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BACKGROUND: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. METHODS: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05. RESULTS: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS. CONCLUSIONS: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.
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Proteína BRCA1 , Proteína BRCA2 , Neoplasias de la Mama , Mutación de Línea Germinal , Receptor ErbB-2 , Humanos , Femenino , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudios Retrospectivos , Adulto , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Proteína BRCA1/genética , Proteína BRCA2/genética , Adulto Joven , Supervivencia sin Enfermedad , PronósticoRESUMEN
Background: Intermediate clinical endpoints (ICEs) are frequently used as primary endpoint in randomised trials (RCTs). We aim to assess whether changes in different ICEs can be used to predict changes in overall survival (OS) in adjuvant breast cancer trials. Methods: Individual patient level data from adjuvant phase III RCTs conducted by the Gruppo Italiano Mammella (GIM) and Mammella Intergruppo (MIG) study groups were used. ICEs were computed according to STEEP criteria. Using a two-stage meta-analytic model, we assessed the surrogacy of each ICE at both the outcome (i.e., OS and ICE are correlated irrespective of treatment) and trial (i.e., treatment effects on ICE and treatment effect on OS are correlated) levels. The following ICEs were considered as potential surrogate endpoints of OS: disease-free survival (DFS), distant disease-free survival (DDFS), distant relapse-free survival (DRFS), recurrence-free survival (RFS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), breast cancer-free interval (BCFI), and invasive breast cancer-free survival (IBCFS). The estimates of the degree of correlation were obtained by copula models and weighted linear regression. Kendall's τ and R2 ≥ 0.70 were considered as indicators of a clinically relevant surrogacy. Findings: Among the 12,397 patients enrolled from November 1992 to July 2012 in six RCTs, median age at enrolment was 57 years (interquartile range (IQR) 49-65). After a median follow-up of 10.3 years (IQR 6.4-14.5), 2131 (17.2%) OS events were observed, with 1390 (65.2%) attributed to breast cancer. At the outcome-level, Kendall's τ ranged from 0.69 for BCFI to 0.84 for DRFS. For DFS, DDFS, DRFS, RFS, RFI, DRFI, BCFI, and IBCFS endpoints, over 95% of the 8-year OS variability was attributable to the variation of the 5-year ICE. At the trial-level, treatment effects for the different ICEs and OS were strongly correlated, with the highest correlation for RFS and DRFS and the lowest for BCFI. Interpretation: Our results provide evidence supporting the use of DFS, DDFS, DRFS, RFS, RFI, DRFI, and IBCFS as primary endpoint in breast cancer adjuvant trials. Funding: This analysis was supported by the Italian Association for Cancer Research ("Associazione Italiana per la Ricerca sul Cancro", AIRC; IG 2017/20760) and by Italian Ministry of Health-5 × 1000 funds (years 2021-2022).
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INTRODUCTION: The CLEOPATRA trial (NCT00567190) established a dual anti-HER2 blockade in combination with docetaxel as the first-line standard of care for patients with metastatic HER2-positive breast cancer. While this treatment is overall associated with significant improvement in progression-free survival (PFS) and overall survival (OS), not all patients respond equally. We hypothesized that a radiological complete response (CR) at week 9 (i.e., first disease re-evaluation) is associated with prolonged OS and PFS compared to radiological partial response (PR) or stable disease (SD). METHODS: We performed an exploratory analysis of the CLEOPATRA study to address this question. RESULTS: Out of 362 patients treated with docetaxel, trastuzumab, and pertuzumab eligible for our analysis, 46 (12.7%) had radiological CR at week 9, 243 (67.1%) PR, and 73 (20.2%) SD per central RECIST v1.0. Radiological CR at first tumor re-evaluation was associated with a 60% risk reduction for death compared to SD (adjusted HR = 0.40 95% confidence interval (CI) 0.23-0.70), whereas no significant impact on survival was observed for PR (adjusted HR = 0.85 95% CI 0.60-1.20). The same was observed for PFS with adjusted HR = 0.30 (95% CI 0.18-0.48) for the CR subgroup and adjusted HR = 0.81 (95% CI 0.60-1.09) for the PR subgroup. In multivariate analysis, no variables were associated with radiological CR. CONCLUSIONS: Our findings suggest that radiological CR at first disease re-evaluation is associated with more prolonged survival; this might result from stronger dependence on HER2 pathway addiction, supporting the need for further translational research.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Docetaxel , Receptor ErbB-2 , Trastuzumab , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/metabolismo , Docetaxel/uso terapéutico , Docetaxel/administración & dosificación , Trastuzumab/uso terapéutico , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Persona de Mediana Edad , Adulto , Anciano , Supervivencia sin ProgresiónRESUMEN
Groin pain syndrome (GPS) is a controversial topic in Sports Medicine. The GPS Italian Consensus Conference on terminology, clinical evaluation and imaging assessment of groin pain in athletes was organized by the Italian Society of Arthroscopy in Milan, on 5 February 2016. In this Consensus Conference (CC) GPS etiology was divided into 11 different categories for a total of 63 pathologies. The GPS Italian Consensus Conference update 2023 is an update of the 2016 CC. The CC was based on a sequential, two-round online Delphi survey, followed by a final CC in the presence of all panelists. The panel was composed of 55 experts from different scientific and clinical backgrounds. Each expert discussed 6 different documents, one of which regarded the clinical and imaging definition of sports hernias, and the other 5 dealt with 5 new clinical situations thought to result in GPS. The panelists came to an agreement on the definition of a sports hernia. Furthermore, an agreement was reached, recognizing 4 of the 5 possible proposed pathologies as causes to GPS. On the contrary, the sixth pathology discussed did not find consensus given the insufficient evidence in the available scientific literature. The final document includes a new clinical and imaging definition of sports hernia. Furthermore, the etiology of GPS was updated compared to the previous CC of 2016. The new taxonomic classification includes 12 categories (versus 11 in the previous CC) and 67 pathologies (versus 63 in the previous CC).
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Ingle , Deportes , Humanos , Ingle/diagnóstico por imagen , Hernia , Dolor , ItaliaRESUMEN
AIM: To compare interleukin-2 levels (IL-2) and IL-2 gene site 1 methylation levels between preterm newborns (PN) and full-term newborns (FN) and investigate their association with the environmental exposure of their mothers during pregnancy. METHODS: IL-2 and IL-2 gene site 1 methylation levels were assessed in 50 PN and 56 FN. Newborns' mothers filled in questionnaires about their living and occupational environments, habits, diets, and hobbies. RESULTS: The mothers of PN were significantly more frequently agrarian/rural residents than the mothers of FN. PN had significantly higher IL-2 levels, and significantly lower methylation of IL-2 gene site 1 levels than FN. CONCLUSION: IL-2 levels, hypomethylation of the IL-2 gene site 1, and the mother's rural residence (probably due to pesticide exposure) were predictive biomarkers for preterm birth. For the first time, we present the reference values for the methylation of IL-2 gene site 1 in PN and FN, which can be used in the clinical setting and biomonitoring.
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Nacimiento Prematuro , Femenino , Embarazo , Recién Nacido , Humanos , Nacimiento Prematuro/genética , Interleucina-2/genética , Exposición a Riesgos Ambientales , Metilación de ADN , BiomarcadoresRESUMEN
BACKGROUND: Treatment options for advanced melanoma have increased with the US Food and Drug Administration approval of the anti-LAG3 plus anti-PD-1 relatlimab/nivolumab combination. To date, ipilimumab/nivolumab is the benchmark of overall survival, despite a high toxicity profile. Furthermore, in BRAF-mutant patients, BRAF/MEK inhibitors and the atezolizumab/vemurafenib/cobimetinib triplet are also available treatments, making the first-line therapy selection more complex. To address this issue, we conducted a systematic review and network meta-analysis of the available first-line treatment options in advanced melanoma. METHODS: Randomised clinical trials of previously untreated, advanced melanoma were included if at least one intervention arm contained a BRAF/MEK or an immune-checkpoint inhibitor (ICI). The aim was to indirectly compare the ICIs combinations ipilimumab/nivolumab and relatlimab/nivolumab, and these combinations with all the other first-line treatment options for advanced melanoma (irrespective of BRAF status) in terms of activity and safety. The coprimary end-points were progression-free survival (PFS), overall response rate (ORR) and grade ≥3 treatment-related adverse events (≥ G3 TRAEs) rate, defined according to Common Terminology Criteria for Adverse Events. RESULTS: A total of 9070 metastatic melanoma patients treated in 18 randomised clinical trials were included in the network meta-analysis. No difference in PFS and ORR was observed between ipilimumab/nivolumab and relatlimab/nivolumab (HR = 0.99 [95% CI 0.75-1.31] and RR = 0.99 [95% CI 0.78-1.27], respectively). The PD-(L)1/BRAF/MEK inhibitors triplet combinations were superior to ipilimumab/nivolumab in terms of both PFS (HR = 0.56 [95% CI 0.37-0.84]) and ORR (RR = 3.07 [95% CI 1.61-5.85]). Ipilimumab/nivolumab showed the highest risk of developing ≥ G3 TRAEs. Relatlimab/nivolumab trended to a lower risk of ≥ G3 TRAEs (RR = 0.71 [95% CI 0.30-1.67]) versus ipilimumab/nivolumab. CONCLUSION: Relatlimab/nivolumab showed similar PFS and ORR compared to ipilimumab/nivolumab, with a trend for a better safety profile.
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Melanoma , Nivolumab , Humanos , Nivolumab/uso terapéutico , Ipilimumab , Metaanálisis en Red , Proteínas Proto-Oncogénicas B-raf/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Melanoma/patología , Quinasas de Proteína Quinasa Activadas por MitógenosRESUMEN
BACKGROUND AND AIM: Surgical gastrojejunostomy (GJJ) and endoscopic stenting (ES) are the two most available treatments for palliation of malignant gastric obstruction (MGOO). The aim of this study is to compare these two techniques regarding efficacy, safety, time of hospitalization and survival. METHODS: We performed a literature search from January 2010 to September 2020 to identify available randomized controlled studies and observational studies that compared ES and GJJ for the treatment of MGOO. RESULTS: A total of 17 studies were found. ES and GJJ showed similar technical and clinical success rate. ES was superior to obtain early oral re-feeding, shorter length of hospitalization and a lower incidence of complications than GJJ. Surgical palliation had a lower recurrence rate of obstructive symptoms and longer overall survival than ES. CONCLUSIONS: Both procedures have advantages and disadvantages. Probably we should not find the best palliation but the best approach based on the patient characteristics and tumor type.
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Derivación Gástrica , Obstrucción de la Salida Gástrica , Humanos , Cuidados Paliativos/métodos , Obstrucción de la Salida Gástrica/etiología , Obstrucción de la Salida Gástrica/cirugía , Gastroscopía/métodos , Stents/efectos adversos , Derivación Gástrica/efectos adversos , Derivación Gástrica/métodos , Resultado del Tratamiento , Estudios RetrospectivosRESUMEN
Studies have indicated that air pollution, including surface-level ozone (O3), can significantly influence the risk of chronic diseases. To better understand the carcinogenic mechanisms of air pollutants and identify predictive disease biomarkers, we examined the association between traffic-related pollutants with DNA methylation alterations and bulky DNA adducts, two biomarkers of carcinogen exposure and cancer risk, in the peripheral blood of 140 volunteers-95 traffic police officers, and 45 unexposed subjects. The DNA methylation and adduct measurements were performed by bisulfite-PCR and pyrosequencing and 32P-postlabeling assay. Airborne levels of benzo(a)pyrene [B(a)P], carbon monoxide, and tropospheric O3 were determined by personal exposure biomonitoring or by fixed monitoring stations. Overall, air pollution exposure was associated with a significant reduction (1.41 units) in global DNA methylation (95% C.I. -2.65-0.04, p = 0.026). The decrement in ALU repetitive elements was greatest in the policemen working downtown (95% C.I. -3.23--0.49, p = 0.008). The DNA adducts were found to be significantly increased (0.45 units) in the municipal officers with respect to unexposed subjects (95% C.I. 0.02-0.88, p = 0.039), mainly in those who were controlling traffic in downtown areas (95% C.I. 0.39-1.29, p < 0.001). Regression models indicated an increment of ALU methylation at higher B(a)P concentrations (95% C.I. 0.03-0.60, p = 0.032). Moreover, statistical models showed a decrement in ALU methylation and an increment of DNA damage only above the cut-off value of 30 µg/m3 O3. A significant increment of 0.73 units of IL-6 gene methylation was also found in smokers with respect to non-smokers. Our results highlighted the role of air pollution on epigenetic alterations and genotoxic effects, especially above the target value of 30 µg/m3 surface-level O3, supporting the necessity for developing public health strategies aimed to reduce traffic-related air pollution molecular alterations.
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Contaminantes Atmosféricos , Contaminación del Aire , Ozono , Humanos , Aductos de ADN/genética , Ozono/toxicidad , Daño del ADN , Contaminantes Atmosféricos/toxicidad , Contaminantes Atmosféricos/análisis , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , BiomarcadoresRESUMEN
BACKGROUND: The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment-induced gonadotoxicity. PATIENTS AND METHODS: The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the "biological window" of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). RESULTS: The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33-42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56-2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45-2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01-0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. CONCLUSIONS: This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.
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Neoplasias de la Mama , Reserva Ovárica , Humanos , Femenino , Adulto , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Paclitaxel/efectos adversos , Lapatinib/uso terapéutico , BiomarcadoresRESUMEN
BACKGROUND: Cosmetic and social aspects of breast anomalies in Poland syndrome are not negligible. Early diagnosis and appropriate therapeutic timing may have a positive impact on quality of life. METHODS: Females affected by Poland syndrome, who had breast reconstruction between 2014 and 2018, were asked to complete the Body Uneasiness Test and the postoperative Breast-Q. Correlation between scores was evaluated. Correlation between scores was statistically evaluated. RESULTS: Thirty patients who had completed breast reconstruction at 20.9 ± 6.5 yo fulfilled the questionnaires at the average age of 26.5 ± 8.1 yo. BUT scores were similar to healthy population considering different age groups, with the exception of Compulsive Self-Monitoring subscale for 16-17-year age group. A correlation between Depersonalization and "Thighs" and "Legs" was present. On average, satisfaction with breast resulted 79.1%, satisfaction with surgical outcome was 94.9%, psychosocial well-being was 78.5%, sexual well-being was 75.3%, and relative physical well-being in chest and upper body was 36.9%. Global Uneasiness, Avoidance, Weight Phobia, Body Image Concern and Depersonalization were significantly correlated with lower psychosocial well-being. Avoidance was significantly correlated with lower sexual well-being. CONCLUSIONS: Breast reconstruction in Poland syndrome can help to improve quality of life. However, general body uneasiness can affect satisfaction with the final result. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 .
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Mamoplastia , Síndrome de Poland , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Resultado del Tratamiento , Calidad de Vida , Mamoplastia/métodos , Imagen Corporal/psicología , Estudios Retrospectivos , EstéticaRESUMEN
Tailored treatments for metastatic colorectal cancer (mCRC) have not yet completely evolved due to the variety in response to drugs. Therefore, artificial intelligence has been recently used to develop prognostic and predictive models of treatment response (either activity/efficacy or toxicity) to aid in clinical decision making. In this systematic review, we have examined the ability of learning methods to predict response to chemotherapy alone or combined with targeted therapy in mCRC patients by targeting specific narrative publications in Medline up to April 2022 to identify appropriate original scientific articles. After the literature search, 26 original articles met inclusion and exclusion criteria and were included in the study. Our results show that all investigations conducted on this field have provided generally promising results in predicting the response to therapy or toxic side-effects. By a meta-analytic approach we found that the overall weighted means of the area under the receiver operating characteristic (ROC) curve (AUC) were 0.90, 95% C.I. 0.80-0.95 and 0.83, 95% C.I. 0.74-0.89 in training and validation sets, respectively, indicating a good classification performance in discriminating response vs. non-response. The calculation of overall HR indicates that learning models have strong ability to predict improved survival. Lastly, the delta-radiomics and the 74 gene signatures were able to discriminate response vs. non-response by correctly identifying up to 99% of mCRC patients who were responders and up to 100% of patients who were non-responders. Specifically, when we evaluated the predictive models with tests reaching 80% sensitivity (SE) and 90% specificity (SP), the delta radiomics showed an SE of 99% and an SP of 94% in the training set and an SE of 85% and SP of 92 in the test set, whereas for the 74 gene signatures the SE was 97.6% and the SP 100% in the training set.
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BACKGROUND: Sports-related concussion (SRC) is a subset of mild traumatic brain injuries occurring in contact sports. Most people recover spontaneously, but in retired professional players, the risk for neurodegenerative diseases is increased. A biomarker, such as neurofilament light chains (NfL), would help to address this issue and demonstrate sports' safety. Assessing NfL in professional soccer players may be the best way to investigate if repetitive head-impact exposure in the typical lower and asymptomatic range is harmful. OBJECTIVE: To evaluate whether the NfL in serum is a sensitive biomarker to detect mild brain injury in professional soccer players. METHODS: Thirty-six soccer players belonging to a professional Italian team underwent serum NfL assessment using ultrasensitive single-molecule array technology. Sixteen healthy nonathletic controls were also enrolled. Differences between groups and changes over time, considering pre-season vs. season, were considered. RESULTS: Serum NfL concentrations were comparable in the soccer professional players (median [interquartile range], 6.44 pg/mL [4.60-8.27] and controls (6.50 pg/mL [5.26-7.04]), with a median difference of - 0.06 pg/mL (95% CI -1.36 to 1.18), p = 0.957. No significant differences according to players' role (goalkeeper, defender, midfielder or forward) or according to timing of sampling (pre-season vs. season) were found. CONCLUSIONS: These results suggest that professional soccer, even when played at the highest level of competition, may be considered safe. Future studies assessing serum NfL levels after soccer-related concussions should be carried out, to evaluate their usefulness as a return-to-play marker avoiding second impact syndrome.
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Conmoción Encefálica , Fútbol , Deportes , Biomarcadores , Conmoción Encefálica/diagnóstico , Humanos , Filamentos Intermedios , Fútbol/lesionesRESUMEN
PURPOSE: Inferior overall response rate with abemaciclib plus endocrine therapy was observed in patients with hormone receptor-positive/HER2-negative advanced breast cancer (BC) and BMI ≥ 25. We assessed the impact of baseline BMI on KI67% changes, achievement of complete cell cycle arrest (CCCA), clinical, and radiological responses in patients included in the NEOMONARCH trial. METHODS: Exploratory post hoc analysis of the NEOMONARCH trial was performed. Patients were classified according to baseline BMI into underweight/normal weight (BMI < 25 kg/m2) and overweight/obese (BMI ≥ 25 kg/m2). RESULTS: 222 patients (84.4%) had baseline BMI information available. In the overall cohort, mean Ki67% changes at 2 weeks were similar between the two BMI groups: - 19 (IQR - 27.8 to - 10.4) for patients with BMI < 25 and - 17.2 (IQR - 26.8 to - 11) for patients with BMI ≥ 25 (p = 0.760). There was no statistical difference in patients achieving CCCA after 2 weeks of treatment according to BMI (p = 0.096). Mean Ki67% reduction at 2 weeks was significantly higher for patients receiving abemaciclib plus anastrozole when compared to either anastrozole or abemaciclib alone, regardless of BMI. At the end of treatment, there was no significant difference regarding radiological (p = 0.366) or clinical response (p = 0.261). CONCLUSION: BMI categorized by the threshold of 25 did not significantly impact KI67% changes or clinical and radiological response. Although limited by the small sample size, these results are reassuring that the combination of abemaciclib plus anastrazole appears to be active in the early setting regardless of baseline BMI. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02441946.
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Neoplasias de la Mama , Terapia Neoadyuvante , Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles , Índice de Masa Corporal , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Terapia Neoadyuvante/métodos , Receptor ErbB-2/metabolismoRESUMEN
PURPOSE: Symptoms of treatment-induced menopause negatively affect quality of life and adherence to endocrine therapy of breast cancer (BC) survivors. Nevertheless, the use of systemic hormone replacement therapy (HRT) to mitigate these symptoms may be associated with an increased risk of disease recurrence in these patients. This systematic review and meta-analysis aimed to assess the safety of systemic HRT on risk of disease recurrence in BC survivors. METHODS: A systematic search of PubMed up to April 20, 2021 was conducted to identify randomized controlled trials (RCTs) that investigated the risk of disease recurrence with the use of HRT in BC survivors. A random-effect model was applied to calculate the risk of recurrence, reported as pooled hazard ratio (HR) with 95% confidence intervals (CI). A subgroup analysis was performed to estimate the risk of recurrence according to hormone receptor status. RESULTS: Four RCTs were included in the meta-analysis (n = 4050 patients). Overall, 2022 patients were randomized to receive HRT (estrogen/progestogen combination or tibolone) and 2023 to the control group with placebo or no HRT. HRT significantly increased the risk of BC recurrence compared to placebo (HR 1.46, 95% CI 1.12-1.91, p = 0.006). At the subgroup analysis, the risk of BC recurrence with the use of HRT was significantly increased in patients with hormone receptor-positive disease (HR 1.8, 95% CI 1.15-2.82, p = 0.010) but not in those with hormone receptor-negative tumors (HR 1.19, 95% CI 0.80-1.77, p = 0.390). CONCLUSION: Use of HRT was associated with a detrimental prognostic effect in BC survivors, particularly in those with hormone receptor-positive disease. Alternative interventions to mitigate menopause-related symptoms should be proposed.
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Neoplasias de la Mama , Supervivientes de Cáncer , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/epidemiología , Terapia de Reemplazo de Estrógeno/efectos adversos , Femenino , Terapia de Reemplazo de Hormonas/efectos adversos , Humanos , Recurrencia Local de Neoplasia/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto , SobrevivientesRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionised clinical practice in oncology in the last years, leading to a survival benefit in several tumour types. To investigate whether these benefits are associated with improved quality of life, we conducted a systematic review and meta-analysis comparing patient-reported outcomes (PROs) between ICIs and standard chemotherapy (CT) in patients with advanced solid tumours. METHODS: Clinical trials comparing the efficacy of ICIs (either programmed death receptor-1 and programmed death-ligand 1 inhibitors or cytotoxic T-lymphocyte antigen 4 inhibitors, as single agent or in combination) versus CT were included. Trials evaluating treatment with ICIs plus CT versus CT alone were also included, whereas studies in which the control arm included other anticancer agents (such as targeted therapy and other ICIs) or placebo alone were excluded. The aim of our meta-analysis was to compare PROs in subjects treated with ICIs or ICIs plus CT (intervention) with those reported by patients receiving CT (control). The co-primary endpoints were time from baseline to first deterioration in PROs, defined as the time from baseline to the first clinically significant deterioration in PROs, and the changes in PROs from baseline to follow-up between ICI and CT treatment groups (PROSPERO registration number CRD42021247440). RESULTS: A total of 8341 patients from 17 randomised trials of ICI versus CT were included in the analysis. Treatment with ICI delayed clinical deterioration over standard CT in Global Health Status/QoL EORTC QLQ-C30 (hazard ratio [HR] 0.81; 95% confidence interval [CI], 0.74-0.89), and in both EQ-5D utility index (HR 0.65; 95% CI, 0.52-0.82) and EQ-5D visual analogue scale (VAS; HR 0.70; 95% CI, 0.61-0.80). The difference in mean change between the ICI-treated group and the CT-treated group was 5.82 (95% CI, 4.11-7.53) in favour of ICI. Similarly, in the EQ-5D, the mean change differences favoured treatment with ICIs in both Utility Index and VAS, with differences of 0.05 (95% CI, 0.03-0.07) and 5.41 (95% CI, 3.39-7.43), respectively. CONCLUSIONS: ICIs are associated with higher levels of quality of life and longer time to clinical deterioration on several PROs scales compared with CT in different types of solid tumours.
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Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Calidad de Vida , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Male infertility is increasingly becoming a health and demographic problem. While it may originate from congenital or acquired diseases, it can also result from environmental exposure. Hence, the complexity of involved molecular mechanisms often requires a multiparametric approach. This study aimed to associate semen parameters with sperm DNA fragmentation, chromatin maturity and seminal plasma protein N-glycosylation. METHODS: The study was conducted with 166 participants, 20-55 y old, 82 normozoospermic and 84 with pathological diagnosis. Sperm was analyzed by Halosperm assay and aniline blue staining, while seminal plasma total protein N-glycans were analyzed by ultra-high-performance liquid chromatography. RESULTS: Sperm DNA fragmentation was significantly increased in the pathological group and was inversely correlated with sperm motility and viability. Seminal plasma total protein N-glycans were chromatographically separated in 37 individual peaks. The pattern of seminal plasma N-glycan peaks (SPGP) showed that SPGP14 significantly differs between men with normal and pathological semen parameters (p < 0.001). The multivariate analysis showed that when sperm chromatin maturity increases by 10%, SPGP17 decreases by 14% while SPGP25 increases by 25%. CONCLUSION: DNA integrity and seminal plasma N-glycans are associated with pathological sperm parameters. Specific N-glycans are also associated with sperm chromatin maturity and have a potential in future fertility research and clinical diagnostics.
RESUMEN
Estradiol (E), testosterone (T), and their ratio are crucial axis in life. Especially during intrauterine growth, they orchestrate the complex development of organs and their interaction, which have lifelong impact on health and an organism's capacity to respond to environmental stressors. The aim of this study was to compare for the first time E, T, and their ratio levels with aromatase (CYP19) gene methylation levels between preterm newborns (PN) and full-term newborns (FN) with respect to their mother's environmental exposure and diet. In this study, 56 FN of 37-42 weeks of gestation age (GA) and 46 PN at GA 27-36 weeks were analysed for E and T levels and CYP19A1 gene pI.3/II promoter region methylation. Results showed there was no difference in E levels between PN and FN, but there were significantly lower levels of T in PN than in FN (2.81 nmol vs. 3.76 nmol, respectively) and consequently a significantly higher E/T ratio in PN than in FN (5278.04 vs. 2891.23, respectively). CYP19A1 methylation was significantly lower in PN than in FN (86.04% vs. 90.04%, respectively). CYP19A1 methylation was significantly reduced in newborns whose mothers reported daily milk consumption. Our study is the first to provide referent values for CYP19A1 methylation levels in FN and PN and shows that PN and FN significantly differ in CYP19A1 methylation levels, T levels, and E/T ratio. Future research should further investigate the mechanisms involved in GA-dependent CYP19A1 methylation levels and mechanisms of sex hormone disturbances which may contribute to preterm birth.
Asunto(s)
Estradiol/análisis , Desarrollo Fetal , Edad Gestacional , Hormonas Esteroides Gonadales , Nacimiento Prematuro/sangre , Testosterona/análisis , Aromatasa/análisis , Aromatasa/genética , Preescolar , Estradiol/sangre , Femenino , Sangre Fetal/química , Humanos , Lactante , Recién Nacido/sangre , Masculino , Metilación , Madres , Testosterona/sangreRESUMEN
The comet assay or single cell gel electrophoresis, is the most common method used to measure strand breaks and a variety of other DNA lesions in human populations. To estimate the risk of overall mortality, mortality by cause, and cancer incidence associated to DNA damage, a cohort of 2,403 healthy individuals (25,978 person-years) screened in 16 laboratories using the comet assay between 1996 and 2016 was followed-up. Kaplan-Meier analysis indicated a worse overall survival in the medium and high tertile of DNA damage (p < 0.001). The effect of DNA damage on survival was modelled according to Cox proportional hazard regression model. The adjusted hazard ratio (HR) was 1.42 (1.06-1.90) for overall mortality, and 1.94 (1.04-3.59) for diseases of the circulatory system in subjects with the highest tertile of DNA damage. The findings of this study provide epidemiological evidence encouraging the implementation of the comet assay in preventive strategies for non-communicable diseases.