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Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions.

ABSTRACT: The interest in tumor-infiltrating lymphocytes (TILs) as a prognostic biomarker in breast cancer has grown in recent years. Biomarkers must undergo comprehensive evaluation in terms of analytical validity, clinical validity and clinical utility before they can be accepted as part of clinical practice. The International Immuno-Oncology Biomarker Working Group has developed a practice guideline on scoring TILs in breast cancer in order to standardize TIL assessment. The prognostic value of TILs as a biomarker in early-stage breast cancer has been established by assessing tumor samples in thousands of patients from large prospective clinical trials of adjuvant therapy. There is a strong linear relationship between increase in TILs and improved disease-free survival for triple-negative and HER2-positive disease. Higher levels of TILs have also been associated with increased rates of pathological complete response to neoadjuvant therapy. TILs have potential clinical utility in breast cancer in a number of areas. These include prediction of responders to immune checkpoint blockade, identification of primary HER2-positive and triple-negative patients who have excellent prognoses and may thus be appropriate for treatment de-escalation, and potentially incorporation into a neoadjuvant endpoint which may be a better surrogate maker for drug development.

SUBMITTER: Wein L

PROVIDER: S-EPMC5540942 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions.

Wein Lironne L Savas Peter P Luen Stephen J SJ Virassamy Balaji B Salgado Roberto R Loi Sherene S

Frontiers in oncology 20170803

The interest in tumor-infiltrating lymphocytes (TILs) as a prognostic biomarker in breast cancer has grown in recent years. Biomarkers must undergo comprehensive evaluation in terms of analytical validity, clinical validity and clinical utility before they can be accepted as part of clinical practice. The International Immuno-Oncology Biomarker Working Group has developed a practice guideline on scoring TILs in breast cancer in order to standardize TIL assessment. The prognostic value of TILs as ...[more]

PMID: 28824872

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Project description:Glucocorticoids are the most effective anti-inflammatory therapy for asthma yet are relatively ineffective in chronic obstructive pulmonary disease. Glucocorticoids suppress inflammation via several molecular mechanisms. Glucocorticoids suppress the multiple inflammatory genes that are activated in chronic inflammatory diseases, such as asthma, by reversing histone acetylation of activated inflammatory genes through binding of ligand-bound glucocorticoid receptors (GR) to co-activator molecules and recruitment of histone deacetylase-2 to the activated inflammatory gene transcription complex (trans-repression). At higher concentrations of glucocorticoids GR homodimers interact with DNA recognition sites to activate transcription through increased histone acetylation of anti-inflammatory genes and transcription of several genes linked to glucocorticoid side effects (trans-activation). Glucocorticoids also have post-transcriptional effects and decrease stability of some pro-inflammatory mRNA species. Decreased glucocorticoid responsiveness is found in patients with severe asthma and asthmatics who smoke, as well as in all patients with chronic obstructive pulmonary disease. Several molecular mechanisms of glucocorticoid resistance have now been identified which involve post-translational modifications of GR. Histone deacetylase-2 is markedly reduced in activity and expression as a result of oxidative/nitrative stress so that inflammation becomes resistant to the anti-inflammatory actions of glucocorticoids. Dissociated glucocorticoids and selective GR modulators which show improved trans-repression over trans-activation effects have been developed to reduce side effects, but so far it has been difficult to dissociate anti-inflammatory effects from adverse effects. In patients with glucocorticoid resistance alternative anti-inflammatory treatments are being investigated as well as drugs that may reverse the molecular mechanisms of glucocorticoid resistance.

Project description:BackgroundCurrent evidence-based treatments for adult anorexia nervosa (AN) have limitations, with high attrition, very poor outcomes for 20% of people, and no clearly superior manualised therapy for adults with AN. Specialist Supportive Clinical Management (SSCM) was designed as a control treatment but has evolved as a valid first line treatment. The present paper aims to provide an overview of the evidence base for SSCM and a pedagogical reconceptualization with expansion by theoretical integration (TI). BODY: A secondary meta-analysis endorses SSCM as a promising treatment. This paper positions SSCM as a manualised therapy for adult AN with six unique features, namely (1) a philosophy which is person-centred, non-prescriptive, and informed by the person's strengths and values, (2) a focus on the person through inclusion of supportive psychotherapy and problem (clinical management), within target symptoms as defined in relation to AN, (3) a flexible and responsive therapy that could be delivered by a variety of clinicians with experience treating AN (4) a commitment to reversing starvation though a directional approach and a defined yet flexible stance on dietetic intervention (5) a commitment to the therapeutic relationship within all three phases of treatment, and (6) a therapy 'uncluttered' by specific mandates. In addition, this paper positions SSCM as a treatment that may be strengthened by other modalities and may also be adapted to the treatment of other eating disorders (ED), not just AN. The level of therapist sophistication to deliver upon the supportive psychotherapy component is explored and future directions are offered.ConclusionSSCM is a unique and valid first line treatment for AN and would benefit from further expansion in line with emerging understandings of AN to strengthen it as a treatment. Speculation on aspects of potency would benefit from further testing. The proposed re-conceptualisation of SSCM in the context of its evidence may strengthen it as a treatment overall, position it as adaptable for treatment of other eating disorders and make it more accessible to clinicians.

Dataset Information

Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions.

Publications

Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions.

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