Anthracycline-related cardiotoxicity in patients with breast cancer harboring mutational signature of homologous recombination deficiency (HRD).

BACKGROUND: The BRCA proteins play a key role in the homologous recombination (HR) pathway. Beyond BRCA1/2, other genes are involved in the HR repair (HRR). Due to the prominent role in the cellular repair process, pathogenic or likely pathogenic variants (PV/LPVs) in HRR genes may cause inadequate DNA damage repair in cardiomyocytes. PATIENTS AND METHODS: This was a multicenter, hospital-based, retrospective cohort study to investigate the heart toxicity from anthracycline-containing regimens (ACRs) in the adjuvant setting of breast cancer (BC) patients carrying germline BRCA PV/LPVs and no-BRCA HRR pathway genes. The left ventricular ejection fraction (LVEF) was assessed using cardiac ultrasound before starting ACR therapy and at subsequent time points according to clinical indications. RESULTS: Five hundred and three BC patients were included in the study. We predefined three groups: (i) BRCA cohort; (ii) no-BRCA cohort; (iii) variant of uncertain significance (VUS)/wild-type (WT) cohort. When baseline (T0) and post-ACR (T1) LVEFs between the three cohorts were compared, pre-treatment LVEF values were not different (BRCA1/2 versus HRR-no-BRCA versus VUS/WT cohort). Notably, during monitoring (T1, median 3.4 months), patients carrying BRCA or HRR no-BRCA germline pathogenic or likely pathogenic variants showed a statistically significant reduction of LVEF compared to baseline (T0). To assess the relevance of HRR on the results, we included the analysis of the subgroup of 20 BC patients carrying PV/LPVs in other genes not involved in HRR, such as mismatch repair genes (MUTYH, PMS2, MSH6). Unlike HRR genes, no significant differences in T0-T1 were found in this subgroup of patients. CONCLUSION: Our data suggest that deleterious variants in HRR genes, leading to impaired HR, could increase the sensitivity of cardiomyocytes to ACR in early BC patients. In this subgroup of patients, other measurements, such as the global longitudinal strain, and a more in-depth assessment of risk factors may be proposed in the future to optimize cardiovascular risk management and improve long-term survival.

Accuracy evaluation of orthodontic movements with aligners: a prospective observational study.

BACKGROUND: Since their introduction in orthodontics, clear aligners have been appreciated by patients, including adults, for their comfort and low aesthetic impact. Despite the enormous mobilization of financial resources all over the world aimed at producing new product lines, few clinical studies or high-quality evidence have been produced regarding the real effectiveness of such treatment. Given the few limited kinds of research on the subject, this study aims to produce and critically evaluate other data, to establish the concrete reliability of clear aligners in orthodontic therapy. RESULTS: Significant sample sizes were obtained for intrusion, vestibulo/lingual (V/L) crown tipping, and rotation. The overall accuracy for rotation resulted in 86%, ranging from 96% for maxillary central incisors to 70.4% for mandibular first premolars. The intrusion was registered only for anterior teeth; mean predictability was 92%, with the worst result being 86.7% for mandibular canines and the best being 98% for mandibular central incisors. V/L tipping was the most accurate movement: 93.1% of the prescribed movement was completed. Maxillary central incisors showed the lowest accuracy (80.7%), while mandibular central incisors were the highest (97.5%). CONCLUSIONS: The present study provided reassuring data in support of the accuracy of the Invisalign® system. Vestibulo/lingual tipping was the most predictable movement, while rotation of canines, premolars, and lateral incisors were the least predictable. Intrusion resulted highly predictable up to 2 mm. When careful treatment planning follows a correct diagnosis, together with the use of auxiliary features and refinements, the planned results can be achieved in a clinically successful way. Authors believe that there is a major need for greater samples to overcome bias related to variables if we want to answer the unsolved questions, such as the predictability of severe malocclusions treatment.

Efficacy and safety of first-line checkpoint inhibitors-based treatments for non-oncogene-addicted non-small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Frontline immune checkpoint inhibitors (ICI)-based regimens in non-oncogene-addicted non-small-cell lung cancer (NSCLC) have been deeply investigated. To rank the available therapeutic options, we carried out a systematic review and Bayesian meta-analysis. METHODS: A comprehensive search for randomized controlled trials (RCTs) of ICI regimens, and a pairwise and a network meta-analysis (NMA) with an all-comers and a stratified strategy were conducted. Endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse events (TRAEs). RESULTS: Nineteen RCTs involving 17 treatment regimens were included. For the all-comers population, pembrolizumab/chemotherapy (CT) and cemiplimab were most likely the best treatments. For programmed death-ligand 1 (PD-L1) <1% nivolumab/ipilimumab with/without CT, for PD-L1 >1% and 1%-49% pembrolizumab/CT and for PD-L1 >50% cemiplimab ranked first for OS. In non-squamous (NSQ), pembrolizumab with/without CT ranked first for OS; cemiplimab ranked worse than the unselected population. In squamous (SQ), pooled hazard ratio (HR) showed a better chance in improving efficacy for combination strategy, while monotherapy did not, except for cemiplimab that ranked second. Atezolizumab/CT/bevacizumab ranked first in most subgroups for PFS. Direct comparison showed a non-statistically significant benefit of ICI regimens for the liver metastases cohort in OS, with a good ranking for pembrolizumab/CT and atezolizumab/bevacizumab/CT. Regarding brain metastases, all ICI regimens demonstrated an improvement in OS and PFS compared to CT. Nivolumab/ipilimumab/CT ranked better in this subset. CONCLUSIONS: Our meta-analysis updated on the most recent findings demonstrates that different ICI treatments rank differently in specific NSCLC settings (histology, biomarker and clinical presentation) offering a novel challenging scenario for clinical decision making and research planning.

The prognostic impact of tumor mutational burden (TMB) in the first-line management of advanced non-oncogene addicted non-small-cell lung cancer (NSCLC): a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The role of tumor mutational burden (TMB) is still debated for selecting advanced non-oncogene addicted non-small-cell lung cancer (NSCLC) patients who might benefit from immune checkpoint inhibitors (ICIs). Of note, TMB failed to predict a benefit in overall survival (OS) among such patients. MATERIALS AND METHODS: The purpose of this meta-analysis was to compare efficacy outcomes among first-line immune-oncology (IO) agents versus standard platinum-based chemotherapy (CT) within two subgroups (TMB-low and TMB-high on either tissue or blood). We collected hazard ratios (HRs) to evaluate the association for progression-free survival (PFS) and OS, with the relative 95% confidence intervals (CIs). Risk ratios (RRs) were used as an association measure for objective response rate (ORR). RESULTS: Eight different cohorts of five randomized controlled phase III studies (3848 patients) were analyzed. In TMB-high patients, IO agents were associated with improved ORR (RRs 1.37, 95% CI 1.13-1.66), PFS (HR 0.69, 95% CI 0.61-0.79) and OS (HR 0.67, 95% CI 0.59-0.77) when compared with CT, thus suggesting a possible predictive role of high TMB for IO regimens. In TMB-low patients, the IO strategy did not lead to any significant benefit in survival and activity, whereas the pooled results of both ORR and PFS were intriguingly associated with a statistical significance in favor of CT. CONCLUSIONS: This meta-analysis resulted in a proven benefit in OS in favor of IO agents in the TMB-high population. Although more prospective data are warranted, we postulated the hypothesis that monitoring TMB, in addition to the existing programmed death-ligand 1 (PD-L1) expression level, could represent the preferable option for future clinical research in the first-line management of advanced non-oncogene addicted NSCLC patients.

The use of SAMe in chemotherapy-induced liver injury.

Drug-induced liver injury (DILI) remains the most common cause of acute liver failure in the Western world. Chemotherapy is one of the major class of drugs most frequently associated with idiosyncratic DILI. For this reason, patients who receive chemotherapy require careful assessment of liver function prior to treatment to determine which drugs may not be appropriate and which drug doses should be modified. S-adenosylmethionine (SAMe) is an endogenous agent derived from methionine. Its supplementation is effective in the treatment of liver disease, in particular intrahepatic cholestasis (IHC). The target of this review is to analyze the mechanisms of hepatotoxicity of the principal anticancer agents and the role of SAMe in the prevention of this complication.

Ramucirumab and its use in gastric cancer treatment.

The inhibition of the mechanisms of tumor neo-angiogenesis represents a milestone that in the last 10 years has seen the advent of numerous molecules to target action against the vascular endothelial growth factor (VEGF). More recently, new molecules have been developed that inhibit tumor spread by the blockade of specific VEGF receptors (VEGFRs), thereby preventing the binding of a ligand to its receptor and the cascade of proliferative events downstream. Ramucirumab is a fully humanized IgG1 monoclonal antibody that performs its action by blocking the isoform 2 of the VEGF receptor (VEGFR-2). Numerous preclinical and clinical studies have demonstrated its activity in several solid tumors, demonstrating a remarkable efficacy in terms of progression-free survival and overall survival in addition to a favorable toxicity profile. This review analyzes in detail the role of ramucirumab in the treatment of advanced gastric and gastroesophageal junction cancers.

Hallazgos en niñas y púberes sexualmente abusadas / Findings in girls and prepubertal girls victims of sexual abuse

Objetivos: Valorar indicadores psicológicos, sociales y físicos así como hallazgos génito-anales y Enfermedades Sexualmente Transmisibles (EST) en 70 casos certeros de Abuso Sexual (AS). Resultados: Hallazgos génito-anales: * Grupo IA Normal 8,70 por ciento. * Grupo IB Inespecíficos 13,04 por ciento. * Grupo II Sugestivo Abuso Sexual (SAS) 42,03 por ciento. * Grupo III Concluyente Abuso Sexual (ConAS) 34,78 por ciento. * Grupo IV Certeza Abuso Sexual (CerAS) 1,45 por ciento. Hallazgos microbiológicos: Grupo I (Inespecífico): Flora endógena 58,62 por ciento, Patógenos Respiratorios 6,90 por ciento o Intestinales 6,90 por ciento. Grupo II (SAS): G. vaginalis 6,90 por ciento, U. urealyticum 3,45 por ciento, HSV, HPV. Grupo III (ConAS): G. trachomatis > 4 años 31,82 por ciento; T. vaginales > 1 año 3,45 por ciento. Grupo IV (CerAS): N. gonorrhoeae; Sífilis; HIV. Conclusiones: 1. Relato de la niña en 87,14 por ciento; 2. AS intrafamiliar 68,57 por ciento, AS extrafamiliar 24,28 por ciento y no supo en 7,14 por ciento; 3. De los casos intrafamiliares, en 43,75 por ciento el abusador fue el padre; 4. Hallazgos genito-anales SAS 42,03 por ciento y ConAS 34,78 por ciento. Estos índices se modifican a 33,33 por ciento y 46,37 por ciento, al incorporar EST en el criterio diagnóstico; 5. Si bien la vulvovaginitis es un signo inespecífico, el hallazgo de EST en 31,03 por ciento obliga a cultivar las niñas con flujo persistente y/o intermitente; 6. Violencia familiar 45,71 por ciento y alcoholismo y otras drogas 27,14 por ciento; 7. Antecedentes AS en madre o padre 27,14 por ciento; 8. Trastornos escolares 46,15 por ciento; 9. Pareja parental oroginal ya no existía en 70 por ciento