes of SGCs. Interestingly, in some SGC histotypes, predominant mutations have been identified, which in some cases behave as "driver mutations", namely mutations capable of governing the carcinogenesis process. Targeting these driver mutations may be an effective therapeutic strategy. Nonetheless, it is not always possible to have drugs suitable for targeting driver mutations-and targeting driver mutations is not always accompanied by a clinical benefit. In this review, we will analyze the main mutations predominant in the various histotypes of SGCs.

Preliminary data on artificial intelligence tool in magnetic resonance imaging assessment of degenerative pathologies of lumbar spine.

PURPOSE: To evaluate the ability of an artificial intelligence (AI) tool in magnetic resonance imaging (MRI) assessment of degenerative pathologies of lumbar spine using radiologist evaluation as a gold standard. METHODS: Patients with degenerative pathologies of lumbar spine, evaluated with MRI study, were enrolled in a retrospective study approved by local ethical committee. A comprehensive software solution (CoLumbo; SmartSoft Ltd., Varna, Bulgaria) designed to label the segments of the lumbar spine and to detect a broad spectrum of degenerative pathologies based on a convolutional neural network (CNN) was employed, utilizing an automatic segmentation. The AI tool efficacy was compared to data obtained by a senior neuroradiologist that employed a semiquantitative score. Chi-square test was used to assess the differences among groups, and Spearman's rank correlation coefficient was calculated between the grading assigned by radiologist and the grading obtained by software. Moreover, agreement was assessed between the value assigned by radiologist and software. RESULTS: Ninety patients (58 men; 32 women) affected with degenerative pathologies of lumbar spine and aged from 60 to 81 years (mean 66 years) were analyzed. Significant correlations were observed between grading assigned by radiologist and the grading obtained by software for each localization. However, only when the localization was L2-L3, there was a good correlation with a coefficient value of 0.72. The best agreements were obtained in case of L1-L2 and L2-L3 localizations and were, respectively, of 81.1% and 72.2%. The lowest agreement of 51.1% was detected in case of L4-L5 locations. With regard canal stenosis and compression, the highest agreement was obtained for identification of in L5-S1 localization. CONCLUSIONS: AI solution represents an efficacy and useful toll degenerative pathologies of lumbar spine to improve radiologist workflow.

Machine learning-based radiomics analysis in predicting RAS mutational status using magnetic resonance imaging.

PURPOSE: To assess the efficacy of radiomics features, obtained by magnetic resonance imaging (MRI) with hepatospecific contrast agent, in pre-surgical setting, to predict RAS mutational status in liver metastases. METHODS: Patients with MRI in pre-surgical setting were enrolled in a retrospective study. Manual segmentation was made by means 3D Slicer image computing, and 851 radiomics features were extracted as median values using the PyRadiomics Python package. The features were extracted considering the agreement with the Imaging Biomarker Standardization Initiative (IBSI). Balancing was performed through synthesis of samples for the underrepresented classes using the self-adaptive synthetic oversampling (SASYNO) approach. Inter- and intraclass correlation coefficients (ICC) were calculated to assess the between-observer and within-observer reproducibility of all radiomics characteristics. For continuous variables, nonparametric Wilcoxon-Mann-Whitney test was utilized. Benjamini and Hochberg's false discovery rate (FDR) adjustment for multiple testing was used. Receiver operating characteristics (ROC) analysis with the calculation of area under the ROC curve (AUC), sensitivity (SENS), specificity (SPEC), positive predictive value (PPV), negative predictive value (NPV) and accuracy (ACC) were assessed for each parameter. Linear and non-logistic regression model (LRM and NLRM) and different machine learning-based classifiers including decision tree (DT), k-nearest neighbor (KNN) and support vector machine (SVM) were considered. Moreover, features selection were performed before and after a normalized procedure using two different methods (3-sigma and z-score). McNemar test was used to assess differences statistically significant between dichotomic tables. All statistical procedures were done using MATLAB R2021b Statistics and Machine Toolbox (MathWorks, Natick, MA, USA). RESULTS: Seven normalized radiomics features, extracted from arterial phase, 11 normalized radiomics features, from portal phase, 12 normalized radiomics features from hepatobiliary phase and 12 normalized features from T2-W SPACE sequence were robust predictors of RAS mutational status. The multivariate analysis increased significantly the accuracy in RAS prediction when a LRM was used, combining 12 robust normalized features extracted by VIBE hepatobiliary phase reaching an accuracy of 99%, a sensitivity 97%, a specificity of 100%, a PPV of 100% and a NPV of 98%. No statistically significant increase was obtained, considering the tested classifiers DT, KNN and SVM, both without normalization and with normalization methods. CONCLUSIONS: Normalized approach in MRI radiomics analysis allows to predict RAS mutational status.

Oxidative stress and mitochondrial dysfunction in brain of vinclozolin exposed animals.

Vinclozolin (VCZ) is a widely used fungicide in agriculture, especially in fruits and wine. Various studies have detailed the effects of VCZ exposure on different organs, but no information is available on its effects on brain tissues. This paper investigated the effects of VCZ exposure on the oxidative stress and mitochondrial dysfunction in brain tissue. C57BL/6 mice were exposed to VCZ (100 mg/kg) by oral gavage for 28 days. Mitochondrial homeostasis, often known as mitochondrial quality control, involves a range of processes, including mitochondrial biogenesis, mitochondrial fusion and fission, mitophagy and autophagy. VCZ administration modified the mRNA expression levels of Sirt1, Sirt3, PGC-1α, TFAM, Nrf1, VDAC-1 and Cyt c in brain tissue, as compared to control animals (CTR). The analyses also showed increased oxidative stress, in particular VCZ administration reduced SOD and CAT activities and GSH levels while increased T-AOC levels and lipid peroxidation. Additionally, brain tissues from VCZ group showed DNA oxidation (increased PARP-1 immunostaining) and apoptosis (increased TUNEL+ cells, increased expression of Bax mRNA level and reduced Bcl-2 levels). Western blot and immunohistochemical analyses showed increased mitophagic pathway with the accumulation of PINK1 and Parkin in mitochondria. Additionally, autophagic pathway was also increased with the increased expression and colocalization of LC3 with Neun and GFAP. Overall, this study showed that chronic VCZ exposure impaired mitochondrial homeostasis and increased oxidative stress in brain tissues.

Calcified uterine leiomyoma from an 18th-century nunnery in North Italy.

OBJECTIVE: To develop a differential diagnosis of a mass retrieved alongside skeletal remains in the crypt of the church of Santissima Annunziata of Valenza (Province of Alessandria, Northern Italy). MATERIAL: A calcified mass measuring 40 × 39 mm and 17.62 × 16.3817.62 × 16.38 mm. METHOD: The analysis utilized macroscopic assessment and histologic examination (including histochemical and immunohistochemical analyses). RESULTS: Morphological traits include an irregular and spongy external surface. Holes of different sizes lead toward the inner part of the object. A section of the mass shows an "intertwined bundle" pattern, confirmed by microscopic examination. CONCLUSIONS: Differential diagnosis determined the mass to be consistent with calcified leiomyoma. SIGNIFICANCE: Identifying uterine leiomyoma adds to the paucity of paleopathological literature on the condition and to calcified tumors more broadly. It also allows for an important discussion of women's gynecological health in the past and potentially among nulliparous women. LIMITATIONS: Neither histochemical staining nor immunohistochemical analysis demonstrated the certain muscular nature of the specimens due to the rehydration and decalcification processes, for which there are no gold standards. SUGGESTIONS FOR FURTHER RESEARCH: Calcified masses are common in the clinical literature but remain rare in paleopathological literature. Careful excavation and improved recognition of apparently calcified masses are necessary to improve recognition, diagnosis, and interpretation.

An Informative Review of Radiomics Studies on Cancer Imaging: The Main Findings, Challenges and Limitations of the Methodologies.

The aim of this informative review was to investigate the application of radiomics in cancer imaging and to summarize the results of recent studies to support oncological imaging with particular attention to breast cancer, rectal cancer and primitive and secondary liver cancer. This review also aims to provide the main findings, challenges and limitations of the current methodologies. Clinical studies published in the last four years (2019-2022) were included in this review. Among the 19 studies analyzed, none assessed the differences between scanners and vendor-dependent characteristics, collected images of individuals at additional points in time, performed calibration statistics, represented a prospective study performed and registered in a study database, conducted a cost-effectiveness analysis, reported on the cost-effectiveness of the clinical application, or performed multivariable analysis with also non-radiomics features. Seven studies reached a high radiomic quality score (RQS), and seventeen earned additional points by using validation steps considering two datasets from two distinct institutes and open science and data domains (radiomics features calculated on a set of representative ROIs are open source). The potential of radiomics is increasingly establishing itself, even if there are still several aspects to be evaluated before the passage of radiomics into routine clinical practice. There are several challenges, including the need for standardization across all stages of the workflow and the potential for cross-site validation using real-world heterogeneous datasets. Moreover, multiple centers and prospective radiomics studies with more samples that add inter-scanner differences and vendor-dependent characteristics will be needed in the future, as well as the collecting of images of individuals at additional time points, the reporting of calibration statistics and the performing of prospective studies registered in a study database.

Scientific Status Quo of Small Renal Lesions: Diagnostic Assessment and Radiomics.

Background: Small renal masses (SRMs) are defined as contrast-enhanced renal lesions less than or equal to 4 cm in maximal diameter, which can be compatible with stage T1a renal cell carcinomas (RCCs). Currently, 50-61% of all renal tumors are found incidentally. Methods: The characteristics of the lesion influence the choice of the type of management, which include several methods SRM of management, including nephrectomy, partial nephrectomy, ablation, observation, and also stereotactic body radiotherapy. Typical imaging methods available for differentiating benign from malignant renal lesions include ultrasound (US), contrast-enhanced ultrasound (CEUS), computed tomography (CT), and magnetic resonance imaging (MRI). Results: Although ultrasound is the first imaging technique used to detect small renal lesions, it has several limitations. CT is the main and most widely used imaging technique for SRM characterization. The main advantages of MRI compared to CT are the better contrast resolution and tissue characterization, the use of functional imaging sequences, the possibility of performing the examination in patients allergic to iodine-containing contrast medium, and the absence of exposure to ionizing radiation. For a correct evaluation during imaging follow-up, it is necessary to use a reliable method for the assessment of renal lesions, represented by the Bosniak classification system. This classification was initially developed based on contrast-enhanced CT imaging findings, and the 2019 revision proposed the inclusion of MRI features; however, the latest classification has not yet received widespread validation. Conclusions: The use of radiomics in the evaluation of renal masses is an emerging and increasingly central field with several applications such as characterizing renal masses, distinguishing RCC subtypes, monitoring response to targeted therapeutic agents, and prognosis in a metastatic context.

Machine Learning and Radiomics Analysis for Tumor Budding Prediction in Colorectal Liver Metastases Magnetic Resonance Imaging Assessment.

PURPOSE: We aimed to assess the efficacy of machine learning and radiomics analysis using magnetic resonance imaging (MRI) with a hepatospecific contrast agent, in a pre-surgical setting, to predict tumor budding in liver metastases. METHODS: Patients with MRI in a pre-surgical setting were retrospectively enrolled. Manual segmentation was made by means 3D Slicer image computing, and 851 radiomics features were extracted as median values using the PyRadiomics Python package. Balancing was performed and inter- and intraclass correlation coefficients were calculated to assess the between observer and within observer reproducibility of all radiomics extracted features. A Wilcoxon-Mann-Whitney nonparametric test and receiver operating characteristics (ROC) analysis were carried out. Balancing and feature selection procedures were performed. Linear and non-logistic regression models (LRM and NLRM) and different machine learning-based classifiers including decision tree (DT), k-nearest neighbor (KNN) and support vector machine (SVM) were considered. RESULTS: The internal training set included 49 patients and 119 liver metastases. The validation cohort consisted of a total of 28 single lesion patients. The best single predictor to classify tumor budding was original_glcm_Idn obtained in the T1-W VIBE sequence arterial phase with an accuracy of 84%; wavelet_LLH_firstorder_10Percentile was obtained in the T1-W VIBE sequence portal phase with an accuracy of 92%; wavelet_HHL_glcm_MaximumProbability was obtained in the T1-W VIBE sequence hepatobiliary excretion phase with an accuracy of 88%; and wavelet_LLH_glcm_Imc1 was obtained in T2-W SPACE sequences with an accuracy of 88%. Considering the linear regression analysis, a statistically significant increase in accuracy to 96% was obtained using a linear weighted combination of 13 radiomic features extracted from the T1-W VIBE sequence arterial phase. Moreover, the best classifier was a KNN trained with the 13 radiomic features extracted from the arterial phase of the T1-W VIBE sequence, obtaining an accuracy of 95% and an AUC of 0.96. The validation set reached an accuracy of 94%, a sensitivity of 86% and a specificity of 95%. CONCLUSIONS: Machine learning and radiomics analysis are promising tools in predicting tumor budding. Considering the linear regression analysis, there was a statistically significant increase in accuracy to 96% using a weighted linear combination of 13 radiomics features extracted from the arterial phase compared to a single radiomics feature.

An overview on multimodal imaging for the diagnostic workup of pleural mesothelioma.

Pleural mesothelioma (PM) is an aggressive disease that has a strong causal relationship with asbestos exposure and represents a major challenge from both a diagnostic and therapeutic viewpoint. Despite recent improvements in patient care, PM typically carries a poor outcome, especially in advanced stages. Therefore, a timely and effective diagnosis taking advantage of currently available imaging techniques is essential to perform an accurate staging and dictate the most appropriate treatment strategy. Our aim is to provide a brief, but exhaustive and up-to-date overview of the role of multimodal medical imaging in the management of PM.

Elongated styloid process of an autopsied skull from the Cemetery of Santa Maria Maggiore in Vercelli, 18th-19th century (Piedmont, northern Italy).

We discuss the coexistence of a postmortem cut and a pathological alteration, recorded on a skeleton belonging to an adult man that was discovered during the archaeological investigations of the cemetery of the Church of Santa Maria Maggiore in Vercelli (northern Italy, 18th-19th century). The skull presents an oblique cleft, which from the top of the frontal bone bends towards the occipital, and the left styloid process is elongated compared to normal values (48 mm). The elongated styloid process is due to the ossification of the styloid ligament which has several possible causes. To increase the knowledge about this pathological condition in the past, it was necessary to compare all the data present in the literature today and consider the few cases published in the paleopathological field. In this paper, our main goals are: i) to investigate the reasons for which the craniotomy was performed; ii) to examine the possible cause of the ossification of the styloid process, described as Eagle's syndrome; iii) to enrich the archaeological literature of elongated styloid process cases and iv) to investigate the presence of a hypothetical relationship between the autopsy cut and the diagnosed Eagle's syndrome on this skull.

Redox Modulation of Meniere Disease by Coriolus Versicolor Treatment, a Nutritional Mushroom Approach with Neuroprotective Potential.

BACKGROUND: Meniere's disease (MD) is a cochlear neurodegenerative disease. Hearing loss appears to be triggered by oxidative stress in the ganglion neurons of the inner ear. OBJECTIVE: Here, we confirm the variation of markers of oxidative stress and inflammation in patients with Meniere and hypothesize that chronic treatment with Coriolus mushroom helps in the response to oxidative stress and acts on α-synuclein and on NF-kB-mediated inflammatory processes. METHODS: Markers of oxidative stress and inflammation were evaluated in MD patients with or without Coriolus treatment for 3 or 6 months. RESULTS: MD patients had a small increase in Nrf2, HO-1, γ-GC, Hsp70, Trx and sirtuin-1, which were further increased by Coriolus treatment, especially after 6 months. Increased markers of oxidative damage, such as protein carbonyls, HNE, and ultraweak chemiluminescence, associated with a decrease in plasma GSH/GSSG ratio, were also observed in lymphocytes from MD patients. These parameters were restored to values similar to the baseline in patients treated with Coriolus for both 3 and 6 months. Furthermore, treated MD subjects showed decreased expression of α-synuclein, GFAP and Iba-1 proteins and modulation of the NF-kB pathway, which were impaired in MD patients. These changes were greatest in subjects taking the supplements for 6 months. CONCLUSIONS: Our study suggests MD as a model of cochlear neurodegenerative disease for the identification of potent inducers of the Nrf2-vitagene pathway, able to reduce the deleterious consequences associated with neurodegenerative damage, probably by indirectly acting on α-synuclein expression and on inflammatory processes NF- kB-mediated.

Comments on "Current status and quality of radiomic studies for predicting KRAS mutations in colorectal cancer patients: A systematic review and meta-analysis".

We read with interest the article from Dr Jia LL and colleagues in Eur J Radiol in which they assessed the methodological quality of radiomics-based studies for non-invasive preoperative prediction of Kirsten rat sarcoma (KRAS) mutations in patients with colorectal cancer. They systematically evaluated the prediction models diagnostic accuracy of twenty-nine studies between February 2014 and March 2022 and we congratulate the Authors on their accuracy in reporting recent published manuscript about radiomics-based studies to predict KRAS mutations in patients with colorectal cancer however they did not report the impact of contrast administration and the different phases of the contrast study (arterial, portal and transient phase) compared to the EOB phase in this research field.

Oligo-metastatic neoPlasms from the gastro-intestinal tract: iDentIfiCaTIon of cliNical and molecular drivers: the PREDICTION study.

BACKGROUND: Metastatic disease in tumors originating from the gastrointestinal tract can exhibit varying degrees of tumor burden at presentation. Some patients follow a less aggressive disease course, characterized by a limited number of metastatic sites, referred to as "oligo-metastatic disease" (OMD). The precise biological characteristics that define the oligometastatic behavior remain uncertain. In this study, we present a protocol designed to prospectively identify OMD, with the aim of proposing novel therapeutic approaches and monitoring strategies. METHODS: The PREDICTION study is a monocentric, prospective, observational investigation. Enrolled patients will receive standard treatment, while translational activities will involve analysis of the tumor microenvironment and genomic profiling using immunohistochemistry and next-generation sequencing, respectively. The first primary objective (descriptive) is to determine the prevalence of biological characteristics in OMD derived from gastrointestinal tract neoplasms, including high genetic concordance between primary tumors and metastases, a significant infiltration of T lymphocytes, and the absence of clonal evolution favoring specific driver genes (KRAS and PIK3CA). The second co-primary objective (analytic) is to identify a prognostic score for true OMD, with a primary focus on metastatic colorectal cancer. The score will comprise genetic concordance (> 80%), high T-lymphocyte infiltration, and the absence of clonal evolution favoring driver genes. It is hypothesized that patients with true OMD (score 3+) will have a lower rate of progression/recurrence within one year (20%) compared to those with false OMD (80%). The endpoint of the co-primary objective is the rate of recurrence/progression at one year. Considering a reasonable probability (60%) of the three factors occurring simultaneously in true OMD (score 3+), using a significance level of α = 0.05 and a test power of 90%, the study requires a minimum enrollment of 32 patients. DISCUSSION: Few studies have explored the precise genetic and biological features of OMD thus far. In clinical settings, the diagnosis of OMD is typically made retrospectively, as some patients who undergo intensive treatment for oligometastases develop polymetastatic diseases within a year, while others do not experience disease progression (true OMD). In the coming years, the identification of true OMD will allow us to employ more personalized and comprehensive strategies in cancer treatment. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT05806151.

Psyche and human thought from the anatomies of the past.

De Blasio's research focuses on the anthropology of the late 19th and early 20th centuries. His investigations extend from criminalistics to ancient mummies, driven by his passion for archaeology and human history. He delves into the intricate relationship between anatomy and the human psyche, intertwining disciplines like archaeology, anthropology, and history. His examination of ancient human remains, though lacking modern tools, reveals insights into embalming practices and cultural beliefs. De Blasio's interest in craniology leads to the exploration of cranial deformations, considering as cultural factors. By connecting anthropology with psychology, he questions the cognitive effects of cranial deformations and even associates certain traits with skull morphology. This interplay showcases his ability to merge natural and cultural sciences, offering unique perspectives on human development and cultural practices.

Imaging of human papilloma virus (HPV) related oropharynx tumour: what we know to date.

The tumours of head and neck district are around 3% of all malignancies and squamous cell carcinoma is the most frequent histotype, with rapid increase during the last two decades because of the increment of the infection due to human papilloma virus (HPV). Even if the gold standard for the diagnosis is histological examination, including the detection of viral DNA and transcription products, imaging plays a fundamental role in the detection and staging of HPV + tumours, in order to assess the primary tumour, to establish the extent of disease and for follow-up. The main diagnostic tools are Computed Tomography (CT), Positron Emission Tomography-Computed Tomography (PET-CT) and Magnetic Resonance Imaging (MRI), but also Ultrasound (US) and the use of innovative techniques such as Radiomics have an important role. Aim of our review is to illustrate the main imaging features of HPV + tumours of the oropharynx, in US, CT and MRI imaging. In particular, we will outline the main limitations and strengths of the various imaging techniques, the main uses in the diagnosis, staging and follow-up of disease and the fundamental differential diagnoses of this type of tumour. Finally, we will focus on the innovative technique of texture analysis, which is increasingly gaining importance as a diagnostic tool in aid of the radiologist.

Radiomics and artificial intelligence analysis by T2-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging to predict Breast Cancer Histological Outcome.

OBJECTIVE: The objective of the study was to evaluate the accuracy of radiomics features obtained by MR images to predict Breast Cancer Histological Outcome. METHODS: A total of 217 patients with malignant lesions were analysed underwent MRI examinations. Considering histological findings as the ground truth, four different types of findings were used in both univariate and multivariate analyses: (1) G1 + G2 vs G3 classification; (2) presence of human epidermal growth factor receptor 2 (HER2 + vs HER2 -); (3) presence of the hormone receptor (HR + vs HR -); and (4) presence of luminal subtypes of breast cancer. RESULTS: The best accuracy for discriminating HER2 + versus HER2 - breast cancers was obtained considering nine predictors by early phase T1-weighted subtraction images and a decision tree (accuracy of 88% on validation set). The best accuracy for discriminating HR + versus HR - breast cancers was obtained considering nine predictors by T2-weighted subtraction images and a decision tree (accuracy of 90% on validation set). The best accuracy for discriminating G1 + G2 versus G3 breast cancers was obtained considering 16 predictors by early phase T1-weighted subtraction images in a linear regression model with an accuracy of 75%. The best accuracy for discriminating luminal versus non-luminal breast cancers was obtained considering 27 predictors by early phase T1-weighted subtraction images and a decision tree (accuracy of 94% on validation set). CONCLUSIONS: The combination of radiomics analysis and artificial intelligence techniques could be used to support physician decision-making in prediction of Breast Cancer Histological Outcome.

Hormesis defines the limits of lifespan.

This commentary provides a novel synthesis of how biological systems adapt to a broad spectrum of environmental and age-related stresses that are underlying causes of numerous degenerative diseases and debilitating effects of aging. It proposes that the most fundamental, evolutionary-based integrative strategy to sustain and protect health is based on the concept of hormesis. This concept integrates anti-oxidant, anti-inflammatory and cellular repair responses at all levels of biological organization (i.e., cell, organ and organism) within the framework of biphasic dose responses that describe the quantitative limits of biological plasticity in all cells and organisms from bacteria and plants to humans. A major feature of the hormetic concept is that low levels of biological, chemical, physical and psychological stress upregulate adaptive responses that not only precondition, repair and restore normal functions to damaged tissues/organs but modestly overcompensate, reducing ongoing background damage, thereby enhancing health beyond that in control groups, lacking the low level "beneficial" stress. Higher doses of such stress often become counterproductive and eventually harmful. Hormesis is active throughout the life-cycle and can be diminished by aging processes affecting the onset and severity of debilitating conditions/diseases, especially in elderly subjects. The most significant feature of the hormetic dose response is that the limits of biological plasticity for adaptive processes are less than twice that of control group responses, with most, at maximum, being 30-60 % greater than control group values. Yet, these modest increases can make the difference between health or disease and living or dying. The quantitative features of these adaptive hormetic dose responses are also independent of mechanism. These features of the hormetic dose response determine the capacity to which systems can adapt/be protected, the extent to which biological performance (e.g., memory, resistance to injury/disease, wound healing, hair growth or lifespan) can be enhanced/extended and the extent to which synergistic interactions may occur. Hormesis defines the quantitative rules within which adaptive processes operate and is central to evolution and biology and should become transformational for experimental concepts and study design strategies, public health practices and a vast range of therapeutic strategies and interventions.