High-Resolution Magic-Angle-Spinning NMR in Revealing Hepatoblastoma Hallmarks

Cancer is one of the leading causes of death in children and adolescents worldwide; among the types of liver cancer, hepatoblastoma (HBL) is the most common in childhood. Although it affects only two to three individuals in a million, it is mostly asymptomatic at diagnosis, so by the time it is detected it has already advanced. There are specific recommendations regarding HBL treatment, and ongoing studies to stratify the risks of HBL, understand the pathology, and predict prognostics and survival rates. Although magnetic resonance imaging spectroscopy is frequently used in diagnostics of HBL, high-resolution magic-angle-spinning (HR-MAS) NMR spectroscopy of HBL tissues is scarce. Using this technique, we studied the alterations among tissue metabolites of ex vivo samples from (a) HBL and non-cancer liver tissues (NCL), (b) HBL and adjacent non-tumor samples, and (c) two regions of the same HBL samples, one more centralized and the other at the edge of the tumor. It was possible to identify metabolites in HBL, then metabolites from the HBL center and the border samples, and link them to altered metabolisms in tumor tissues, highlighting their potential as biochemical markers. Metabolites closely related to liver metabolisms such as some phospholipids, triacylglycerides, fatty acids, glucose, and amino acids showed differences between the tissues

The Role of Immunohistochemical Analysis as a Tool for the Diagnosis, Prognostic Evaluation and Treatment of Prostate Cancer: A Systematic Review of the Literature

Background: Prostate cancer (PCa) is a heterogeneous disease that lends itself toward numerous therapeutic options depending on its risk stratification. One of the greatest challenges in PCa urologic practice is to select patients who should be referred for biopsy and, for those patients who are diagnosed with cancer, to differentiate between patients with indolent disease from those with an unfavorable prognosis and, to determine ideal patient management and avoid unnecessary interventions. Accordingly, there is a growing body of literature reporting immunohistochemical studies with the objective of determining a prostate cancer prognosis. Among the most frequent biomarkers studied are Ki-67, p53, PTEN, MYC, and ERG. Based on these findings, we systematically reviewed articles that assessed the role of these main prognostic markers in prostate cancer.Methods: Consistent with PRISMA guidelines, we performed a systematic literature search throughout the Web of Science and PubMed Medline databases. We considered all types of studies evaluating the role of Ki-67, p53, PTEN, MYC, and ERG immunohistochemical analysis in prostate cancer until July 2017.Results: We identified 361 articles, 44 of which were summarized in this review. Diagnostically, no single immunohistochemical marker was able to define a tumor as benign or malignant. Prognostically, Ki-67, p53, and MYC were related to the tumor grade given by Gleason score and to the tumor stage (higher levels related to higher tumor grade). Furthermore, Ki-67 was also related to higher PSA levels, shorter disease-free intervals and shorter tumor-specific survival; the latter was also related to p53. The loss of PTEN protein expression showed a higher association with biochemical recurrence and with a worse prognosis, beyond that predicted by the Gleason score and tumor stage. ERG staining also showed a strong association with biochemical recurrence.Conclusion: There are several studies relating immunohistochemical markers with clinical-laboratorial outcomes in prostate cancer, the most frequent being Ki-67, p53, ERG, PTEN, and MYC. However, none of these markers have been validated by literary consensus to be routinely applied in medical practice

Down-regulation of ANAPC13 and CLTCL1: Early Events in the Progression of Preinvasive Ductal Carcinoma of the Breast

Alterations in the gene expression profile in epithelial cells during breast ductal carcinoma (DC) progression have been shown to occur mainly between pure ductal carcinoma in situ (DCIS) to the in situ component of a lesion with coexisting invasive ductal carcinoma (DCIS-IDC) implying that the molecular program for invasion is already established in the preinvasive lesion. For assessing early molecular alterations in epithelial cells that trigger tumorigenesis and testing them as prognostic markers for breast ductal carcinoma progression, we analyzed, by reverse transcription-quantitative polymerase chain reaction, eight genes previously identified as differentially expressed between epithelial tumor cells populations captured from preinvasive lesions with distinct malignant potential, pure DCIS and the in situ component of DCIS-IDC. ANAPC13 and CLTCL1 down-regulation revealed to be early events of DC progression that anticipated the invasiveness manifestation. Further down-regulation of ANAPC13 also occurred after invasion appearance and the presence of the protein in invasive tumor samples was associated with higher rates of overall and disease-free survival in breast cancer patients. Furthermore, tumors with low levels of ANAPC13 displayed increased copy number alterations, with significant gains at 1q (1q23.1-1q32.1), 8q, and 17q (17q24.2), regions that display common imbalances in breast tumors, suggesting that down-regulation of ANAPC13 contributes to genomic instability in this disease.Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (CEPID/FAPESP) [98/14335]Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (CEPID/FAPESP)CNPqCNPq [142790/2008-7]FAPESP [2009/00669-2, 2009/02457-2]FAPES

Reappraisal of Morphological Differences between Renal Medullary Carcinoma, Collecting Duct Carcinoma, and Fumarate Hydratase-Deficient Renal Cell Carcinoma

Renal medullary carcinomas (RMCs) and collecting duct carcinomas (CDCs) are rare subsets of lethal high-stage, high-grade distal nephron-related adenocarcinomas with a predilection for the renal medullary region. Recent findings have established an emerging group of fumarate hydratase (FH)-deficient tumors related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC-RCCs) syndrome within this morphologic spectrum. Recently developed, reliable ancillary testing has enabled consistent separation between these tumor types. Here, we present the clinicopathologic features and differences in the morphologic patterns between RMC, CDC, and FH-deficient RCC in consequence of these recent developments. This study included a total of 100 cases classified using contemporary criteria and ancillary tests. Thirty-three RMCs (SMARCB1/INI1-deficient, hemoglobinopathy), 38 CDCs (SMARCB1/INI1-retained), and 29 RCCs defined by the FH-deficient phenotype (FH/2SC or FH/2SC with FH mutation, regardless of HLRCC syndromic stigmata/history) were selected. The spectrum of morphologic patterns was critically evaluated, and the differences between the morphologic patterns present in the 3 groups were analyzed statistically. Twenty-five percent of cases initially diagnosed as CDC were reclassified as FH-deficient RCC on the basis of our contemporary diagnostic approach. Among the different overlapping morphologic patterns, sieve-like/cribriform and reticular/yolk sac tumor-like patterns favored RMCs, whereas intracystic papillary and tubulocystic patterns favored FH-deficient RCC. The tubulopapillary pattern favored both CDCs and FH-deficient RCCs, and the multinodular infiltrating papillary pattern favored CDCs. Infiltrating glandular and solid sheets/cords/nested patterns were not statistically different among the 3 groups. Viral inclusion-like macronucleoli, considered as a hallmark of HLRCC-RCCs, were observed significantly more frequently in FH-deficient RCCs. Despite the overlapping morphology found among these clinically aggressive infiltrating high-grade adenocarcinomas of the kidney, reproducible differences in morphology emerged between these categories after rigorous characterization. Finally, we recommend that definitive diagnosis of CDC should only be made if RMC and FH-deficient RCC are excluded

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Urological cancer related to familial syndromes

ABSTRACT Cancer related to hereditary syndromes corresponds to approximately 5-10% of all tumors. Among those from the genitourinary system, many tumors had been identified to be related to genetic syndromes in the last years with the advent of new molecular genetic tests. New entities were described or better characterized, especially in kidney cancer such as hereditary leiomyomatosis renal cell carcinoma (HLRCC), succinate dehydrogenase kidney cancer (SDH-RCC), and more recently BAP1 germline mutation related RCC. Among tumors from the bladder or renal pelvis, some studies had reinforced the role of germline mutations in mismatch repair (MMR) genes, especially in young patients. In prostate adenocarcinoma, besides mutations in BRCA1 and BRCA2 genes that are known to increase the incidence of high-risk cancer in young patients, new studies have shown mutation in other gene such as HOXB13 and also polymorphisms in MYC, MSMB, KLK2 and KLK3 that can be related to hereditary prostate cancer. Finally, tumors from testis that showed an increased in 8 - 10-fold in siblings and 4 - 6-fold in sons of germ cell tumors (TGCT) patients, have been related to alteration in X chromosome. Also genome wide association studies GWAS pointed new genes that can also be related to increase of this susceptibility

Análise imuno-histoquímica das sintases do óxido nítrico em adenocarcinomas gástricos Immunohistochemical expression of nitric oxide synthases in gastric adenocarcinomas

INTRODUÇÃO: O óxido nítrico (NO) é uma molécula mediadora de diversas funções, tais como vasodilatação, neurotransmissão e metabolismo do ferro. Os efeitos do NO na biologia tumoral são ambíguos e complexos. A atividade das sintases do óxido nítrico (NOS) tem sido demonstrada em diversos tumores humanos. OBJETIVO: Pesquisar a expressão das isoformas das NOS em carcinomas gástricos e correlacionar estes achados com características demográficas e histopatológicas destes tumores. MATERIAL E MÉTODOS: O estudo imuno-histoquímico das NOS (NOS-1, NOS-2 e NOS-3) foi realizado em 128 casos de carcinomas gástricos classificados de acordo com o sistema de Lauren. RESULTADOS: A positividade para NOS-1 foi detectada em 92/128 (70%) dos casos, para NOS-2 em 36/128 (30%) e para NOS-3 em 54/128 (42%) dos casos. Na análise estatística observou-se correlação com o tipo intestinal e expressão de NOS-3, e tumores avançados mostraram maior expressão de NOS-2. CONCLUSÃO: Os carcinomas gástricos mostram expressão das três isoformas de NOS, sendo as NOS constitutivas presentes em maior número de casos. A freqüente expressão de NOS induzida nos carcinomas gástricos avançados sugere uma participação de NOS na progressão e na disseminação tumoral na mucosa gástrica.<br>INTRODUCTION: Nitric oxide is an important bioactive and signaling molecule that mediates a diverse array of actions such as vasodilatation, neurotransmission, and iron metabolism. Also, it can act as a carcinogen. Recent studies have examined the expression and activity of the NOS isoforms in several human cancers. OBJECTIVES: To investigate the expression of nitric oxide synthases in gastric carcinomas and correlate the results. MATERIAL AND METHODS: The immunohistochemistry expression of constitutive and inducible nitric oxide synthases (NOS-1, NOS-2 e NOS-3) were evaluated in 128 cases of gastric cancer classified according to Lauren system. RESULTS: The rate of expression of NOS-1 was 92 (70%) of the 12 cases, NOS-2 was 36 (30%) and NOS-3 was 54 (42%) of the cases. The expression of NOS-3 was associated with the intestinal type of carcinoma and deeply invasive tumors showed high rate of expression of NOS-2. CONCLUSION: There is high expression of all the isoforms of nitric oxide synthases in gastric cancer; the constitutive isoforms show higher expression than the inducible forms. The high expression of the inducible form in deeply invasive tumors is related with tumoral progression and dissemination in the gastric mucosa

Radical prostatectomy and positive surgical margins: relationship with prostate cancer outcome

Introduction Positive surgical margins (PSMs) are an adverse factor that may predict a worse outcome in patients submitted to radical prostatectomy (RP). However, not all of these cases will evolve to biochemical (BCR) or clinical (CR) recurrence, therefore relationship between PSMs and these recurrent events has to be correlated with other clinical and pathologic findings to indicate complementary treatment for selected patients. Materials and Methods Of 1250 patients submitted to open retropubic radical prostatectomy (RRP), between March 1991 and June 2008, the outcome of 161 patients with PSMs and of 67 without PSMs as a control group, comprising a total of 228 cases were retrospectively reviewed. A minimum follow-up time of 2 years after surgery was considered. BCR was determined when PSA &#8805; 0.2ng/mL. CR was determined whenever there was clinical evidence of tumor. Chi-square test was used to correlate clinical and pathologic variables with PSMs. Time interval to biochemical recurrence was analyzed by the Kaplan-Meier product limit analysis using the log-rank test for comparison between groups. Univariate and multivariate Cox stepwise logistic regression models were used to identify significant predictors of risk of shorter intervals to BCR. Results Prostate circumference margin was the most common site with 78 cases (48.44%). Regarding the outcome of 228 cases from both groups, BCR occurred in 68 patients (29.82%), and CR in 10 (4.38%). Univariate analysis showed statistically significant associations (p < 0.001) between presence of PSMs with BCR, but not with CR (p = 0.05). At follow-up of the 161 patients with PSMs, only 61(37.8%) presented BCR, while 100 (62.8%) did not. BCR correlated with pathologic stage; Gleason score; preoperative PSA; tumor volume in the specimen; capsular and perineural invasion; presence and number of PSMs. CR correlated only with angiolymphatic invasion and Gleason score. Considering univariate analysis of clinical and pathologic factors predicting progression-free survival at 5 years, prostate weight; preoperative PSA; Gleason score; pathologic stage; tumor volume; PSMs; capsular and perineural invasion were correlated with BCR. At multivariate analysis, only Gleason score and percentage of tumor volume correlated as significant independent predictors of BCR. Conclusion At univariate analysis, presence, number and location of PSMs have consistent correlation with BCR after RRP, but at follow-up BCR occurred only in 37.8% of patients with PSMs. However at multivariate analysis, the significant risk factors for BCR were percentage of tumor volume (p = 0.022) and Gleason score (p < 0.005) in the surgical specimen. Angiolymphatic invasion and Gleason score were significantly correlated with CR