A preoperative risk score based on early recurrence for estimating outcomes after resection of hepatocellular carcinoma in the non-cirrhotic liver.

BACKGROUND: Liver resection is the mainstay treatment option for patients with hepatocellular carcinoma in the non-cirrhotic liver (NCL-HCC), but almost half of these patients will experience a recurrence within five years of surgery. Therefore, we aimed to develop a rationale-based risk evaluation tool to assist surgeons in recurrence-related treatment planning for NCL-HCC. METHODS: We analyzed single-center data from 263 patients who underwent liver resection for NCL-HCC. Using machine learning modeling, we first determined an optimal cut-off point to discriminate early versus late relapses based on time to recurrence. We then constructed a risk score based on preoperative variables to forecast outcomes according to recurrence-free survival. RESULTS: We computed an optimal cut-off point for early recurrence at 12 months post-surgery. We identified macroscopic vascular invasion, multifocal tumor, and spontaneous tumor rupture as predictor variables of outcomes associated with early recurrence and integrated them into a scoring system. We thus stratified, with high concordance, three groups of patients on a graduated scale of recurrence-related survival. CONCLUSION: We constructed a preoperative risk score to estimate outcomes after liver resection in NCL-HCC patients. Hence, this score makes it possible to rationally stratify patients based on recurrence risk assessment for better treatment planning.

Deciphering anti-infectious compounds from Peruvian medicinal Cordoncillos extract library through multiplexed assays and chemical profiling.

High prevalence of parasitic or bacterial infectious diseases in some world areas is due to multiple reasons, including a lack of an appropriate health policy, challenging logistics and poverty. The support to research and development of new medicines to fight infectious diseases is one of the sustainable development goals promoted by World Health Organization (WHO). In this sense, the traditional medicinal knowledge substantiated by ethnopharmacology is a valuable starting point for drug discovery. This work aims at the scientific validation of the traditional use of Piper species ("Cordoncillos") as firsthand anti-infectious medicines. For this purpose, we adapted a computational statistical model to correlate the LCMS chemical profiles of 54 extracts from 19 Piper species to their corresponding anti-infectious assay results based on 37 microbial or parasites strains. We mainly identified two groups of bioactive compounds (called features as they are considered at the analytical level and are not formally isolated). Group 1 is composed of 11 features being highly correlated to an inhibiting activity on 21 bacteria (principally Gram-positive strains), one fungus (C. albicans), and one parasite (Trypanosoma brucei gambiense). The group 2 is composed of 9 features having a clear selectivity on Leishmania (all strains, both axenic and intramacrophagic). Bioactive features in group 1 were identified principally in the extracts of Piper strigosum and P. xanthostachyum. In group 2, bioactive features were distributed in the extracts of 14 Piper species. This multiplexed approach provided a broad picture of the metabolome as well as a map of compounds putatively associated to bioactivity. To our knowledge, the implementation of this type of metabolomics tools aimed at identifying bioactive compounds has not been used so far.

Metabotyping of Andean pseudocereals and characterization of emerging mycotoxins.

Pseudocereals are best known for three crops derived from the Andes: quinoa (Chenopodium quinoa), canihua (C. pallidicaule), and kiwicha (Amaranthus caudatus). Their grains are recognized for their nutritional benefits; however, there is a higher level of polyphenism. Meanwhile, the chemical food safety of pseudocereals remains poorly documented. Here, we applied untargeted and targeted metabolomics approaches by LC-MS to achieve both: i) a comprehensive chemical mapping of pseudocereal samples collected in the Andes; and ii) a quantification of their contents in emerging mycotoxins. An inventory of the fungal community was also realized to better know the fungi present in these grains. Metabotyping permitted to add new insights into the chemotaxonomy of pseudocereals, confirming the previously established phylotranscriptomic clades. Sixteen samples from Peru (out of 27) and one from France (out of one) were contaminated with Beauvericin, an emerging mycotoxin. Several mycotoxigenic fungi were detected, including Aspergillus sp., Penicillium sp., and Alternaria sp.

Exposure assessment of 170 pesticide ingredients and derivative metabolites in people from the Central Andes of Peru.

The Central Andes of Peru are a region of great concern regarding pesticide risk to the health of local communities. Therefore, we conducted an observational study to assess the level of pesticide contamination among Andean people. Analytical chemistry methods were used to measure the concentrations of 170 pesticide-related compounds in hair samples from 50 adult Andean subjects living in rural and urban areas. As part of the study, a questionnaire was administered to the subjects to collect information regarding factors that increase the risk of pesticide exposure. Our results indicate that Andean people are strongly exposed to agrochemicals, being contaminated with a wide array of pesticide-related compounds at high concentration levels. Multivariate analyses and geostatistical modeling identified sociodemographic factors associated with rurality and food origin that increase pesticide exposure risk. The present study represents the first comprehensive investigation of pesticide-related compounds detected in body samples collected from people living in the Central Andes of Peru. Our findings pinpoint an alarming environmental situation that threatens human health in the region and provide a rationale for improving public policies to protect local communities.

Estimating the burden of hepatitis B virus infection in Laos between 2020 and 2021: A cross-sectional seroprevalence survey.

Background: Laos is considered highly endemic for persistent infection with hepatitis B virus (HBV). To eliminate this burden, it has gradually implemented universal anti-hepatitis B immunisation of newborns over the past two decades. Methods: Using VIKIA® HBsAg, a rapid test for the qualitative detection of the HBV surface antigen, we conducted between Sep 1st, 2020 and Aug 31st, 2021 the largest prospective prevalence survey ever in Laos. This survey included blood donors (BD, n = 42,277), patients attending care in capital and provincial hospitals (n = 37,347) including attending mothers (n = 20,548), HIV-infected patients (n = 7439, recruited from 2009 to 2020), students from the Health Sciences University (n = 609), and outpatients (n = 350) coming for diagnosis at the Center Infectiology Lao-Christophe Mérieux in Vientiane. In total, 88,022 persons were tested, representing approximately 1.22% of the national population. To reach a reasonable estimate of HBsAg prevalence in Laos, we segmented the population according to three variables, age (≤20 years as a cut-off), sex, and geographical origin. BD values were used to estimate HBsAg prevalence in patients aged <20 while hospital survey prevalence was used to estimate the prevalence in those aged older than 20 years. Findings: We observed an HBsAg seroprevalence ranging from 2.6% in blood donors to 8.0% in HIV-infected patients. In BD, men were significantly more at risk to be carriers than women (RR = 1.2, P = 0.00063). For BD, attending mothers, or HIV-infected patients, HBsAg was significantly more prevalent in northern Laos (5.1-8.4%) than in central (2.0-8.1%) or southern parts of the country (2.2-6.9%), thereby delineating a North-to-South gradient. Interpretation: We considered that HBsAg prevalence probably ranges between 5.0% and 6.0% of the total population. Thus, we consider that Laos may no longer be highly endemic for chronic HBV infection but rather a country with intermediate endemicity. Funding: The funding sources were the Agence Universitaire de la Francophonie, the French Government, the French Institute for Sustainable Development (IRD), and European Union's Horizon 2020 Marie Sklodowska-Curie Actions (MSCA) - Research and Innovation Staff Exchange - (RISE) under grant agreement N° 823935.

Survival after curative pancreaticoduodenectomy for ampullary adenocarcinoma in a South American population: A retrospective cohort study.

BACKGROUND: Ampullary adenocarcinoma (AAC) is a rare neoplasm that accounts for only 0.2% of all gastrointestinal cancers. Its incidence rate is lower than 6 cases per million people. Different prognostic factors have been described for AAC and are associated with a wide range of survival rates. However, these studies have been exclusively conducted in patients originating from Asian, European, and North American countries. AIM: To evaluate the histopathologic predictors of overall survival (OS) in South American patients with AAC treated with curative pancreaticoduodenectomy (PD). METHODS: We analyzed retrospective data from 83 AAC patients who underwent curative (R0) PD at the National Cancer Institute of Peru between January 2010 and October 2020 to identify histopathologic predictors of OS. RESULTS: Sixty-nine percent of patients had developed intestinal-type AAC (69%), 23% had pancreatobiliary-type AAC, and 8% had other subtypes. Forty-one percent of patients were classified as Stage I, according to the AJCC 8th Edition. Recurrence occurred primarily in the liver (n = 8), peritoneum (n = 4), and lung (n = 4). Statistical analyses indicated that T3 tumour stage [hazard ratio (HR) of 6.4, 95% confidence interval (CI) of 2.5-16.3, P < 0.001], lymph node metastasis (HR: 4.5, 95%CI: 1.8-11.3, P = 0.001), and pancreatobiliary type (HR: 2.7, 95%CI: 1.2-6.2, P = 0.025) were independent predictors of OS. CONCLUSION: Extended tumour stage (T3), pancreatobiliary type, and positive lymph node metastasis represent independent predictors of a lower OS rate in South American AAC patients who underwent curative PD.

Cáncer de hígado: ¿Antigua o nueva amenaza para los jóvenes de países en vía de desarrollo?

Entre las neoplasias malignas más frecuentes del mundo, el carcinoma hepatocelular (CHC) es la segunda causa de muerte relacionada con el cáncer (1). Su incidencia se ha duplicado durante las dos últimas décadas y la mayor carga se produce en los países de ingresos bajos y medianos. Los tumores hepáticos primarios malignos suelen describirse como una patología que afecta principalmente a hombres mayores de 40 años con un hígado cirrótico; rara vez se han registrado en personas más jóvenes y normalmente, en menores de 40, lo más común es el hepatoblastoma

A preoperative nomogram for predicting long-term survival after resection of large hepatocellular carcinoma (>10 cm).

BACKGROUND: It has previously been demonstrated that a fraction of patients with hepatocellular carcinoma (HCC) > 10 cm can benefit from liver resection. However, there is still a lack of effective decision-making tools to inform intervention in these patients. METHODS: We analysed a comprehensive set of clinical data from 234 patients who underwent liver resection for HCC >10 cm at the National Cancer Institute of Peru between 1990 and 2015, monitored their survival, and constructed a nomogram to predict the surgical outcome based on preoperative variables. RESULTS: We identified cirrhosis, multifocality, macroscopic vascular invasion, and spontaneous tumour rupture as independent predictors of survival and integrated them into a nomogram model. The nomogram's ability to forecast survival at 1, 3, and 5 years was subsequently confirmed with high concordance using an internal validation. Through applying this nomogram, we stratified three groups of patients with different survival probabilities. CONCLUSION: We constructed a preoperative nomogram to predict long-term survival in patients with HCC >10 cm. This nomogram is useful in determining whether a patient with large HCC might truly benefit from liver resection, which is paramount in low- and middle-income countries where HCC is often diagnosed at advanced stages.

Single-Cell RNAseq Profiling of Human γδ T Lymphocytes in Virus-Related Cancers and COVID-19 Disease.

The detailed characterization of human γδ T lymphocyte differentiation at the single-cell transcriptomic (scRNAseq) level in tumors and patients with coronavirus disease 2019 (COVID-19) requires both a reference differentiation trajectory of γδ T cells and a robust mapping method for additional γδ T lymphocytes. Here, we incepted such a method to characterize thousands of γδ T lymphocytes from (n = 95) patients with cancer or adult and pediatric COVID-19 disease. We found that cancer patients with human papillomavirus-positive head and neck squamous cell carcinoma and Epstein-Barr virus-positive Hodgkin's lymphoma have γδ tumor-infiltrating T lymphocytes that are more prone to recirculate from the tumor and avoid exhaustion. In COVID-19, both TCRVγ9 and TCRVγnon9 subsets of γδ T lymphocytes relocalize from peripheral blood mononuclear cells (PBMC) to the infected lung tissue, where their advanced differentiation, tissue residency, and exhaustion reflect T cell activation. Although severe COVID-19 disease increases both recruitment and exhaustion of γδ T lymphocytes in infected lung lesions but not blood, the anti-IL6R therapy with Tocilizumab promotes γδ T lymphocyte differentiation in patients with COVID-19. PBMC from pediatric patients with acute COVID-19 disease display similar γδ T cell lymphopenia to that seen in adult patients. However, blood γδ T cells from children with the COVID-19-related multisystem inflammatory syndrome are not lymphodepleted, but they are differentiated as in healthy PBMC. These findings suggest that some virus-induced memory γδ T lymphocytes durably persist in the blood of adults and could subsequently infiltrate and recirculate in tumors.

Cannabinoids vs. whole metabolome: Relevance of cannabinomics in analyzing Cannabis varieties.

Cannabis sativa has a long history of domestication both for its bioactive compounds and its fibers. This has produced hundreds of varieties, usually characterized in the literature by chemotypes, with Δ9-THC and CBD content as the main markers. However, chemotyping could also be done based on minor compounds (phytocannabinoids and others). In this work, a workflow, which we propose to name cannabinomics, combines mass spectrometry of the whole metabolome and statistical analysis to help differentiate C. sativa varieties and deciphering their characteristic markers. By applying this cannabinomics approach to the data obtained from 20 varieties of C. sativa (classically classified as chemotype I, II, or III), we compared the results with those obtained by a targeted quantification of 11 phytocannabinoids. Cannabinomics can be considered as a complementary tool for phenotyping and genotyping, allowing the identification of minor compounds playing a key role as markers of differentiation.

Metallomic profile in non-cirrhotic hepatocellular carcinoma supports a phenomenon of metal metabolism adaptation in tumor cells.

We have previously described a form of hepatocellular carcinoma (HCC) in non-cirrhotic liver (HCC-NC) developed by Peruvian patients. We analyzed the metallomic profile in hepatic tissues from two independent cohorts exhibiting HCC-NC. Clinical, histopathological data, and HCC and non-tumoral liver (NTL) samples of 38 Peruvian and 38 French HCC-NC patients, were studied. Twelve metals were quantified using ICP/MS: Mn, Fe, Cu, Co, Zn, As, Se, Rb, Mo, Cd, Pb, and Sn. Associations between metals and survival were assessed. Our data showed significant differences between cohorts. Mean ages were 40.6 ± 20, 67.5 ± 9 years old for Peruvians and French, respectively. Fifty percent of the Peruvian patients were positive for the HBsAg, versus 3% in French patients. Mn, Cu, Zn, As, Se, Rb, Mo, Cd, Sn metal concentrations were higher in NTL of Peruvians. Importantly, metal concentrations were lower in HCC areas compared to NTL tissues in both cohorts, except for Cu for which mean concentration was higher in HCC (p < 0.05). Se concentration in HCC was associated with extended survival only in Peruvians. Our data, obtained in Peruvian and French HCC-NC cohorts, highlights similarity in the metallomic profile of HCC compared to NTL during the hepatic tumorigenesis in these specific groups of patients.

Natural Occurrence of Mycotoxin-Producing Fusaria in Market-Bought Peruvian Cereals: A Food Safety Threat for Andean Populations.

Consumption of cereals contaminated by mycotoxins poses health risks. For instance, Fumonisins B, mainly produced by Fusarium verticillioides and Fusariumproliferatum, and the type B trichothecene deoxynivalenol, typically produced by Fusarium graminearum, are highly prevalent on cereal grains that are staples of many cultural diets and known to represent a toxic risk hazard. In Peru, corn and other cereals are frequently consumed on a daily basis under various forms, the majority of food grains being sold through traditional markets for direct consumption. Here, we surveyed mycotoxin contents of market-bought grain samples in order to assess the threat these mycotoxins might represent to Peruvian population, with a focus on corn. We found that nearly one sample of Peruvian corn out of six was contaminated with very high levels of Fumonisins, levels mostly ascribed to the presence of F. verticillioides. Extensive profiling of Peruvian corn kernels for fungal contaminants could provide elements to refine the potential risk associated with Fusarium toxins and help define adapted food safety standards.

Global DNA hypermethylation pattern and unique gene expression signature in liver cancer from patients with Indigenous American ancestry.

Hepatocellular carcinoma (HCC) usually afflicts individuals in their maturity after a protracted liver disease. Contrasting with this pattern, the age structure of HCC in Andean people displays a bimodal distribution with half of the patients developing HCC in adolescence and early adulthood. To deepen our understanding of the molecular determinants of the disease in this population, we conducted an integrative analysis of gene expression and DNA methylation in HCC developed by 74 Peruvian patients, including 39 adolescents and young adults. While genome-wide hypomethylation is considered as a paradigm in human HCCs, our analysis revealed that Peruvian tumors are associated with a global DNA hypermethylation. Moreover, pathway enrichment analysis of transcriptome data characterized an original combination of signatures. Peruvian HCC forgoes canonical activations of IGF2, Notch, Ras/MAPK, and TGF-ß signals to depend instead on Hippo/YAP1, MYC, and Wnt/ß-catenin pathways. These signatures delineate a homogeneous subtype of liver tumors at the interface of the proliferative and non-proliferative classes of HCCs. Remarkably, the development of this HCC subtype occurs in patients with one of the four Native American mitochondrial haplogroups A-D. Finally, integrative characterization revealed that Peruvian HCC is apparently controlled by the PRC2 complex that mediates cell reprogramming with massive DNA methylation modulating gene expression and pinpointed retinoid signaling as a potential target for epigenetic therapy.

Depression in women with a diagnosis of breast cancer. Prevalence of symptoms of depression in Peruvian women with early breast cancer and related sociodemographic factors.

We sought to review literature on the prevalence of symptoms of depression in women with a diagnosis of breast cancer (BC) and in the Peruvian population determine the prevalence of symptoms of depression and to describe the association with sociodemographic characteristics. Descriptive cross-sectional analytical study of 254 patients from the National Cancer Institute of Peru (Instituto Nacional de Enfermedades Neoplásicas) with a diagnosis of clinical stage I or II BC. The patients included women aged between 26 and 67 years old. Symptoms of depression were monitored by the Beck Depression Inventory-II. Moreover, clinical features and patient sociodemographic characteristics were analyzed and their association with depression was assessed by logistic regression. The average age of the patients was 47.8 ± 9.2 years; 5.4% of the patients were postmenopausal at the time of the questionnaire. About 55% of women were from Lima, 58.3% had completed secondary education (11 ± 3.2 years), 45.7% were not working, and 46.5% were single. The prevalence of depression was 25.6% at the time of BC diagnosis. Of those patients with symptoms of depression, 16.9% showed symptoms of mild depression, 6.3% moderate, and 2.4% severe. A multivariable logistic regression model showed that in Peruvian women with a diagnosis of BC being married or employed significantly decreased the odds of presenting depressive symptoms (P = 0.029 and 0.017, respectively). Our main limitation was the lack of evaluation of depressive symptoms before the diagnosis, during or at the end of treatment. Another limitation was that the Beck Depression Inventory-II test could only identify depressive symptoms, but not depression as a disease. We have reviewed relevant literature on depression in women with a diagnosis of BC. The data presented suggests an association between both employment and marital status with depressive symptoms among Peruvian women with a diagnosis of BC. Pre-emptive support for women at risk could influence resilience and/or motivation for compliance with antineoplastic treatments.

On hepatocellular carcinoma in South America and early-age onset of the disease.

Hepatocellular carcinoma (HCC) is one of the most predominant tumor types worldwide, being particularly prevalent in sub-Saharan Africa and East Asia. However, HCC is inexplicably underreported in South America, despite unsettling clinical epidemiological trends of the disease on this continent. Here, we review the current knowledge on HCC presentation in Peru. We emphasize the well-documented occurrence of an early-age nosological form of the disease in Andean descent populations. We further discuss the reasons for such HCC clinical presentation, as well as the implications for liver cancer screening, management, and prevention.

Early-onset liver cancer in South America associates with low hepatitis B virus DNA burden.

In Peru, hepatocellular carcinoma (HCC) arises in young non-cirrhotic patients. Hepatitis B virus (HBV) is suspected to be the prominent etiological agent. We thus performed a comprehensive molecular study of HBV infection in 65 Peruvian HCC patients. Only 51% were considered as persistently infected at the onset. HBV DNA was found by PCR in the tumor and/or matched non-tumor liver tissues in more than 80% of cases (n = 53/65). HBV DNA was significantly more abundant in livers of younger patients than in those of the older ones. We consistently observed low viral DNA burden (0.1-6.5 copies for 100 cells), with viral genomes in younger patients displaying higher proportion of mutations at di-pyrimidines (TpT and CpC, P = 0.006). A drastic activation of multiple DNA repair pathways in tumors of younger patients was observed. Our observations clearly challenge the current vision that associates high HBV DNA load with earlier tumor development. We concluded that in Peru, and maybe in other populations with Americas' indigenous ancestry, HBV-associated liver tumorigenesis might differ significantly from that generally observed in the rest of the world. Procedures used to screen for HCC development in subjects at risk should be adapted to the local situation.

Liver clear cell foci and viral infection are associated with non-cirrhotic, non-fibrolamellar hepatocellular carcinoma in young patients from South America.

We previously described a divergent clinical and molecular presentation of hepatocellular carcinoma (HCC) in Peru. The present study aimed to further characterize the tissue features associated with this singular nosological form of HCC in order to gain insight into the natural history of the disease. We performed an exploratory analysis of the histology of both tumor and non-tumor liver (NTL) tissues from 50 Peruvian HCC patients, and compared with that of 75 individuals with non-HCC liver tumor or benign liver lesions as a baseline for NTL features. We complemented this approach with a transcriptome analysis in a subset of NTL tissue samples and also performed an ultra-sensitive hepatitis B virus (HBV) detection in liver tissues of the patients. Overall, results highlighted the low rate of liver parenchymal alterations in a young patient cohort (median age: 40 years old), despite a strong prevalence of underlying HBV infection (c. 67%). Withal, liver clear cell foci of cellular alteration were genuinely associated with HCC and appended to some changes in immune and G protein-coupled receptor gene expression ontologies. Our findings confirm the occurrence of a particular setting of HCC in South America, a region where the pathophysiology of liver cancer remains largely unexplored.

Bancos de cerebro: Un reto para Latinoamérica / Brain Banks: A challenge for Latin America

Muchos de los progresos recientes en la comprensión de la patogénesis de trastornos comunes y raros del sistema nervioso se han producido mediante el uso de tejido cerebral humano post-mortem. Los bancos de cerebros han tenido un papel crucial en este proceso, proporcionando material raro e invaluable. La función de un banco de cerebro moderno es recolectar material post-mortem o de biopsia de casos clínicamente y patológicamente bien caracterizados de manera continua y sistemática, considerando cuestiones de seguridad y éticas que rodean el uso de tejido humano donado para investigación médica. El presente artículo llama la atención sobre la importancia de los bancos de cerebro, en la recolección y almacenamiento de material post-mortem para satisfacer las necesidades de proyectos de investigación específicos, los aspectos tanto técnicos como éticos y legales, relacionados a la donación y manipulación de material biológico, así como proponer el desarrollo de una red en América Latina de bancos de cerebro que permita contar con material de estudio de diversos padecimientos en nuestra población.

Many of the latest findings to understand the pathogenesis of common and rare disorders of the nervous system have been produced by the use of post-mortem human brain tissue. Brain banks have played a crucial role in this process, rare and invaluable material. The function of a modern brain bank is the collection of post-mortem material or biopsy of clinically and pathologically well-characterized cases in a continuous and systematic manner, considering safety and ethical issues surrounding the use of human tissue for medical research. This review give importance of brain banks in the collection and storage of post-mortem material to satisfy the needs of specific research projects, the technical, ethical and legal aspects related to donation and manipulation of biological material, as well as proposing the development of a network in Latin America of brain banks that allows us to have material for the study of various diseases in our population.

Hepatitis C in Laos: A 7-Year Retrospective Study on 1765 Patients.

Hepatitis C virus (HCV) is a global health concern, notably in Southeast Asia, and in Laos the presentation of the HCV-induced liver disease is poorly known. Our objective was thus to describe a comprehensive HCV infection pattern in order to guide national health policies. A study on a group of 1765 patients formerly diagnosed by rapid test in health centres was conducted at the Centre of Infectiology Lao Christophe Merieux in Vientiane. The demographic information of patients, their infection status (viral load: VL), liver function (aminotransferases) and treatments were analysed. Results showed that gender distribution of infected people was balanced; with median ages of 53.8 for men and 51.6 years for women (13-86 years). The majority of patients (72%) were confirmed positive (VL > 50 IU/mL) and 28% of them had high VL (> 6log10). About 23% of patients had level of aminotransferases indicative of liver damage (> 40 IU/mL); but less than 20% of patients received treatment. Patients rarely received a second sampling or medical imaging. The survey also showed that cycloferon, pegylated interferon and ribavirin were the drugs prescribed preferentially by the medical staff, without following any international recommendations schemes. In conclusion, we recommend that a population screening policy and better management of patients should be urgently implemented in the country, respecting official guidelines. However, the cost of biological analysis and treatment are significant barriers that must be removed. Public health resolutions should be immediately enforced in the perspective of meeting the WHO HCV elimination deadline by 2030.