Background: Metastatic breast cancer (MBC) represents a life-threatening disease with a median survival time of 18–24 months that often can only be treated palliatively. The majority of women suffering from MBC are those who had been previously diagnosed with locally advanced disease and subsequently experienced cancer recurrence in the form of metastasis. However, according to guidelines, no systemic follow-up for monitoring purposes is recommended for these women. The purpose of this article is to review current methods of recurrent risk assessment as well as non-invasive monitoring options for women at risk for distant disease relapse and metastasis formation. Methods: We used PubMed and national guidelines, such as the National Comprehensive Cancer Network (NCCN), to find recently published studies on breast cancer recurrence risk assessment and systemic monitoring of breast cancer patients through non-invasive means. Results: The options for recurrence risk assessment of locally invasive breast cancer has improved due to diverse genetic tests, such as Oncotype DX, MammaPrint, the PAM50 (now known as the “Prosigna Test”) assay, EndoPredict (EP), and the Breast Cancer Index (BCI), which evaluate a women’s risk of relapse according to certain cancer-gene expression patterns. Different promising non-invasive urinary protein-based biomarkers with metastasis surveillance potential that have been identified are MMP-2, MMP-9, NGAL, and ADAM12. In particular, ααCTX, ββCTX, and NTX could help to monitor bone metastasis. Conclusion: In times of improved recurrence risk assessment of women with breast cancer, non-invasive biomarkers are urgently needed as potential monitoring options for women who have an increased risk of recurrence. Urine as a bioliquid of choice provides several advantages – it is non-invasive, can be obtained easily and frequently, and is economical. Promising biomarkers that could help to follow up women with increased recurrence risk have been identified. In order for them to be implemented in clinical usage and national guideline recommendations, further validation in larger independent cohorts will be needed.
Delayed-type drug hypersensitivity reactions (dtDHR) are immune-mediated reactions with skin and visceral manifestations ranging from mild to severe. Clinical care is negatively impacted by a limited understanding of disease pathogenesis. Though T cells are believed to orchestrate disease, the type of T cell and the location and mechanism of T cell activation remain unknown. Resident memory T cells (TRM) are a unique T cell population potentially well situated to act as key mediators in disease pathogenesis, but significant obstacles to defining, identifying, and testing TRM in dtDHR preclude definitive conclusions at this time. Deeper mechanistic interrogation to address these unanswered questions is necessary, as involvement of TRM in disease has significant implications for prediction, diagnosis, and treatment of disease.
ImportanceStevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a severe hypersensitivity reaction. Identifying a culprit drug is critical for patient care, yet identification is based on clinical judgment. Data are limited on the accuracy in or approach to identifying a culprit drug.ObjectiveTo evaluate patient allergy list outcomes, current approaches in identifying culprit drugs, and potential methods of improving culprit drug identification.Design, Setting, and ParticipantsThis retrospective cohort study spanned 18 years (January 2000 to July 2018), was conducted at Brigham and Women’s Hospital and Massachusetts General Hospital (Boston), and included patients with clinically and histologically confirmed cases of SJS/TEN overlap and TEN.Main Outcomes and MeasuresThis study descriptively analyzed potential culprits to SJS/TEN, patients’ allergy lists, and currently used approaches that led to those lists. It then tested the theoretical contribution of incorporating various parameters to allergy list outcomes.ResultsOf 48 patients (29 women [60.4%]; 4 Asian [8.3%], 6 Black [12.5%], 5 Hispanic [10.4%], and 25 White [52.1%] individuals; median age, 40 years [range, 1-82 years]), the mean (SD) number of drugs taken per patient at disease onset was 6.5 (4.7). Physicians labeled 17 patients as allergic to a single culprit drug. Comparatively, 104 drugs were added to allergy lists across all patients. Physicians’ approaches relied largely on heuristic identification of high-notoriety drugs and the timing of drug exposure. Use of a vetted database for drug risk improved sensitivity. Algorithm for Drug Causality for Epidermal Necrolysis scoring was discordant in 28 cases, labeling an additional 9 drugs missed by physicians and clearing 43 drugs labeled as allergens by physicians. Human leukocyte antigen testing could have potentially affected 20 cases. Consideration of infection as a culprit was limited.Conclusions and RelevanceThe results of this cohort study suggest that currently used approaches to identify culprit drugs in SJS/TEN are associated with overlabeling patients allergic to likely nonculprit drugs and less commonly missed possible culprit drugs. Incorporation of a systematized unbiased approach could potentially improve culprit drug identification, although ultimately a diagnostic test is necessary.
Introduction: Breast cancer (BC) is a complex heterogenous disease and is a leading cause of death in women. Following primary BC therapy ~40% of patients will develop metastatic BC (MBC) and 60-70% of the recurrent disease will occur at distant sites. Median survival of MBC patients with distant recurrence is ~2-3 yr. While the early detection and monitoring of BC progression are essential to improve prognosis and reduce BC-related mortality, there is a lack of surveillance strategies for monitoring patients for distant recurrence of MBC. The aim of our study was to identify urinary biomarkers for detection and monitoring of MBC. Method: We have conducted a comparative label-free LC-MS/MS analysis of the urinary proteome of patients with MBC and healthy age-matched controls (HC). A hybrid quadrupole time of flight (Q-Tof™) mass spectrometer was used for urine analysis via liquid chromatography (LC) with tandem mass spectrometry (MS/MS). Three different database search algorithms were used for peptide identification including MASCOT, Protein Lynx Global Server and Ion Accounting software. Only peptides detected in at least two out of three replicated LC-MS experiments were counted towards protein identification. Identified candidate biomarkers were validated via ELISA assays. Results: Using this approach, we identified ~400 urinary proteins of which ~104 and 89 were unique to the MBC and HC groups, respectively. Upregulated proteins in the MBC cohort were associated with angiogenesis, apoptosis, proteolysis, ECM regulation, and cell adhesion pathways. Using bioinformatic and in silico approaches, we identified a specific metastasis signature comprised of CALB1, S100A8, ZAG, VTN and TN. Diagnostic accuracies of these candidate markers were validated using independent training and validation sets according to the REMARK criteria. Urinary VTN (uVTN) and uTN levels correlated significantly with disease status in MBC patients when compared to patients with locally invasive BC and HC. Interestingly, a small subset of patients with bone metastasis also had significantly higher uVTN levels. A multiplexed marker panel of uVTN and uTN could discriminate between HC and MBC groups (AUC=0.831, P<0.001). Blinded testing indicated that uVTN levels (cutoff>1018 ng/ml) could discriminate (AUC=0.782, P<0.006) between MBC and HC. Longitudinal analysis of samples from MBC patients indicated a strong correlation between uVTN levels and disease status. Conclusions: Our findings suggest that uVTN and uTN have the potential to serve as biomarkers for the detection of MBC. While validation in larger cohorts is necessary, these results may be useful in the development of noninvasive diagnostic tests for monitoring BC progression and recurrence. [Supported by: the Advanced Medical Research Foundation, the Jo Ann Webb Fund for Angiogenesis Research and the S. Elizabeth O’Brien Trust] Citation Format: Roopali Roy, Elisa Schunkert, Petra Olivova, Martin Gilar, Scott Geromanos, Guo-Zhong Li, John Gebler, Adelle Dagher, Andrew El-Hayek, Rama Aldakhlallah, David Zurakowski, Susan Pories, Marsha A. Moses. Global proteomic analysis of urine using a label-free LC-MS/MS approach identifies potential biomarkers of metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3433.
Allergic contact dermatitis (ACD) affects 20% of patients and combined with irritant contact dermatitis (ICD) account for more than 90% of occupational skin diseases. Patch testing is the gold standard for diagnosis of ACD but result interpretation may be patient and physician dependent. The purpose of this study is to examine whether noninvasive tape stripping can be used to differentiate ACD, ICD, and normal skin. We examined 39 immune and barrier genes expressed in various skin layers. Patients referred to the Massachusetts General Hospital Contact Dermatitis Clinic with confirmed diagnosis of ACD through patch testing were recruited. 100% petrolatum vehicle served as control and 2% and/or 4% sodium lauryl sulphate was used to induce ICD. 20 consecutive tape strips were collected on sites of ACD, ICD, and vehicle-control skin. Tape strip samples were extracted to isolate total RNA and profiled by quantitative real-time PCR to analyze molecular biomarkers. A total of 9 patients, 7 females and 2 males; mean age, 38.6 years (range, 24-72 years), had at least one ACD reaction on patch testing. 13 ACD, 10 ICD, and 9 vehicle-control samples were obtained from 9 patients. All 39 biomarkers were detected amongst the samples with 4/39 markers significantly different between ACD and vehicle-control samples. Our analysis revealed that CD1A (Langerhans cell marker) was significantly increased, whereas loricrin (skin barrier component), KRT1 (suprabasal epidermal keratin), and KRT14 (basal epidermal keratin) were significantly decreased in ACD relative to vehicle-control samples (p<.05). In comparison of ACD and ICD samples, loricrin and KRT1 demonstrated significant differences (p<.05). These findings illustrate divergent epidermal molecular differences associated with ACD, ICD, and normal skin. We propose skin tape stripping as a novel strategy that potentially enables noninvasive and molecular marker-based diagnosis of ACD.
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