Leonardo Cardili

SARS-CoV-2, responsible for COVID-19, affects multiple bodily systems, including placenta. Understanding its effects on placental angioactive factors is vital due to its vascular implications. Herein, we hypothesized that maternal SARS-CoV-2 infection could impact placental morphology and the expression of angioactive and inflammatory factors. The study included 23 pregnant women tested for COVID-19 through reverse transcription polymerase chain reaction (RT-qPCR) and IgG serology around time of delivery and discriminated as: Viremia Group (VG, n = 6, maternal positive RT-qPCR, early infection), Serology Group (SG, n = 10, maternal positive serology, late infection), and Control Group (CG, n = 7, negative for SARS-CoV-2). PCR and immunolocalization of SARS-CoV-2 in the placenta tested negative. Placental morphology was examined using H&E-stained sections, along with immunostaining for vascular endothelial growth factor (VEGF), placental growth factor (PlGF), inducible and endothelial nitric oxide synthase (iNOS, eNOS), and cyclooxygenase 2 (COX2). SG showed a significant higher level of placental morphological changes compared to control samples, which included an increase in syncytial knots and fibrin deposits on the villous surface, and villous peripheral and central infarctions. In contrast, samples from VG exhibited more frequent vascular dilation, congestion, and chorioangiosis. Compared with the control group, immunohistochemical analysis showed significantly higher expression of VEGF ( P = 0.001), COX2 ( P = 0.03), and eNOS ( P = 0.02) in VG. Conversely, in the SG, PlGF levels decreased ( P = 0.01), while COX2 ( P = 0.01) and iNOS ( P = 0.01) levels were elevated. Our data suggests a temporal adaptation of the placenta to maternal SARS-CoV-2 infection, triggering structural, angioactive, and inflammatory responses, enhancing our understanding of potential placental pathways to cope with SARS-CoV-2 infection.

Objective To prospectively determine the ability of visible lesions on multiparametric MRI (PI-RADS 4–5) and commonly used biomarkers to predict disease upgrading on rebiopsy in men with low-risk prostate cancer (PCa) enrolled in active surveillance (AS). Materials and methods For this prospective study, approved by the Institutional Review Board (IRB), we selected consecutive patients with low-risk, low-grade, and localized prostate cancer (PCa) from our active surveillance (AS) program, who were enrolled between March 2014 and December 2020. Patients who had undergone previous prostate surgery, hormonal treatment, had contraindications for mpMRI, or transrectal ultrasound-guided (TRUS) biopsy were excluded from this study. All eligible patients underwent mpMRI at least 3 months after the initial biopsy, followed by MRI-targeted TRUS-guided re-biopsy within 12 months after enrollment. The mpMRI studies were evaluated by an experienced radiologist using the PI-RADS v2 classification. Statistical significance was determined by comparing the results from the MRI with the pathology data from rebiopsy. Results There were 240 patients included. Overall upgrading rate was 41.2% (99/240), higher among patients classified as PIRADS 4 or 5 (77%). MRI sensitivity was 77.7% and specificity was 83.6% on re-biopsy. Visible lesion on mpMRI, PSA density and 3 + /12 positive cores at the first biopsy were good predictors of disease upgrade on rebiopsy. On our predictive model, patients with PI-RADS 4 or 5, PSA density > 0.15 ng/mL/cm³, and 3 + /12 positive cores at first biopsy had 92.4% chance of having clinically significant PCa. Conclusion Patients in AS with PI-RADS 4 or 5 lesions, PSA density > 0.15 ng/mL/cm³ and 3 + /12 positive cores at first biopsy have a high probability of having significant PCa on re-biopsy.

Introduction: The incidence of melanoma has been increasing in recent decades. BRAF mutations appear in 50%–70% of melanomas. The BRAF‐targeted therapy increased the disease‐free survival of patients with metastatic melanoma, but this response may be short, due to several resistance mechanisms, such as the presence of other subclones with mutations. Evaluation of mutations and heterogeneity in the coding region of the BRAF , MAP2K1 , and MAP2K2 genes in primary and metastatic melanomas. Patients and Methods: Twenty‐seven samples of primary and metastatic superficial spreading melanoma (SSM) and acral lentiginous melanoma (ALM) were analyzed for BRAF , MAP2K1 , and MAP2K2 mutations using the next‐generation sequencing technique. Results: In ALM, the mutation rate found was 50% in the BRAF and MAP2K1 genes and 28.6% in MAP2K2 . In the SSM, BRAF was mutated in 76.9%, MAP2K1 in 30.8%, and MAP2K2 in 23.2% of the cases. All samples were formed by distinct tumor subclones in the same lesion. Intertumoral heterogeneity was present between primary and metastatic lesions of ALM in BRAF , MAP2K1 , and MAP2K2 ; the cases of SSM were heterogeneous for BRAF and MAP2K1 . Conclusion: We sought to evaluate the mutations in the BRAF, MAP2K1, and MAP2K2 genes, revealing a heterogeneous mutation profile in samples of ALM and SSM.

Purpose High-risk localized prostate cancer (HRLPC) commonly progresses to metastatic disease after local treatment. Neoadjuvant androgen deprivation therapy (nADT) before radical prostatectomy (RP) has recently been suggested to improve early oncological outcomes in HRLPC. We aimed to perform an exploratory analysis of the pathological outcomes from a prospective trial testing nADT before RP. Methods Prospective, single-centered, phase II, randomized trial performed between October 2018 and July 2021. Random assignment (1:1) for nADT modalities: goserelin (10.8 mg) plus abiraterone acetate (1000 mg/d) plus prednisone (5 mg/d), with or without apalutamide (240 mg/d) for 12 weeks, followed by RP (within 30 days) and extended lymph node dissection. Baseline clinical and pathological variables were assessed in needle biopsies before nADT. Tumor regression was histologically evaluated in surgical specimens using the residual cancer burden index (RCB). Results Sixty-two patients reached the surgical phase. Good response (RCB ≤ 0.25 cm³) was achieved in 14 patients (22.5%). Overall stage migration rate between baseline status (MRI before nADT) and final status (after surgery) was 27.4%. Late stage detection (high tumor burden, perineural invasion) and altered PTEN/ERG immunostatus showed significant association with poor response in univariate analysis. Higher baseline tumor burden was the only independent factor related to poor response in multivariate analysis. Conclusions There are subgroups of patients, such as those with low baseline cancer burden and PTEN/ERG wild-type status, more likely to achieve good response with nADT. In the case of long term oncological benefit to be proven, nADT might be an additional therapeutic resource for these patients.

Introducción. Los antiinflamatorios, inmunosupresores e inmunobiológicos se utilizan comúnmente para tratar la enfermedad intestinal inflamatoria. Sin embargo, algunos pacientes no presentan una respuesta adecuada o pierden respuesta efectiva durante el tratamiento. En un estudio reciente, se encontró un potencial efecto antiinflamatorio del extracto hidroalcohólico de Mimosa caesalpiniifolia en la colitis inducida por el ácido trinitrobenceno sulfónico utilizando ratas Wistar. Objetivo. Evaluar los efectos de la preformulación de M. caesalpiniifolia sobre la barrera intestinal durante la colitis inducida por sulfato de dextrano sódico. Materiales y métodos. Los extractos de hojas se prepararon con una solución que contenía 70 % de etanol y se secaron con un secador por aspersión Mini B19 de Buchi usando una solución con 20 % de Aerosil®. Treinta y dos ratas Wistar macho se aleatorizaron en cuatro grupos: control basal, colitis sin tratar, control con preformulación (125 mg/kg/día) y colitis tratada con preformulación (125 mg/kg/día). El índice de actividad clínica se registró diariamente y todas las ratas se sacrificaron el noveno día. Los fragmentos de colon se fijaron y se procesaron para análisis histológicos y ultraestructurales. Se recolectaron muestras de heces y se procesaron para el análisis de ácidos grasos de cadena corta. Resultados. El tratamiento con la preformulación disminuyó la actividad clínica (diarrea sanguinolenta), el infiltrado inflamatorio y las úlceras. La preformulación no reparó la barrera epitelial y no hubo diferencias significativas en el índice de células caliciformes. Se obtuvo una diferencia significativa en los niveles de butirato en las ratas tratadas con la preformulación. Conclusiones: La preformulación minimizó los síntomas clínicos de colitis e inflamación intestinal pero no minimizó el daño a la barrera intestinal.

Background: Colorectal cancer is the third cause of cancer worldwide and a quarter of them are in the rectum. DEK oncogene is involved in several nuclear processes and can accelerate tumorigenesis. Objective: This study aims to evaluate the immunoexpression of DEK and Phospho-P38 proteins before neoadjuvant therapy in patients with rectum adenocarcinoma and correlate it with a clinical response and survival. Methods: Patients with adenocarcinoma of the middle and low rectum who underwent chemotherapy and radiotherapy followed by surgical tumor resection were included. The expression and quantification were studied by immunohistochemistry in the tumor biopsy tissues using a HScore system. Score ≥4 were considered positive and those with <4 negative. Results: 22 patients were included with a mean age of 63.55 years (SD: ±13.49). The clinical-stage before treatment was T3 on 72.7%, T4 on 18.2%, 31.8% were N1, 50% N0 and all M0. After chemo and radiotherapy, 54.6% were T3; 22.7% were classified as T2; 9.1% as T1, and 13.6% were T0. Among the tumors, 22.7% were positive for DEK and 63.6% positive for Phospho-P38. There was a positive correlation between DEK protein before treatment and pTNM stage (P=0.011). Phospho-P38 protein showed no correlation with these parameters. Patients with a negative HScore had a mean survival of 141.33 months (95%CI: 112.41-170.25) and those with a positive HSscore had a mean survival of 25.10 months (95%CI: 17.36-32.84; P<0.001). Conclusion: A higher expression of DEK was observed in advanced stages. Patients who presented DEK expression <4 had a higher survival, being a factor of worst prognosis.

Background: Gastric cancer (GC) with microsatellite instability (MSI) is a less aggressive disease and associated with resistance to 5‐fluorouracil (5‐FU)‐based chemotherapy (CMT). Thymidylate synthase (TS) is inhibited by 5‐FU, and another potential mediator of therapeutic resistance to 5‐FU. Therefore, we aimed to analyze the association between MSI and TS expression in GC, and its impact on disease outcomes.Methods: We retrospectively evaluated GC who underwent D2‐gastrectomy. MSI and TS were analyzed by immunohistochemistry. We also investigated p53 expression, PD‐L1 status, and tumor‐infiltrating lymphocytes (CD4 and CD8).Results: Out of 284 GC, 60 (21.1%) were MSI. Median TS‐score for all cases was 16.5. TS expression was significantly higher in MSI compared to microsatellite‐stable (MSS; p < 0.001). Considering both status, GC were classified in four groups: 167 (58.8%) MSS + TS‐low; 57 (20.1%) MSS + TS‐High; 24 (8.5%) MSI + TS‐low; and 36 (12.7%) MSI + TS‐high. MSI + TS‐high group had less advanced pTNM stage, higher CD8+T cells levels (p < 0.001) and PD‐L1 positivity (p < 0.001). Normal p53 expression was related to MSI GC (p < 0.001). Improved survival was observed in MSI + TS‐high, but no survival benefit was seen with CMT.Conclusion: MSI GC was associated with high TS levels, which may explain therapeutic resistance to 5‐FU. Additionally, MSI + TS‐high showed better survival, but without improvement with CMT.

Background: Recently, markers related to molecular classification were suggested as promising therapeutic targets for treatment and prediction of prognosis in gastric cancer (GC), including c-MET, RhoA, and Claudin-18 (CLDN18). This study aimed to investigate their expression in GC and its correlation with clinicopathological characteristics and survival. Methods: We retrospectively evaluated GC patients who underwent curative gastrectomy. c-MET, RhoA, and CLDN18 were analyzed through immunohistochemistry (IHC), and groups for analysis were determined according to the median values obtained for each marker. Results: Among the 349 GC evaluated, 180 (51.6%), 59 (16.9%), and 61 (17.5%) patients were completely negative for c-MET, RhoA, and CLDN18, respectively. Total gastrectomy, D1 lymphadenectomy, poorly differentiated histology, and greater inflammatory infiltrate were more frequent in the c-MET-negative group. Diffuse type, greater inflammatory infiltrate, and advanced pT and pTNM stage were associated with low-RhoA GC. The venous invasion was more frequent in the low-CLDN18 group. Furthermore, c-MET was positively correlated with RhoA and negatively with CLDN18. HER2 expression was associated with c-MET-positive and high-CLDN18 GC; and loss of E-cadherin expression in c-MET-negative and low-RhoA GC. c-MET-negative and Low-RhoA were significantly associated with worse disease-free survival. Conclusions: c-MET, RhoA, and CLD18 expression occurred frequently in GC. RhoA GC had distinct clinicopathological characteristics related to prognosis. c-MET and RhoA were associated with survival but were not independent predictors of prognosis.