Identification of Lynch syndrome carriers among patients with small bowel adenocarcinoma

Background: Small bowel adenocarcinoma (SBA) is a rare disease which can be associated with Lynch syndrome (LS). LS tumors are characterized by the presence of microsatellite instability (MSI) and/or the loss of mismatch repair (MMR) protein expression. In SBA, the frequency of MMR deficient (MMRd) tumors varies from 5% to 35%. This study aims to describe the prevalence of LS carriers among patients with MMRd small bowel adenocarcinomas. Methods: A multicenter retrospective study with identification and MMR testing of all consecutive SBA between 2004 and 2020 in a multicenter Spanish study. Demographical data, tumor characteristics, follow-up and survival information were collected. Germline testing was driven by identification of MMRd tumors. Results: A total of 94 individuals diagnosed with SBA were recruited. We observed 20 (21.3%) MMRd tumors. In 9/15 (60%) patients with MMRd tumors, a pathogenic variant was identified (three MLH1, four MSH2, one MSH6 and one PMS2). Accordingly, the prevalence of LS among all SBA cases was 10.1%. Conclusions: More than one-fifth of SBA display MMRd and in more than a half is due to LS. Our data supports the implementation of universal MMR tumor testing among SBA for the identification of LS families

Alteraciones del olfato en la COVID-19, revisión de la evidencia e implicaciones en el manejo de la pandèmia

Existe debate sobre si las alteraciones en el olfato deberían considerarse un síntoma de la COVID-19. Se realizó una revisión sistemática bibliográfica de los artículos indexados en PubMed sobre alteraciones del olfato en cuadros virales de vías respiratorias, con especial énfasis en la COVID-19. El objetivo principal fue encontrar evidencia de interés clínico que apoye la relación entre ansomia y COVID-19. Las alteraciones del olfato en procesos infecciosos de vías altas son frecuentes y en su mayoría responden a una causa obstructiva por edema de la mucosa nasal. Ocasionalmente aparece una disfunción olfatoria posviral de tipo neurosensorial, de pronóstico variable. La evidencia acerca de la anosmia en pacientes con COVID-19 es muy limitada, correspondiente a un grado 5 o D del Centre for Evidence-Based Medicine. De acuerdo con la evidencia disponible, parece razonable aplicar medidas de aislamiento, higiene y distanciamiento social a los pacientes con alteraciones del olfato de reciente aparición como único síntoma, aunque se debería estudiar la utilidad de la realización de pruebas diagnósticas a este tipo de sujetos

Laparoscopic partial splenectomy for giant cyst using a radiofrequency-assisted device: a case report

Background: Although radiofrequency-assisted devices have sometimes been used in partial splenectomy, this is not a common technique. This report describes the first case of laparoscopic partial splenectomy using an RF-assisted device (Coolinside) which allows both coagulation and transection of the parenchyma and eventually the protective coagulation of the remnant side. Case presentation: A 27-year-old woman was found to have a giant hydatic cyst measuring 12.0 × 14.0 × 16.6 cm that mainly occupied the lower pole of the spleen and retroperitoneal space. The patient underwent a laparoscopic partial splenectomy using an RF-based device designed to accomplish both the coagulation and dissection of the splenic tissue. The estimated blood loss was less than 200 mL. Conclusions: Even though RF ablation has traditionally been used for hepatic parenchymal transection, it seems equally suited to partial splenectomy. This device seems to provide good results, minimizing blood loss during partial splenectomy; however, randomized trials will be necessary to see if the results are superior to those of other techniques.This work was partially supported by the Spanish “Programa Estatal de Investigación, Desarrollo e Innovación Orientada a los Retos de la Sociedad” under Grant TEC2014-52383-C3-R (TEC2014-52383-C3-1-R and TEC2014-52383-C3-3-R)

A systems approach identifies time-dependent associations of multimorbidities with pancreatic cancer risk

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients. METHODS: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (<3 years) and long term (≥3 years). The MPs and PDAC genetic networks were explored with DisGeNET bioinformatics-tool which focuses on gene-diseases associations available in curated databases. RESULTS: Three MPs were observed: gastric (heartburn, acid regurgitation, Helicobacter pylori infection, and ulcer), metabolic syndrome (obesity, type-2 diabetes, hypercholesterolemia, and hypertension), and atopic (nasal allergies, skin allergies, and asthma). Strong associations with PDAC were observed for ≥2 recently diagnosed gastric conditions [odds ratio (OR), 6.13; 95% confidence interval CI 3.01-12.5)] and for ≥3 recently diagnosed metabolic syndrome conditions (OR, 1.61; 95% CI 1.11-2.35). Atopic conditions were negatively associated with PDAC (high adherence score OR for tertile III, 0.45; 95% CI, 0.36-0.55). Combining type-2 diabetes with gastric MP resulted in higher PDAC risk for recent (OR, 7.89; 95% CI 3.9-16.1) and long-term diagnosed conditions (OR, 1.86; 95% CI 1.29-2.67). A common genetic basis between MPs and PDAC was observed in the bioinformatics analysis. CONCLUSIONS: Specific multimorbidities aggregate and associate with PDAC in a time-dependent manner. A better characterization of a high-risk population for PDAC may help in the early diagnosis of this cancer. The common genetic basis between MP and PDAC points to a mechanistic link between these conditions.The work was partially supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III-FEDER, Spain (PI11/01542, PI0902102, PI12/01635, PI12/00815, PI13/00082, and CP10/00524); Red Tematica de Investigacion Cooperativa en Cancer, Spain (RD12/0036/0034, RD12/0036/0050, and RD12/0036/0073); World Cancer Research (WCR 15-0391); Accion Especial de Gen omica, Spain (GEN2001-4748-c05-03); EU-6FP Integrated Project (018771-MOLDIAG-PACA), EUFP7-HEALTH (259737-CANCERALIA, 256974-EPC-TM-Net, and 602783-Cam-Pac), Associazione Italiana Ricerca sul Cancro (AIRC 12182); Cancer Focus Northern Ireland and Department for Employment and Learning; ALF (SLL20130022), Sweden; Italian Foundation for Cancer Research (FIRC) (no grant numbers apply). Th

The prognostic potential of CDX2 in colorectal cancer: Harmonizing biology and clinical practice

Adjuvant chemotherapy following surgical intervention remains the primary treatment option for patients with localized colorectal cancer (CRC). However, a significant proportion of patients will have an unfavorable outcome after current forms of chemotherapy. While reflecting the increasing complexity of CRC, the clinical application of molecular biomarkers provides information that can be utilized to guide therapeutic strategies. Among these, caudal-related homeobox transcription factor 2 (CDX2) emerges as a biomarker of both prognosis and relapse after therapy. CDX2 is a key transcription factor that controls intestinal fate. Although rarely mutated in CRC, loss of CDX2 expression has been reported mostly in right-sided, microsatellite-unstable tumors and is associated with aggressive carcinomas. The pathological assessment of CDX2 by immunohistochemistry can thus identify patients with high-risk CRC, but the evaluation of CDX2 expression remains challenging in a substantial proportion of patients. In this review, we discuss the roles of CDX2 in homeostasis and CRC and the alterations that lead to protein expression loss. Furthermore, we review the clinical significance of CDX2 assessment, with a particular focus on its current use as a biomarker for pathological evaluation and clinical decision-making. Finally, we attempt to clarify the molecular implications of CDX2 deficiency, ultimately providing insights for a more precise evaluation of CDX2 protein expression

Accumulation of paneth cells in early colorectal adenomas is associated with beta-catenin signaling and poor patient prognosis

Background: previous studies in mice indicated that Paneth cells and c-Kit-positive goblet cells represent the stem cell niche of the small intestine and colon, respectively, partly by supporting Wnt and Notch activation. Whether these cell populations play a similar role in human intestinal cancer remains unexplored. Methods: we performed histopathological evaluation and immunohistochemical analysis of early colorectal adenomas and carcinoma adenoma from patients at the Hospital del Mar in Barcelona. We then determined the possible correlation between the different parameters analyzed and with patient outcomes. Results: paneth cells accumulate in a subset of human colorectal adenomas directly associated with Notch and Wnt/β-catenin activation. Adenoma areas containing Paneth cells display increased vessel density in the lamina propria and higher levels of the stem cell marker EphB2. In an in-house cohort of 200 colorectal adenoma samples, we also observed a significant correlation between the presence of Paneth cells and Wnt activation. Kaplan-Meier analysis indicated that early adenoma patients carrying Paneth cell-positive tumors display reduced disease-free survival compared with patients with Paneth cell-free lesions. Conclusions: our results indicate that Paneth cells contribute to the initial steps of cancer progression by providing the stem cell niche to adenoma cells, which could be therapeutically exploited

Snail1 expression in endothelial cells controls growth, angiogenesis and differentiation of breast tumors

Snail1 is a transcriptional factor required for epithelial to mesenchymal transition and activation of cancer-associated fibroblasts (CAF). Apart from that, tumor endothelial cells also express Snail1. Here, we have unraveled the role of Snail1 in this tissue in a tumorigenic context. Methods: We generated transgenic mice with an endothelial-specific and inducible Snail1 depletion. This murine line was crossed with MMTV-PyMT mice that develop mammary gland tumors and the consequence of Snail1 depletion in the endothelium were investigated. We also interfere Snail1 expression in cultured endothelial cells. Results: Specific Snail1 depletion in the endothelium of adult mice does not promote an overt phenotype; however, it delays the formation of mammary gland tumors in MMTV-PyMT mice. These effects are associated to the inability of Snail1-deficient endothelial cells to undergo angiogenesis and to enhance CAF activation in a paracrine manner. Moreover, tumors generated in mice with endothelium-specific Snail1 depletion are less advanced and show a papillary phenotype. Similar changes on onset and tumor morphology are observed by pretreatment of MMTV-PyMT mice with the angiogenic inhibitor Bevacizumab. Human breast papillary carcinomas exhibit a lower angiogenesis and present lower staining of Snail1, both in endothelial and stromal cells, compared with other breast neoplasms. Furthermore, human breast tumors datasets show a strong correlation between Snail1 expression and high angiogenesis. Conclusion: These findings show a novel role for Snail1 in endothelial cell activation and demonstrate that these cells impact not only on angiogenesis, but also on tumor onset and phenotype.This study was funded by grants awarded to AGH by Agencia Estatal de Investigación (AEI) and Fondos FEDER (SAF2016-76461-R) and AEI (PID2019-104695RB-100/AEI/10.13039/501100011033). We also acknowledge support from the Instituto Carlos III / FEDER (PIE15/00008; PT17/0015/0011) and the "Xarxa de Bancs de tumors” sponsored by Pla Director d'Oncologia de Catalunya (XBTC). DCG was recipient of an FPU predoctoral fellowship from Ministerio de Educació

BRAF-induced tumorigenesis is IKKα-dependent but NF-κB-independent

KRAS mutations contribute to cell proliferation and survival in numerous cancers, including colorectal cancers (CRC). One pathway through which mutant KRAS acts is an inflammatory pathway that involves the kinase IKK and activates the transcription factor NF-κB. BRAF, a kinase that is downstream of KRAS, is mutated in a subset of CRC and is predictive of poor prognosis and therapeutic resistance. We found that, in contrast to mutant KRAS, mutant BRAF (BRAF(V600E)) did not trigger NF-κB activation but instead triggered the phosphorylation of a proteolytic fragment of IKKα (p45-IKKα) in CRC cells. BRAF(V600E) CRC cells had a high abundance of phosphorylated p45-IKKα, which was decreased by a RAF inhibitor. However, the abundance and DNA binding of NF-κB in these cells were unaffected by the RAF inhibitor, and expression of BRAF(V600E) in human embryonic kidney-293T cells did not activate an NF-κB reporter. Moreover, BRAF-induced transformation of NIH-3T3 cells and BRAF-dependent transcription required phosphorylation of p45-IKKα. The kinase TAK1, which was associated with the endosomal compartment, phosphorylated p45-IKKα. Inhibition of endosomal vacuolar adenosine triphosphatase (V-ATPase) with chloroquine or bafilomycin A1 blocked p45-IKKα phosphorylation and induced apoptosis in BRAF-mutant CRC cells independent of autophagy. Treating mice with V-ATPase inhibitors reduced the growth and metastasis of BRAF(V600E) xenograft tumors in the cecum of mice.Funding: P.M. is a recipient of a Formación de Profesorado Universitario (FPU) fellowship (AP2009-2892), and L.E. is an investigator at the Carlos III program. This work was further supported by Instituto de Salud Carlos III-FEDER grants PI13/00448, AGAUR (SGR23), and RTICCS/FEDER (RD12/0036/0054 and RD09/0076/00036) and “Xarxa de Bancs de tumors” sponsored by the Pla Director d’Oncologia de Catalunya (XBTC)

Atypical double colorectal metastasis: spleen and uterus

Oligometastatic disease is a relatively new concept that refers to an intermediate stage between disseminated and localized cancer. Most frequent locations for colorectal metastasis are lung and liver. We present an a typical case of an 85-year-old woman who was diagnosed with a low-grade adenocarcinoma in left colon; she underwent a left laparoscopic hemicolectomy which resulted in a stage IIIb. After 24 months of follow-up, an increase of carcinoembryonic antigen (CEA) leads to the diagnosis of two metastatic lesions in two uncommon locations: spleen and myometrium. Stepwise surgical resection of both lesions was performed without complications. Spleen and uterus are organs that are rarely affected in colorectal cancer, the affection of both organs being even more infrequent. Despite the atypicality, surgical treatment is a valid strategy in this case of oligometastatic disease, which enables the disease-free survival of the patients

miR-24-3p regulates CDX2 during intestinalization of cardiac-type epithelium in a human model of Barrett's esophagus

Background: Cardiac-type epithelium has been proposed as the precursor of intestinal metaplasia in the development of Barrett's esophagus. Dysregulation of microRNAs (miRNAs) and their effects on CDX2 expression may contribute to intestinalization of cardiac-type epithelium. The aim of this study was to examine the possible effect of specific miRNAs on the regulation of CDX2 in a human model of Barrett's esophagus. Methods: Microdissection of cardiac-type glands was performed in biopsy samples from patients who underwent esophagectomy and developed cardiac-type epithelium in the remnant esophagus. OpenArray™ analysis was used to compare the miRNAs profiling of cardiac-type glands with negative or fully positive CDX2 expression. CDX2 was validated as a miR-24 messenger RNA target by the study of CDX2 expression upon transfection of miRNA mimics and inhibitors in esophageal adenocarcinoma cell lines. The CDX2/miR-24 regulation was finally validated by in situ miRNA/CDX2/MUC2 co-expression analysis in cardiac-type mucosa samples of Barrett's esophagus. Results: CDX2 positive glands were characterized by a unique miRNA profile with a significant downregulation of miR-24-3p, miR-30a-5p, miR-133a-3p, miR-520e-3p, miR-548a-1, miR-597-5p, miR-625-3p, miR-638, miR-1255b-1, and miR-1260a, as well as upregulation of miR-590-5p. miRNA-24-3p was identified as potential regulator of CDX2 gene expression in three databases and confirmed in esophageal adenocarcinoma cell lines. Furthermore, miR-24-3p expression showed a negative correlation with the expression of CDX2 in cardiac-type mucosa samples with different stages of mucosal intestinalization. Conclusion: These results showed that miRNA-24-3p regulates CDX2 expression, and the downregulation of miRNA-24-3p was associated with the acquisition of the intestinal phenotype in esophageal cardiac-type epithelium