Anti-nuclear valosin-containing protein-like autoantibody is associated with calcinosis and higher risk of cancer in systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc)-specific autoantibodies allow the diagnosis and predict the prognosis of SSc patients with different clinical characteristics. The aim of this study was to describe new SSc-related autoantibodies by a novel protein immunoprecipitation (IP) assay. METHODS: Serum samples and clinical data were collected from 307 SSc patients. Antinuclear autoantibodies were tested in all patients by indirect immunofluorescence (IIF) on HEp-2 cells. SSc-specific autoantibodies were evaluated with a commercial immunoblot and chemiluminescence immunoassay, and traditional RNA-IP. Patients negative for all these autoantibodies (n = 51) were further tested with a non-radioactive protein IP assay. Protein bands detected on SDS-PAGE were then analysed by mass spectrometry (MS) and confirmed by western blot (WB). Additional 56 patients with nucleolar pattern by IIF were tested by protein IP-WB. RESULTS: Five patients who underwent protein IP testing showed a 110-115kDa molecular weight band on SDS-PAGE and a homogeneous nucleolar pattern by IIF. MS identified the bands as nuclear valosin-containing protein-like (NVL). An additional positive patient was detected by IP-WB. As compared with the remaining 101 negative patients, anti-NVL positive patients showed a greater prevalence of calcinosis (100% vs 18.9%, p< 0.001), and cancer (66.7% vs 8.9%, p= 0.002), with a particular association with synchronous cancer (OR = 16.3; p= 0.024). CONCLUSION: We identified NVL as a new autoantibody target by a novel protein IP assay in SSc patients with a homogeneous nucleolar IIF pattern, testing negative for all known SSc-specific autoantibodies by commercial assays and RNA IP. Anti-NVL identifies a new clinical phenotype, characterized by calcinosis and cancer.

Association of class II HLA alleles with susceptibility to develop immune-mediated diseases in Paraguayan patients.

Genetic and nongenetic factors are involved in the pathogenesis of immune-mediated inflammatory diseases (IMIDs). The best-known genetic factor for susceptibility to IMIDs is the human leukocyte antigen (HLA). The aim of the present study was to evaluate the association of HLA class II genes with the risk of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc) in the Paraguayan population. We included 254 patients with IMIDs (101 SLE, 103 RA, and 50 SSc) and 50 healthy controls. The haplotypes of five genes corresponding to HLA class II genes and their relationship to the IMIDs studied were determined. Note that 84.6% were women, with a mean age of 43.4 ± 14 years. Among the associated HLA alleles, we found the previously identified risk factors in other populations like HLA-DRB1*03:01 and HLA-DRB1*14:02 for RA, as well as new ones not previously identified, such as DPA1*02:01 for SLE and, DB1*02:01 for RA and SSc. In the genetic association analysis, already known associations have been replicated, and unpublished associations have been identified in Paraguayan patients with IMIDs. This is the first genetic association study in Paraguayan patients with IMIDs.

High VEGFR3 Expression Reduces Doxorubicin Efficacy in Triple-Negative Breast Cancer.

Due to the lack of specific targets, cytotoxic chemotherapy still represents the common standard treatment for triple-negative breast patients. Despite the harmful effect of chemotherapy on tumor cells, there is evidence that treatment could modulate the tumor microenvironment in a way favoring the propagation of the tumor. In addition, the lymphangiogenesis process and its factors could be involved in this counter-therapeutic event. In our study, we have evaluated the expression of the main lymphangiogenic receptor VEGFR3 in two triple-negative breast cancer in vitro models, resistant or not to doxorubicin treatment. The expression of the receptor, at mRNA and protein levels, was higher in doxorubicin-resistant cells than in parental cells. In addition, we confirmed the upregulation of VEGFR3 levels after a short treatment with doxorubicin. Furthermore, VEGFR3 silencing reduced cell proliferation and migration capacities in both cell lines. Interestingly, high VEGFR3 expression was significantly positively correlated with worse survival in patients treated with chemotherapy. Furthermore, we have found that patients with high expression of VEGFR3 present shorter relapse-free survival than patients with low levels of the receptor. In conclusion, elevated VEGFR3 levels correlate with poor survival in patients and with reduced doxorubicin treatment efficacy in vitro. Our results suggest that the levels of this receptor could be a potential marker of meager doxorubicin response. Consequently, our results suggest that the combination of chemotherapy and VEGFR3 blockage could be a potentially useful therapeutic strategy for the treatment of triple-negative breast cancer.

Histamine and Tyramine in Chihuahua Cheeses during Shelf Life: Association with the Presence of tdc and hdc Genes.

Cheese is a product of animal origin with a high nutritional value, and it is one of the most consumed dairy foods in Mexico. In addition, Chihuahua cheese is the most consumed matured cheese in Mexico. In the production process of Chihuahua cheese, maturation is carried out by adding acid lactic microorganisms, mainly of the Lactococcus genus and, in some cases, also the Streptococcus and Lactobacillus genus. As part of the metabolism of fermenting microorganisms, biogenic amines can develop in matured foods, which result from the activity of amino decarboxylase enzymes. In cheeses, histamine and tyramine are the main amines that are formed, and the consumption of these represents a great risk to the health of consumers. In this work, the presence of biogenic amines (histamine and tyramine) was determined by HPLC at different times of the shelf life of Chihuahua cheeses. In addition, the presence of genes hdc and tdc that code for the enzymes responsible for the synthesis of these compounds (histidine and tyrosine decarboxylase, or HDC and TDC) was determined by molecular techniques. A significant correlation was observed between the presence of both histamine and tyramine at the end of shelf life with the presence of genes that code for the enzymes responsible for their synthesis.

Trends in COVID-19 Vaccine Acceptance in Spain, September 2020‒May 2021.

Objectives. To analyze factors associated with COVID-19 vaccine acceptance in Spain, over time. Methods. We used data from a national study that included 5 online surveys carried out every 2 months from September 2020 to May 2021. Each round recruited a sample of 1000 participants aged 18 years or older. We performed a multivariable logistic regression with vaccination acceptance as the dependent variable. We evaluated time trends through the interaction terms of each of the explanatory variables and the time. Results. Vaccination acceptance increased from 43.1% in September 2020 to 84.5% in May 2021. Sex, age, concerns about disease severity, health services overload, and people not wearing a face mask, together with adherence to preventive behavior, health literacy, and confidence in scientists, health care professionals' information, and adequacy of governmental decisions, were variables associated with vaccination acceptance. Conclusions. In a changing situation, vaccine acceptance factors and time trends could help in the design of contextualized public health messages. It is important to strengthen the population's trust in institutions, health care professionals, and scientists to increase vaccination rates, as well as to ensure easy access to accurate information for those who are more reluctant. (Am J Public Health. 2022;112(11):1611-1619. https://doi.org/10.2105/AJPH.2022.307039).

Possible substantive improvements in the structure of the Quality of Life in Adult Cancer Survivors (QLACS) scale? A study based on its Spanish version.

PURPOSE: Quality of Life in Adult Cancer Survivors (QLACS) scale is one of the most commonly used and validated measures to assess the Health-Related Quality of Life (HRQoL) in this population. However, there are some aspects related to its structure that still deserve consideration. The aim of this study was to test the substantive improvement over the original QLACS structure resulting from several proposals reflected in the literature. METHOD: Using a cross-sectional design and Confirmatory Factorial Analysis, we explored those proposals. Reliability, convergent validity, and factor invariance across three cancer survivorships phases (re-entry, early, and long term) were also analyzed. 1.862 post-treatment survivors of diverse cancer types completed the Spanish versions of QLACS, Brief Symptom Inventory-18 (BSI-18), and Subjective Happiness Scale (SHS). RESULTS: The original model with twelve domains, grouped (with the exception of benefits) into a single total score, versus two subtotal (Generic and Cancer-specific) obtained a good fit. The values of Cronbach's alpha, Composite reliability, Average Variance Extracted indexes, and Pearson correlations supported the internal consistency and temporal stability (interval of 2-3 weeks) of the QLACS. Results also showed its adequate convergent validity and an invariant factor structure across survival periods (re-entry survivorship, early survivorship, long-term survivorship). CONCLUSION: In its original structure, albeit the replacement of the scores on the two subscales by a total score, our results support QLACS as a valid and useful tool for the assessment of HRQoL in post-treatment cancer survivors throughout the different survival phases.

Pulse Granuloma-Like Reaction on the Forearm Following an Accidental Wound.

ABSTRACT: Pulse granulomas are uncommon reactions to vegetable exogenous matter characterized by the presence of hyaline rings. Although they are usually found in the oral cavity or along the gastrointestinal or respiratory tracts, there are a few cases described outside those regions. We present the first case of a granulomatous reaction with hyaline rings in the skin reaction after an accidental wound and suggest the term pulse granuloma-like to describe lesions that resemble pulse granulomas but with no connection to the gastrointestinal or respiratory tracts. Moreover, we provide a graphic comparison of the hyaline rings observed in our case and the histologic sections of some plants that could have been involved.

First Report on Genome Editing via Ribonucleoprotein (RNP) in Castanea sativa Mill.

Castanea sativa is an important tree nut species worldwide, highly appreciated for its multifunctional role, in particular for timber and nut production. Nowadays, new strategies are needed to achieve plant resilience to diseases, climate change, higher yields, and nutritional quality. Among the new plant breeding techniques (NPBTs), the CRISPR/Cas9 system represents a powerful tool to improve plant breeding in a short time and inexpensive way. In addition, the CRISPR/Cas9 construct can be delivered into the cells in the form of ribonucleoproteins (RNPs), avoiding the integration of exogenous DNA (GMO-free) through protoplast technology that represents an interesting material for gene editing thanks to the highly permeable membrane to DNA. In the present study, we developed the first protoplast isolation protocol starting from European chestnut somatic embryos. The enzyme solution optimized for cell wall digestion contained 1% cellulase Onozuka R-10 and 0.5% macerozyme R-10. After incubation for 4 h at 25 °C in dark conditions, a yield of 4,500,000 protoplasts/mL was obtained (91% viable). The transfection capacity was evaluated using the GFP marker gene, and the percentage of transfected protoplasts was 51%, 72 h after the transfection event. The direct delivery of the purified RNP was then performed targeting the phytoene desaturase gene. Results revealed the expected target modification by the CRISPR/Cas9 RNP and the efficient protoplast editing.

Role of SALL4 in HER2+ Breast Cancer Progression: Regulating PI3K/AKT Pathway.

Treatment for the HER2+ breast cancer subtype is still unsatisfactory, despite breakthroughs in research. The discovery of various new molecular mechanisms of transcription factors may help to make treatment regimens more effective. The transcription factor SALL4 has been related to aggressiveness and resistance therapy in cancer. Its molecular mechanisms and involvement in various signaling pathways are unknown in the HER2+ breast cancer subtype. In this study, we have evaluated the implication of SALL4 in the HER2+ subtype through its expression in patients' samples and gain and loss of function in HER2+ cell lines. We found higher SALL4 expression in breast cancer tissues compared to healthy tissue. Interestingly, high SALL4 expression was associated with disease relapse and poor patient survival. In HER2+ cell lines, transient overexpression of SALL4 modulates PI3K/AKT signaling through regulating PTEN expression and BCL2, which increases cell survival and proliferation while reducing the efficacy of trastuzumab. SALL4 has also been observed to regulate the epithelial-mesenchymal transition and stemness features. SALL4 overexpression significantly reduced the epithelial markers E-cadherin, while it increased the mesenchymal markers ß-catenin, vimentin and fibronectin. Furthermore, it has been also observed an increased expression of MYC, an essential transcription factor for regulating epithelial-mesenchymal transition and/or cancer stem cells. Our study demonstrates, for the first time, the importance of SALL4 in the HER2+ subtype and partial regulation of trastuzumab sensitivity. It provides a viable molecular mechanism-driven therapeutic strategy for an important subset of HER2-overexpressing patients whose malignancies are mediated by SALL4 expression.

[Referral criteria to clinical genetics from primary care: Consensus document]. / Criterios de derivación a genética clínica desde Atención Primaria. Documento de consenso.

INTRODUCTION: Primary care (PC) is the first contact between the patient and the doctor, so it is essential to be clear about the criteria for suspecting a genetic disease and where it should be referred for study. MATERIAL AND METHODS: Four scientific societies: the Spanish Society of Family and Community Medicine (semFYC), the Spanish Association of Human Genetics (AEGH), the Spanish Association of Pediatrics (AEP) and the Spanish Society of Medical Oncology (SEOM), have reviewed the criteria for referral to the clinical genetics services of the different published guidelines with the purpose of define the recommendations for PC. CONCLUSIONS: With this consensus document, the PC doctor and pediatrician will know when, how and where to refer their patients with hereditary and/or genetic pathology to clinical genetics services.

Anti-RNPC-3 antibody predicts poor prognosis in patients with interstitial lung disease associated to systemic sclerosis.

OBJECTIVE: To analyse the prevalence, the clinical characteristics, the overall survival and the event-free survival (EFS) of SSc patients who express anti-U11/U12 RNP (RNPC-3) antibodies. METHODS: A total of 447 SSc patients from Barcelona (n = 286) and Milan (n = 161) were selected. All samples were tested using a particle-based multi-analyte technology. We compared anti-RNPC-3 positive and negative patients. Epidemiological, clinical features and survival were analysed. End-stage lung disease (ESLD) was defined if the patient developed forced vital capacity <50% of predicted, needed oxygen therapy or lung transplantation. EFS was defined as the period of time free of either ESLD or death. RESULTS: Nineteen of 447 (4.3%) patients had anti-RNPC-3 antibodies and interstitial lung disease (ILD) was more frequent (11, 57.9% vs 144, 33.6%, P =0.030) in individuals with anti-RNPC-3 antibodies. More patients reached ESLD in the positive group (7, 36.8% vs 74, 17.3%, P = 0.006), and a higher use of non-glucocorticoid immunosuppressive drugs was observed (11, 57.9% vs 130, 30.4%, P = 0.012). Anti-RNPC-3 positive patients had lower EFS, both in the total cohort (log-rank P =0.001), as well as in patients with ILD (log-rank P = 0.002). In multivariate Cox regression analysis, diffuse cutaneous subtype, age at onset, the presence of ILD or pulmonary arterial hypertension and the expression of anti-RNPC-3 positivity or anti-topo I were independently associated with worse EFS. CONCLUSION: The presence of anti-RNPC-3 was associated with higher frequency of ILD and either ESLD or death. These data suggest anti-RNPC-3 is an independent poor prognosis antibody in SSc, especially if ILD is also present.

The indirect immunofluorescence assay autoantibody profiles of myositis patients without known myositis-specific autoantibodies.

OBJECTIVES: The indirect immunofluorescence assay (IIFA) is used to screen for the presence of autoantibodies. Our objective was to determine the prevalence and clinical features of IIFA positive myositis patients without known myositis-specific autoantibodies (MSA). METHODS: Sera from healthy comparators (HC) and patients with dermatomyositis (DM), inclusion body myositis (IBM), and polymyositis (PM) with no detectable MSA were tested by IIFA on HEp-2 cells. The pattern of positivity was classified according to the International Consensus on Antinuclear Antibody Patterns. The prevalence and frequency of each IIFA pattern were compared between the different groups. RESULTS: Sera from 100 HC, 71 DM, 53 IBM, and 69 PM subjects were included in the study. The IIFA was positive in 35% HC compared to 66% DM (p<0.001), 49% IBM, and 64% (p<0.001) PM sera. Among IIFA positive sera, the staining was moderate or intense in 43% HC compared to 79% DM (p<0.001) but just 54% IBM, and 52% PM sera. IIFA positivity was predominantly nuclear in all groups (all >69%). The most common pattern in myositis patients was fine speckled with no differences between groups. In general, IIFA positive and negative DM patients showed similar clinical features and disease activity. CONCLUSIONS: Half of MSA-negative DM patients have moderate/strong IIFA positivity, predominantly with a fine speckled pattern. In contrast, MSA-negative PM, IBM, and healthy comparators are more often weakly positive for IIFA. These findings suggest that unidentified autoantibodies are more likely to exist in DM patients than in the other myositis groups.

Chronic diseases in the geriatric population: morbidity and use of primary care services according to risk level.

BACKGROUND: Geriatric patients have significant morbidity and greater needs for care and assistance. The objective of this study was to describe the characteristics, morbidity, and use of services in primary care (PC) of patients with chronic diseases older than 65 years according to their risk level assigned by the adjusted morbidity groups (AMG) and to analyse the factors associated with the use of PC services. METHODS: This was a cross-sectional descriptive observational study. Patients older than 65 years from a healthcare service area, classified as chronically ill by the AMG classification system of the PC electronic medical record of the Community of Madrid, were included. Sociodemographic, clinical-care, and PC service utilization variables were collected. Univariate, bivariate and multivariate analyses were done. RESULTS: A total of 3292 chronic patients older than 65 years were identified, of whom 1628 (49.5%) were low risk, 1293 (39.3%) were medium risk and 371 (11.3%) were high risk. Their mean age was 78.1 (SD = 8.1) years and 2167 (65.8%) were women. Their mean number of chronic diseases was 3.8 (SD = 2), 89.4% had multimorbidity and 1550 (47.1%) were polymedicated. The mean number of contacts/year with PC was 19.5 (SD = 18.2) [men: 19.4 (SD = 19.8); women: 19.5 (SD = 17.4)]. The mean number of contacts/year in people over 85 years was 25.2 (SD = 19.6); in people 76-85 years old, it was 22.1 (SD = 20.3); and in people 66-75 years old, it was 14.5 (SD = 13.9). The factors associated with greater use of services were age (B coefficient [BC] = 0.3; 95%CI = 0.2-0.4), high risk level (BC = 1.9; 95%CI =0.4-3.2), weight of complexity (BC = 0.7; 95%CI = 0.5-0.8), and ≥ 4 chronic diseases (BC = 0.7; 95%CI = 0.3-1.1). CONCLUSIONS: In the geriatric population, we found a high number of patients with chronic diseases and there were three levels of risk by AMG with differences in characteristics, morbidity, and use of PC services. The greatest use of services was by patients with older age, high risk level, greater weight of complexity and ≥ 4 chronic diseases. Further research is needed to develop an intervention model more adapted to the reality of the geriatric population based on risk levels by AMG.

Use of primary and hospital care health services by chronic patients according to risk level by adjusted morbidity groups.

BACKGROUND: Patients with chronic diseases have increased needs for assistance and care. The objective of this study was to describe the characteristics and use of primary care (PC) and hospital care (HC) health services by chronic patients according to risk level based on adjusted morbidity groups (AMG) and to analyze the associated factors. METHODS: Cross-sectional descriptive observational study. Patients from a basic health area classified as chronically ill by the AMG classification system of the Madrid PC electronic medical record were included. Sociodemographic, clinical-care characteristics (classified as predisposing factors or need factors) and service utilization variables were collected. Univariate, bivariate and simple linear regression analyses were performed. RESULTS: The sample consisted of 9866 chronic patients and 8332 (84.4%) used health services. Of these service users, 63% were women, mean age was 55.7 (SD = 20.8), 439 (5.3%) were high risk, 1746 (21.2%) were medium risk, and 6041(73.4%) were low risk. A total of 8226 (98.7%) were PC users, and 4284 (51.4%) were HC users. The average number of annual contacts with PC was 13.9 (SD = 15); the average number of contacts with HC was 4.8 (SD = 6.2). Predisposing factors associated with services utilization at both care levels were: age (B coefficient [BC] = 0.03 and 0.018, 95% CI = 0.017-0.052 and 0.008-0.028, respectively, for PC and HC) and Spanish origin (BC = 0.962 and 3.396, 95% CI = 0.198-1.726 and 2.722-4.070); need factors included: palliative care (BC = 10,492 and 5047; 95% CI = 6457-14,526 and 3098-6995), high risk (BC = 4631 and 2730, 95% CI = 3022-6241 and 1.949-3.512), number of chronic diseases (BC = 1.291 and 0.222, 95% CI = 1.068-1.51 and 0.103-0.341) and neoplasms (BC = 2.989 and 4.309, 95% CI = 1.659-4.319 and 3.629-4.989). CONCLUSIONS: The characteristics and PC and HC service utilization of chronic patients were different and varied according to their AMG risk level. There was greater use of PC services than HC services, although utilization of both levels of care was high. Service use was related to predisposing factors such as age and country of origin and, above all, to need factors such as immobility, high risk, and number and type of chronic diseases that require follow-up and palliative care.

Balneotherapy with a psychoeducation program for the promotion of a balanced care in family caregivers of older adults.

This study aimed to analyze the efficacy of an intervention program for informal caregivers of elderly dependent that combined balneotherapy with group psychoeducation (BT-PE) based on the balanced care model. The BT-PE intervention (N = 124) was compared with a comparison group only exposed to balneotherapy (BT) (N = 76). The two modalities included both primary and secondary informal caregivers. A three-way mixed ANOVA was conducted to determine the effects of two between-subjects´ factors (intervention group and caregiver type) and one within-subjects´ factor (time) on burden, depression, anxiety, maladjustment and care satisfaction. Results showed less burden and more care satisfaction in both primary and secondary caregivers participating in the BT-PE program after the interventions. Primary caregivers also showed lower levels of maladjustment in the experimental group at post-intervention. Although depressive symptoms and anxiety decreased significantly in both intervention groups, BT-PE did not show lower scores compared with the application of sole BT. The relevance of caregivers´ psychoeducation on the balanced care model and its combination with balneotherapy is highlighted.

Oral Selective Estrogen Receptor Degraders (SERDs) as a Novel Breast Cancer Therapy: Present and Future from a Clinical Perspective.

Estrogen receptor-positive (ER+) is the most common subtype of breast cancer. Endocrine therapy is the fundamental treatment against this entity, by directly or indirectly modifying estrogen production. Recent advances in novel compounds, such as cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), or phosphoinositide 3-kinase (PI3K) inhibitors have improved progression-free survival and overall survival in these patients. However, some patients still develop endocrine resistance after or during endocrine treatment. Different underlying mechanisms have been identified as responsible for endocrine treatment resistance, where ESR1 gene mutations are one of the most studied, outstanding from others such as somatic alterations, microenvironment involvement and epigenetic changes. In this scenario, selective estrogen receptor degraders/downregulators (SERD) are one of the weapons currently in research and development against aromatase inhibitor- or tamoxifen-resistance. The first SERD to be developed and approved for ER+ breast cancer was fulvestrant, demonstrating also interesting activity in ESR1 mutated patients in the second line treatment setting. Recent investigational advances have allowed the development of new oral bioavailable SERDs. This review describes the evolution and ongoing studies in SERDs and new molecules against ER, with the hope that these novel drugs may improve our patients' future landscape.

Circulating miR-99a-5p Expression in Plasma: A Potential Biomarker for Early Diagnosis of Breast Cancer.

MicroRNAs have emerged as new diagnostic and therapeutic biomarkers for breast cancer. Herein, we analysed miR-99a-5p expression levels in primary tumours and plasma of breast cancer patients to evaluate its usefulness as a minimally invasive diagnostic biomarker. MiR-99a-5p expression levels were determined by quantitative real-time PCR in three independent cohorts of patients: (I) Discovery cohort: breast cancer tissues (n = 103) and healthy breast tissues (n = 26); (II) Testing cohort: plasma samples from 105 patients and 98 healthy donors; (III) Validation cohort: plasma samples from 89 patients and 85 healthy donors. Our results demonstrated that miR-99a-5p was significantly downregulated in breast cancer tissues compared to healthy breast tissues. Conversely, miR-99a-5p levels were significantly higher in breast cancer patients than in healthy controls in plasma samples from both testing and validation cohorts, and ROC curve analysis revealed that miR-99a-5p has good diagnostic potential even to detect early breast cancer. In conclusion, miR-99a-5p's deregulated expression distinguished healthy patients from breast cancer patients in two different types of samples (tissues and plasma). Interestingly, expression levels in plasma were significantly lower in healthy controls than in early-stage breast cancer patients. Our findings suggest circulating miR-99a-5p as a novel promising non-invasive biomarker for breast cancer detection.

[Risk of recurrence in differentiated thyroid cancer]. / Riesgo de recurrencia en cáncer diferenciado de tiroides: escala MINSAL.

BACKGROUND: Differentiated thyroid cancer (DTC) is generally associated with a favorable prognosis. Its treatment requires surgery, selective use of radioiodine and levothyroxine, and its intensity must be adjusted to the initial risks of mortality and recurrence. AIM: To validate the risk of recurrence classification developed by the Chilean Ministry of Health in 2013 (MINSAL 2013), and compare it with the American Thyroid Association (ATA) 2009 and 2015 classifications. MATERIAL AND METHODS: Retrospective study of 362 patients with DTC aged 44.3 ± 13.4 years (84% women), treated with total thyroidectomy, selective radioiodine ablation and levothyroxine and followed for a median of 4.2 years (range 2.0-7.8). Risk of recurrence was estimated with MINSAL 2013, ATA 2009 and ATA 2015 classifications, and risk of mortality with 7th and 8th American Joint Committee on Cancer (AJCC)/TNM systems. Clinical data obtained during follow-up were used to detect structural and biochemical persistence/recurrence. RESULTS: A mean dose of 104 ± 48 mCi radioiodine was received by 91% of patients. MINSAL 2013 classified 148 (41%), 144 (40%), 67 (19%) and 3 (1%) patients as very low, low, intermediate and high risk of recurrence, respectively. Forty-five (12.4%) patients had persistence or recurrence during follow-up: 33 structural and 12 biochemical. Rates of persistence/recurrence on each category of MINSAL 2013 were 4.1%, 7.6%, 37.3% and 100%, respectively (p < 0.01). Areas under Receiver Operating Characteristic curves for persistence or recurrence of MINSAL 2013, ATA 2009 and ATA 2015 were 0.77 vs 0.73 vs 0.72, respectively. CONCLUSIONS: MINSAL 2013 classifies appropriately DTC patients and estimates correctly their risk of persistence or recurrence.

Clinical implications of routine genomic mutation sequencing in PIK3CA/AKT1 and KRAS/NRAS/BRAF in metastatic breast cancer.

BACKGROUND: There is increasing interest in the molecular profiling of tumour tissues in order to investigate alternative breast cancer (BC) therapies. However, the impact of genomic screening for druggable mutations with targeted gene panel sequencing (TGPS) in routine practice remains controversial. METHODS: This is a retrospective analysis of data from a genomic screening programme at our institution, in which we performed simplified TGPS for mutations in PIK3CA, AKT1, KRAS, NRAS, and BRAF in order to select patients for targeted therapy clinical trials. The genomes of archived samples of primary (PT) and/or metastatic (MT) tumours from advanced BC patients were analysed with MassARRAY technology (Sequenom MassARRAY, OncoCarta v1.0). The level of PTEN expression was assessed by immunohistochemistry. The primary endpoint was to identify the proportion of BC patients with PI3 K and MAPK alterations who were included in clinical trials using targeted therapies against these pathways. RESULTS: Two hundred and fifteen metastatic BC patients (65 PT and 168 MT) were included. Fifty-two patients (24.19 %) were enrolled in tailored clinical trials, of whom 29 (55.77, 13.49 % of all patients screened) harboured mutations targeted by the study drug. Moreover, 12 wild-type patients out of the 215 (5.58 %) were included in the clinical trials for which mutation analysis was an inclusion criteria. All the patients received drugs targeting the PI3K-AKT pathway and only two were given combinations directed against the PI3K and MAPK pathways. PI3KCA mutations were present in 33.7 % (61/181) of the patients, 45.83 % in PTs and 29.32 % in MTs. AKT1 mutations were detected in 5.48 % (8/146) of patients and PTEN loss in 34.67 % (52/150). KRAS, NRAS, and BRAF mutations were present in 12.06, 5.67, and 3.18 % of patients, respectively. CONCLUSIONS: Genomic screening with a simplified TGPS is feasible, and was used to identify 13.49 % of patients who were included in clinical trials using targeted therapy against the mutations they harboured; PI3KCA mutations were the most frequent aberration in our series.