Genetic abnormalities as diagnostic and prognostic markers in B cell lymphomas: role of new molecular technologies in personalized medicine for extranodal diffuse large B cell lymphoma (EN-DLBCL) and follicular lymphoma (FL)

A plethora of molecular biomarkers are available nowadays in the field of cancer research. However, it is crucial to understand when and how they can be integrated into the clinical setting, translating experimental results from bench to bedside, with the aim of improving patients\u2019 care. We decided to investigate the role of some of these biomarkers in two subtypes of non-Hodgkin lymphoma which still represent a challenge for both researchers and clinicians. We started from diffuse large B cell lymphomas (DLBCLs), investigating a multicentric series of primary extranodal DLBCLs. Overall, data analysis provided strong evidence that the distribution of immunophenotypic, cytogenetic and survival characteristics is site-dependent. We next moved to follicular lymphoma (FL). The translocation (14;18), leading to BCL2 protein overexpression, is considered the genetic hallmark of FL. We tested the incidence of BCL2 negative FLs in a series of Italian patients from the Insubric region, concluding that BCL2 rearrangement in FL is not as frequent as generally reported and that the genetic landscape of FL is more complex than previously thought. What we learned is that even within an individual clinical entity, there is considerable heterogeneity with respect to genetic alterations, expression of commonly assayed markers and, most important, outcome. The personalized approach acknowledges this complexity and gives us tools for the continuous improvement of patients\u2019 care

Genetic abnormalities as diagnostic and prognostic markers in B cell lymphomas: role of new molecular technologies in personalized medicine for extranodal diffuse large B cell lymphoma (EN-DLBCL) and follicular lymphoma (FL)

A plethora of molecular biomarkers are available nowadays in the field of cancer research. However, it is crucial to understand when and how they can be integrated into the clinical setting, translating experimental results from bench to bedside, with the aim of improving patients’ care. We decided to investigate the role of some of these biomarkers in two subtypes of non-Hodgkin lymphoma which still represent a challenge for both researchers and clinicians. We started from diffuse large B cell lymphomas (DLBCLs), investigating a multicentric series of primary extranodal DLBCLs. Overall, data analysis provided strong evidence that the distribution of immunophenotypic, cytogenetic and survival characteristics is site-dependent. We next moved to follicular lymphoma (FL). The translocation (14;18), leading to BCL2 protein overexpression, is considered the genetic hallmark of FL. We tested the incidence of BCL2 negative FLs in a series of Italian patients from the Insubric region, concluding that BCL2 rearrangement in FL is not as frequent as generally reported and that the genetic landscape of FL is more complex than previously thought. What we learned is that even within an individual clinical entity, there is considerable heterogeneity with respect to genetic alterations, expression of commonly assayed markers and, most important, outcome. The personalized approach acknowledges this complexity and gives us tools for the continuous improvement of patients’ care

Unraveling Tumor Heterogeneity in an Apparently Monolithic Disease: BCL2 and Other Players in the Genetic Landscape of Nodal Follicular Lymphoma

Follicular lymphoma (FL) is the most common form of non-Hodgkin lymphoma in Western countries. Although traditionally considered a well-defined, easy to diagnose lymphoproliferative disorder, in the last few years it has become clear that it is in fact composed of many different clinicopathological entities, encompassing a variegated and complex genetic background. This has led to the inclusion of specific FL variants and separate entities in the latest update of the WHO classification. However, even in the context of classical FL, many aspects of intra- and inter-tumoral heterogeneity have been recognized, with a major influence on diagnosis and clinical practice at different time points during the course of the disease. This review focuses on the molecular cytogenetic heterogeneity in classical FL from precursors and early development to progression and transformation, in terms of both clonal heterogeneity and unusual genetic features. Several factors have been investigated and suggested to contribute to the broad spectrum of clinicopathological, phenotypic, and genetic features observed in otherwise morphologically classical cases. Among them, deregulation of the epigenetic machinery and interactions with tumor microenvironment seem to play a pivotal role, together with genetic aberrations involving well-known molecular pathways and mechanisms physiologically operating in the germinal center. In the era of personalized medicine, precision diagnostics based both on understanding of the complex interplay among all these factors and on novel developments will become crucial to predict the outcome and guide the treatment of FL patients

Aberrant DNA methylation profiles of inherited and sporadic colorectal cancer

Background: Aberrant DNA methylation has been widely investigated in sporadic colorectal carcinomas (CRCs), and extensive work has been performed to characterize different methylation profiles of CRC. Less information is available about the role of epigenetics in hereditary CRC and about the possible clinical use of epigenetic biomarkers in CRC, regardless of the etiopathogenesis. Long interspersed nucleotide element 1 (LINE-1) hypomethylation and gene-specific hypermethylation of 38 promoters were analyzed in multicenter series of 220 CRCs including 71 Lynch (Lynch colorectal cancer with microsatellite instability (LS-MSI)), 23 CRCs of patients under 40 years in which the main inherited CRC syndromes had been excluded (early-onset colorectal cancer with microsatellite stability (EO-MSS)), and 126 sporadic CRCs, comprising 28 cases with microsatellite instability (S-MSI) and 98 that were microsatellite stable (S-MSS). All tumor methylation patterns were integrated with clinicopathological and genetic characteristics, namely chromosomal instability (CIN), TP53 loss, BRAF, and KRAS mutations. Results: LS-MSI mainly showed absence of extensive DNA hypo-and hypermethylation. LINE-1 hypomethylation was observed in a subset of LS-MSI that were associated with the worse prognosis. Genetically, they commonly displayed G:A transition in the KRAS gene and absence of a CIN phenotype and of TP53 loss. S-MSI exhibited a specific epigenetic profile showing low rates of LINE-1 hypomethylation and extensive gene hypermethylation. S-MSI were mainly characterized by MLH1 methylation, BRAF mutation, and absence of a CIN phenotype and of TP53 loss. By contrast, S-MSS showed a high frequency of LINE-1 hypomethylation and of CIN, and they were associated with a worse prognosis. EO-MSS were a genetically and epigenetically heterogeneous group of CRCs. Like LS-MSI, some EO-MSS displayed low rates of DNA hypo-or hypermethylation and frequent G:A transitions in the KRAS gene, suggesting that a genetic syndrome might still be unrevealed in these patients. By contrast, some EO-MSS showed similar features to those observed in S-MSS, such as LINE-1 hypomethylation, CIN, and TP53 deletion. In all four classes, hypermethylation of ESR1, GATA5, and WT1 was very common. Conclusions: Aberrant DNA methylation analysis allows the identification of different subsets of CRCs. This study confirms the potential utility of methylation tests for early detection of CRC and suggests that LINE-1 hypomethylation may be a useful prognostic marker in both sporadic and inherited CRCs

Textbook outcome in urgent early cholecystectomy for acute calculous cholecystitis: results post hoc of the S.P.Ri.M.A.C.C study

Introduction: A textbook outcome patient is one in which the operative course passes uneventful, without complications, readmission or mortality. There is a lack of publications in terms of TO on acute cholecystitis. Objetive: The objective of this study is to analyze the achievement of TO in patients with urgent early cholecystectomy (UEC) for Acute Cholecystitis. and to identify which factors are related to achieving TO. Materials and methods: This is a post hoc study of the SPRiMACC study. It ́s a prospective multicenter observational study run by WSES. The criteria to define TO in urgent early cholecystectomy (TOUEC) were no 30-day mortality, no 30-day postoperative complications, no readmission within 30 days, and hospital stay ≤ 7 days (75th percentile), and full laparoscopic surgery. Patients who met all these conditions were taken as presenting a TOUEC. Outcomes: 1246 urgent early cholecystectomies for ACC were included. In all, 789 patients (63.3%) achieved all TOUEC parameters, while 457 (36.6%) failed to achieve one or more parameters and were considered non-TOUEC. The patients who achieved TOUEC were younger had significantly lower scores on all the risk scales analyzed. In the serological tests, TOUEC patients had lower values for in a lot of variables than non-TOUEC patients. The TOUEC group had lower rates of complicated cholecystitis. Considering operative time, a shorter duration was also associated with a higher probability of reaching TOUEC. Conclusion: Knowledge of the factors that influence the TOUEC can allow us to improve our results in terms of textbook outcome

Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Genetic abnormalities as diagnostic and prognostic markers in B cell lymphomas: role of new molecular technologies in personalized medicine for extranodal diffuse large B cell lymphoma (EN-DLBCL) and follicular lymphoma (FL)

A plethora of molecular biomarkers are available nowadays in the field of cancer research. However, it is crucial to understand when and how they can be integrated into the clinical setting, translating experimental results from bench to bedside, with the aim of improving patients’ care. We decided to investigate the role of some of these biomarkers in two subtypes of non-Hodgkin lymphoma which still represent a challenge for both researchers and clinicians. We started from diffuse large B cell lymphomas (DLBCLs), investigating a multicentric series of primary extranodal DLBCLs. Overall, data analysis provided strong evidence that the distribution of immunophenotypic, cytogenetic and survival characteristics is site-dependent. We next moved to follicular lymphoma (FL). The translocation (14;18), leading to BCL2 protein overexpression, is considered the genetic hallmark of FL. We tested the incidence of BCL2 negative FLs in a series of Italian patients from the Insubric region, concluding that BCL2 rearrangement in FL is not as frequent as generally reported and that the genetic landscape of FL is more complex than previously thought. What we learned is that even within an individual clinical entity, there is considerable heterogeneity with respect to genetic alterations, expression of commonly assayed markers and, most important, outcome. The personalized approach acknowledges this complexity and gives us tools for the continuous improvement of patients’ care

ACTH-producing tumor

ACTH-producing pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms, accounting for a minority of all PanNETs. Nevertheless, they are one of the leading non-pulmonary causes of the so-called ectopic ACTH-dependent Cushing's syndrome (ECS). The first ECS-associated PanNET was described in 1950 by Del Castillo and coworkers. Since then, less than 150 cases have been reported in the English literature The diagnosis of ACTH-producing PanNETs may be a clinical challenge, in particular when the presentation of the Cushing\ue2\u80\u99s syndrome is not typical. The milestones of the diagnosis are the detection of high circulating levels of ACTH and cortisol and the discovery of a pancreatic mass. ACTH-producing PanNETs have a female predominance, and the age of the patients is somewhat younger than in other PanNETs. Morphologically, they show the features of well-differentiated neuroendocrine tumors, but they are often larger than other PanNETs and frequently metastatic at the time of the diagnosis. Immunohistochemical staining helps to define the corticotroph phenotype of tumor cells.The prognosis of these tumors is often poor, with patients dying in a few months or years with metastatic disease

Estudio de la microbiota nativa presente en aguas residuales agrícolas contaminadas con 2,4-D

El aumento de la productividad, debido al incremento poblacional y de las exportaciones, trajo como consecuencia la necesidad de aumentar los rendimientos de los cultivos por parte del sector agroindustrial. La contaminación de los recursos hídricos a partir de la agricultura es una de las principales problemáticas a nivel mundial y ocurre cuando los plaguicidas son aplicados de manera repetitiva e inadecuada. Este escenario ha proporcionado la necesidad de reducir el uso del agua y el impacto negativo que causa la aplicación de plaguicidas y fertilizantes en la actividad agrícola. Con la finalidad de conocer como está compuesta la diversidad de la microbiota nativa de aguas residuales agrícolas y cuál puede ser su rol en la remoción del 2,4-D se prepararon aguas residuales agrícolas acondicionadas con 1, 2,5 y 5 mM de 2,4-D. Las mismos fueron incubados a 25 ºC durante 21 días. Se tomaron alícuotas de cada tratamiento a los 7, 14 y 21 días. Se determinó la diversidad de bacterias, hongos filamentosos y levaduras presentes en aguas residuales con herbicida y los resultados se expresaron en unidades formadoras de colonia por mililitro de muestra (UFC/mL). Se seleccionaron colonias representativas de cada género fúngico para su posterior identificación en base a caracteres morfológicos. Por otra parte, se sembró en superficie sobre medio de cultivo agar nutritivo para determinar la diversidad de bacterias mesófilas totales en las aguas residuales. El recuento fúngico total de las aguas residuales naturales sin la presencia del herbicida fue de 3,65 log10 UFC/mL, donde el único género que se aisló fue Penicillium spp. A medida que los días de incubación y la concentración de 2,4-D aumentaron, el desarrollo de colonias fúngicas se vio totalmente inhibido. Esto puede deberse al progresivo contacto de la micobiota con el herbicida. Solamente en presencia de 1 mM a los 7 días de incubación y con 2,5 mM a los 14 y 21 días de incubación se aislaron colonias pertenecientes a los géneros Penicillium spp. y Aspergillus spp., y al grupo morfológico de levaduras. Por otro lado, cuando se estudió el recuento de bacterias mesófilas totales, se observó que en general los recuentos fueron más altos que los encontrados para hongos y levaduras. Sin el agregado del herbicida y en los controles, el recuento de bacterias totales fue de 3,93 log10 UFC/mL y a medida que los días de incubación aumentaron, el recuento de mesófilos disminuyó con respecto al control, pero siempre manteniendo recuentos entre 3,33 y 3,72 log10 UFC/mL. A los 14 y 21 días de incubación, a medida que la concentración de 2,4-D aumentó, el recuento de bacterias también lo hizo. Con 5 mM de 2,4-D se registraron los mayores recuentos con valores de 3,66 y 3,72 log10 UFC/mL a los 14 y 21 días, respectivamente. Esto indicaría que los grupos bacterianos aislados de aguas residuales naturales (Bacillus spp.) fueron capaces de desarrollar y tolerar diferentes concentraciones de 2,4-D y plantearían una potencial estrategia para la remoción del mismo en las aguas residuales.Fil: Magnoli, Karen. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Investigación en Micología y Micotoxicología. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación en Micología y Micotoxicología; ArgentinaFil: Arsumendi, Paula. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Biotecnología Ambiental y Salud - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Biotecnología Ambiental y Salud; ArgentinaFil: Ruiz, Francesca. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Biotecnología Ambiental y Salud - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Biotecnología Ambiental y Salud; ArgentinaFil: Magnoli, Carina Elizabeth. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Investigación en Micología y Micotoxicología. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación en Micología y Micotoxicología; ArgentinaFil: Barberis, Carla Lorena. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Investigación en Micología y Micotoxicología. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación en Micología y Micotoxicología; ArgentinaIII Jornada Nacional de Agroalimentos y SustentabilidadVilla MaríaArgentinaUniversidad Nacional de Villa María. Instituto Académico y Pedagógico de Ciencias Aplicada

Unraveling Tumor Heterogeneity in an Apparently Monolithic Disease: BCL2 and Other Players in the Genetic Landscape of Nodal Follicular Lymphoma

Follicular lymphoma (FL) is the most common form of non-Hodgkin lymphoma in Western countries. Although traditionally considered a well-defined, easy to diagnose lymphoproliferative disorder, in the last few years it has become clear that it is in fact composed of many different clinicopathological entities, encompassing a variegated and complex genetic background. This has led to the inclusion of specific FL variants and separate entities in the latest update of the WHO classification. However, even in the context of classical FL, many aspects of intra- and inter-tumoral heterogeneity have been recognized, with a major influence on diagnosis and clinical practice at different time points during the course of the disease. This review focuses on the molecular cytogenetic heterogeneity in classical FL from precursors and early development to progression and transformation, in terms of both clonal heterogeneity and unusual genetic features. Several factors have been investigated and suggested to contribute to the broad spectrum of clinicopathological, phenotypic, and genetic features observed in otherwise morphologically classical cases. Among them, deregulation of the epigenetic machinery and interactions with tumor microenvironment seem to play a pivotal role, together with genetic aberrations involving well-known molecular pathways and mechanisms physiologically operating in the germinal center. In the era of personalized medicine, precision diagnostics based both on understanding of the complex interplay among all these factors and on novel developments will become crucial to predict the outcome and guide the treatment of FL patients.Follicular lymphoma (FL) is the most common form of non-Hodgkin lymphoma in Western countries. Although traditionally considered a well-defined, easy to diagnose lymphoproliferative disorder, in the last few years it has become clear that it is in fact composed of many different clinicopathological entities, encompassing a variegated and complex genetic background. This has led to the inclusion of specific FL variants and separate entities in the latest update of the WHO classification. However, even in the context of classical FL, many aspects of intra-and inter-tumoral heterogeneity have been recognized, with a major influence on diagnosis and clinical practice at different time points during the course of the disease. This review focuses on the molecular cytogenetic heterogeneity in classical FL from precursors and early development to progression and transformation, in terms of both clonal heterogeneity and unusual genetic features. Several factors have been investigated and suggested to contribute to the broad spectrum of clinicopathological, phenotypic, and genetic features observed in otherwise morphologically classical cases. Among them, deregulation of the epigenetic machinery and interactions with tumor microenvironment seem to play a pivotal role, together with genetic aberrations involving well-known molecular pathways and mechanisms physiologically operating in the germinal center. In the era of personalized medicine, precision diagnostics based both on understanding of the complex interplay among all these factors and on novel developments will become crucial to predict the outcome and guide the treatment of FL patients