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Abstract Background Benign nerve sheath tumors presenting as solitary retroperitoneal masses (RBNSTs) pose a complex diagnostic challenge for multidisciplinary teams regarding differential diagnosis, staging, and treatment planning. This article reviews the role played by different imaging techniques in assessing RBNSTs and elucidates their typical pathological features with a particular emphasis on the correlation between imaging and histological findings. Furthermore, some examples of retroperitoneal tumors that merit consideration in the process of differential diagnosis based on cross-sectional investigations (CSIs) are reported. The correlation between tissue architecture and appearance on imaging can help increase the accuracy of differential diagnosis with other retroperitoneal neoplasms at CSIs. Critical relevance statement This educational review critically examines the correlation between imaging and histological features in solitary retroperitoneal benign nerve sheath tumors, offering valuable insights for improving the accuracy of differential diagnosis in clinical radiology. Key Points RBNSTs are challenging to diagnose because they lack specific radiological features. Differential diagnosis of RBNSTs from other retroperitoneal neoplasms on imaging is complex. Surgical removal of RBNSTs is recommended for an accurate diagnosis. Graphical Abstract

Gastric cancer (GC) is a complex disease with various etiologies. While Helicobacter pylori infection is still one of the leading risk factors for GC, increasing evidence suggests a link between GC and other infective agents such as Epstein Bar Virus (EBV). EBV-associated gastric cancer (EBVaGC) is now recognized as a distinct subgroup of GC, and the complex interactions between the virus and gastric mucosa may influence its development. A recent integrative analysis of the genome and proteome of GC tissues by The Cancer Genome Atlas project has identified EBVaGC as a specific subtype characterized by PIK3CA and ARID1A mutations, extensive DNA hyper-methylation, and activation of immune signaling pathways. These molecular characteristics are markers of the unique molecular profile of this subset of GC and are potential targets for therapy. This review aims to provide an overview of the current knowledge on EBVaGC. It will focus on the epidemiology, clinic-pathological features, and genetic characteristics of EBVaGC. Additionally, it will discuss recent data indicating the potential use of EBV infection as a predictive biomarker of response to chemotherapy and immune checkpoint inhibitors. The review also delves into potential therapeutic approaches for EBVaGC, including targeted therapies and adoptive immunotherapy, highlighting the promising potential of EBV as a therapeutic target.

Introduction: Decellularized extracellular matrix (ECM) bioscaffolds have emerged as a promising three-dimensional (3D) model, but so far there are no data concerning their use in radiobiological studies. Material and Methods: We seeded two well-known radioresistant cell lines (HMV-II and PANC-1) in decellularized porcine liver-derived scaffolds and irradiated them with both high- (Carbon Ions) and low- (Photons) Linear Energy Transfer (LET) radiation in order to test whether a natural 3D-bioscaffold might be a useful tool for radiobiological research and to achieve an evaluation that could be as near as possible to what happens in vivo. Results: Biological scaffolds provided a favorable 3D environment for cell proliferation and expansion. Cells did not show signs of dedifferentiation and retained their distinct phenotype coherently with their anatomopathological and clinical behaviors. The radiobiological response to high LET was higher for HMV-II and PANC-1 compared to the low LET. In particular, Carbon Ions reduced the melanogenesis in HMV-II and induced more cytopathic effects and the substantial cell deterioration of both cell lines compared to photons. Conclusions: In addition to offering a suitable 3D model for radiobiological research and an appropriate setting for preclinical oncological analysis, we can attest that bioscaffolds seemed cost-effective due to their ease of use, low maintenance requirements, and lack of complex technology

Summary: Background: The oncological safety of minimally invasive surgery has been questioned for several abdominal cancers. Concerns also exist regarding the use of minimally invasive distal pancreatectomy (MIDP) in patients with resectable pancreatic cancer as randomised trials are lacking. Methods: In this international randomised non-inferiority trial, we recruited adults with resectable pancreatic cancer from 35 centres in 12 countries. Patients were randomly assigned to either MIDP (laparoscopic or robotic) or open distal pancreatectomy (ODP). Both patients and pathologists were blinded to the assigned approach. Primary endpoint was radical resection (R0, ≥1 mm free margin) in patients who had ultimately undergone resection. Analyses for the primary endpoint were by modified intention-to-treat, excluding patients with missing data on primary endpoint. The pre-defined non-inferiority margin of −7% was compared with the lower limit of the two-sided 90% confidence interval (CI) of absolute difference in the primary endpoint. This trial is registered with the ISRCTN registry (ISRCTN44897265). Findings: Between May 8, 2018 and May 7, 2021, 258 patients were randomly assigned to MIDP (131 patients) or ODP (127 patients). Modified intention-to-treat analysis included 114 patients in the MIDP group and 110 patients in the ODP group. An R0 resection occurred in 83 (73%) patients in the MIDP group and in 76 (69%) patients in the ODP group (difference 3.7%, 90% CI −6.2 to 13.6%; pnon-inferiority = 0.039). Median lymph node yield was comparable (22.0 [16.0–30.0] vs 23.0 [14.0–32.0] nodes, p = 0.86), as was the rate of intraperitoneal recurrence (41% vs 38%, p = 0.45). Median follow-up was 23.5 (interquartile range 17.0–30.0) months. Other postoperative outcomes were comparable, including median time to functional recovery (5 [95% CI 4.5–5.5] vs 5 [95% CI 4.7–5.3] days; p = 0.22) and overall survival (HR 0.99, 95% CI 0.67–1.46, p = 0.94). Serious adverse events were reported in 23 (18%) of 131 patients in the MIDP group vs 28 (22%) of 127 patients in the ODP group. Interpretation: This trial provides evidence on the non-inferiority of MIDP compared to ODP regarding radical resection rates in patients with resectable pancreatic cancer. The present findings support the applicability of minimally invasive surgery in patients with resectable left-sided pancreatic cancer. Funding: Medtronic Covidien AG, Johnson & Johnson Medical Limited, Dutch Gastroenterology Society.

Gastritis cystica profunda (GCP) has been defined as a rare submucosal benign gastric lesion with cystic gland growth. Due to its unclear etiopathogenesis, this lesion is often misdiagnosed and mistaken for other gastric masses. Currently, a standardized treatment for GCP lesions is still missing. Here, we illustrate a case of a patient admitted to our general surgery department for melena and general discomfort. No history of peptic ulcer or gastric surgery was present. Upper GI endoscopy was performed, showing a distal gastric lesion with a small ulceration on the top. CT-scan and endoscopic ultrasound confirmed the presence of the lesion, compatible with a gastric stromal tumor, without showing any eventual metastasis. Surgical gastric resection was performed. Histological findings were diagnostic for GCP, with cistically ectasic submucosal glands, chronic inflammation, eosinophilic infiltration and foveal hyperplasia. GCP is a very exceptional cause of upper-GI bleeding with specific histological features. Its diagnosis as well as its therapy are challenging, resulting in several pitfalls. Even though it is a rare entity, GCP should always be considered in the differential diagnosis of gastric submucosal lesions.

Rokitansky-Aschoff sinuses (RAS) are a common imaging finding in gallbladder adenomyomatosis (ADM), often presenting as fundal cystic spaces. Intracholecystic papillary neoplasm (ICPN) is a relatively uncommon pre-invasive tumor of the gallbladder epithelium that rarely involves RAS mucosa. We compare two cases that showed similar fundal cystic spaces resembling RAS, in which Magnetic Resonance Diffusion-Weighted Imaging (MR-DWI) was valuable for detecting (or ruling out) an underlying malignant ICPN. Evidence from the literature overall supports the role of MR-DWI for detecting intracholecystic malignant tissue.

Gastrointestinal (GI) involvement of plasma cell neoplasms is extremely rare. Herein, we describe the case of a 74-year-old Caucasian woman who came to our attention with abdominal pain, food vomiting, and weight loss of 10 kg over 1 year. A computed tomography scan of the abdomen revealed circumferential thickening of terminal ileum, for which the patient underwent an urgent 20-cm-long ileal resection. Histopathological and immunophenotypic analysis revealed a plasma cell neoplasm of the ileum. Subsequent investigations found a serum monoclonal immunoglobulin A component, an osteolytic lesion of the left jaw, and a clonal bone marrow plasma cell infiltrate carrying 1q21 amplification. Given the final diagnosis of plasma cell myeloma (PCM), the patient underwent a VMD (bortezomib, melphalan, and dexamethasone) chemotherapy regimen, achieving a complete remission after a 12-month treatment. For disease relapse, two further chemotherapy regimens were later attempted. At the last follow-up 4 years after the diagnosis, the patient is still alive. This case draws attention to the extramedullary presentation of plasma cell neoplasms, even if rare, as a prompt diagnosis seems to result in a better prognosis. In addition, it highlights the relevance of a multidisciplinary approach, involving gastroenterologists, hematologists, and pathologists, to the diagnosis and management of these neoplasms.

The gastrointestinal (GI) tract is the most common extranodal site of occurrence of non-Hodgkin lymphomas. Most GI lymphomas are of B-cell lineage, while T-cell lymphomas are less frequent. The aim of our retrospective study was to depict the clinical–pathological profile of a series of patients affected by intestinal T-cell lymphomas (ITCL) and possibly define hallmarks of these neoplasms. A total of 28 patients were included: 17 enteropathy-associated T-cell lymphomas (EATL), 5 monomorphic epitheliotropic T-cell lymphomas (MEITL), 3 indolent T-cell lymphoproliferative disorders of the gastrointestinal tract (ITCLDGT), and 3 intestinal T-cell lymphomas not otherwise specified (ITCL-NOS). Celiac disease (CD) was diagnosed in around 70% of cases. Diagnosis of EATL showed a significant correlation with CD30 expression, whereas MEITL with angiotropism and CD56 positivity. ITCLDGT cases showed plasma cells infiltration. Peripheral lymphocytosis, the absence of a previous diagnosis of CD, an advanced Lugano clinical stage, and the histological subtype ITCL-NOS were significantly associated with worse survival at multivariate analysis. Our findings about the epidemiological, clinical, and histopathological features of ITCL were in line with the current knowledge. Reliable prognostic tools for these neoplasms are still lacking but according to our results lymphocytosis, diagnosis of CD, Lugano clinical stage, and histological subtype should be considered for patient stratification.

Pathological correlates of potential autoimmune gastritis (AIG), defined by anti-parietal cell antibody (PCA) positivity in the absence of gastric atrophy, have never been described. We herein aimed to assess intraepithelial lymphocyte (IEL) infiltration in gastric corpus of AIG patients. From 2000 to 2021, among 53 potential AIG patients, we focused on nine (median age 61 years, IQR 53-82; four females) who subsequently developed overt AIG. IEL infiltration of the oxyntic mucosa was assessed before and after developing overt AIG by measuring deep and superficial CD3+ IEL. AIG patients with different degrees of corpus atrophy, healthy controls (HC), active H. pylori gastritis, celiac disease (CD), and Hashimoto’s thyroiditis patients were included as controls. Of note, deep, but not superficial, CD3+ IEL count was higher (p7/100 epithelial cells allowed discrimination of any AIG stage and severity (AUC=0.842). We conclude that an increased deep CD3+ IEL infiltration of the oxyntic mucosa could represent a marker of potential AIG. Prospective studies including a larger number of potential AIG patients are needed.

Autoimmune gastritis is a chronic immune-mediated disorder characterized by varied clinical manifestations and that should be endoscopically managed over time, as the gastric atrophy contributes to microenvironmental alterations of the stomach milieu, and an increased cancer risk has been linked to this condition. Here, we report the unusual case of a woman who developed a cardiac high-grade pyloric adenoma in a context of previously undiagnosed autoimmune gastritis with synchronous neuroendocrine cell hyperplastic and dysplastic lesions.

A rhabdoid colorectal tumor (RCT) is a rare cancer with aggressive clinical behavior. Recently, it has been recognized as a distinct disease entity, characterized by genetic alterations in the SMARCB1 and Ciliary Rootlet Coiled-Coil (CROCC). We here investigate the genetic and immunophenotypic profiling of 21 RCTs using immunohistochemistry and next-generation sequencing. Mismatch repair-deficient phenotypes were identified in 60% of RCTs. Similarly, a large proportion of cancers exhibited the combined marker phenotype (CK7-/CK20-/CDX2-) not common to classical adenocarcinoma variants. More than 70% of cases displayed aberrant activation of the mitogen-activated protein kinase (MAPK) pathway with mutations prevalently in BRAF V600E. SMARCB1/INI1 expression was normal in a large majority of lesions. In contrast, ciliogenic markers including CROCC and γ-tubulin were globally altered in tumors. Notably, CROCC and γ-tubulin were observed to colocalize in large cilia found on cancer tissues but not in normal controls. Taken together, our findings indicate that primary ciliogenesis and MAPK pathway activation contribute to the aggressiveness of RCTs and, therefore, may constitute a novel therapeutic target.

Abstract Background Pancreatic adenocarcinoma is a high-mortality neoplasm with a documented 5-years-overall survival around 5%. In the last decades, a real breakthrough in the treatment of the disease has not been achieved. Here we propose a prospective, phase II, multicentre, single-arm study aiming to assess the efficacy and the feasibility of a therapeutic protocol combining chemotherapy, carbon ion therapy and surgery for resectable and borderline resectable pancreatic adenocarcinoma. Method The purpose of this trial (PIOPPO Protocol) is to assess the efficacy and the feasibility of 3 cycles of FOLFIRINOX neoadjuvant chemotherapy followed by a short-course of carbon ion radiotherapy (CIRT) for resectable or borderline resectable pancreatic adenocarcinoma patients. Primary outcome of this study is the assessment of local progression free survival (L-PFS). The calculation of sample size is based on the analysis of the primary endpoint “progression free survival” according to Fleming’s Procedure. Discussion Very preliminary results provide initial evidence of the feasibility of the combined chemotherapy and CIRT in the neoadjuvant setting for resectable or borderline resectable pancreatic cancer. Completion of the accrual and long term results are awaited to see if this combination of treatment is advisable and will provide the expected benefits. Trial registration ClinicalTrials.gov Identifier: NCT03822936 registered on January 2019.

Gastric carcinoma (GC) represents one of the most common and most lethal malignancies worldwide. The histopathological characterization of GC precursor lesions has provided great knowledge about gastric carcinogenesis, with the consequent introduction of effective strategies of primary and secondary prevention. In recent years, a large amount of data about the molecular events in GC development is emerging, flanking the histomorphological descriptions. In this review, we describe the landscape of molecular alterations in gastric pre-invasive lesions with a glance at their potential use in the diagnostic and therapeutic decision-making process.

The persistence or recurrence of symptoms in patients with coeliac disease (CD), despite a gluten-free diet (GFD), must prompt further work-up for excluding refractory CD (RCD). The aim of this study was to assess the accuracy of serum markers in predicting refractoriness in CD patients. This study included 72 patients affected by CD followed-up at our center, namely 49 uncomplicated CD before and after GFD and 23 RCD. Serum levels of chromogranin A (CgA) and β2-microglobuline were measured at baseline and at follow-up (median time of 13 months) in each group of patients. Cut-off points for each marker were estimated to differentiate RCD from uncomplicated CD patients. Serum levels of CgA and β2-microglobuline were significantly higher in patients with RCD compared to uncomplicated CD (p < 0.001), both at baseline and at follow-up, with no significant difference between RCD type 1 and type 2. The estimated cut-off point for CgA was 90.2 ng/mL (sensitivity 83%, specificity 100%), while for β2-microglobuline it was 696 mcg/L (sensitivity 100%, specificity of 100%). To conclude, CgA and β2-microglobuline could be useful serological markers of refractoriness in CD, with the ability to discriminate those patients who should undergo upper gastrointestinal endoscopy for making a definite diagnosis.

The wider use of gastrointestinal endoscopic procedures has led to an increased detection of small intestinal preneoplastic and neoplastic epithelial lesions, most of which are identified in the duodenum and ampullary region. Like their malignant counterparts, small intestinal glandular precursor lesions, which include adenomas and hamartomas, may arise sporadically or be associated with hereditary tumor syndromes, such as familial adenomatous polyposis, MUTYH-associated polyposis, Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and Cowden syndrome. In addition, dysplastic, preinvasive lesions have been observed adjacent to small bowel adenocarcinomas complicating immune-related disorders, such as celiac or Crohn’s disease. Adenomatous lesions may exhibit an intestinal-type, gastric-type, or, very rarely, serrated differentiation, related to different molecular pathogenetic mechanisms. Finally, in the background of multiple endocrine neoplasia 1 syndrome, precursor neuroendocrine growths have been described. In this review we offer a comprehensive description on the histo-molecular features of the main histotypes of small bowel epithelial precursors lesions, including: (i) sporadic adenomas (intestinal-type and gastric-type; non-ampullary and ampullary); (ii) syndromic adenomas; (iii) small bowel dysplasia in celiac and Crohn’s disease; (iv) serrated lesions; (v) hamartomatous lesions; and (vi) neuroendocrine precursor lesions.

Special AT-rich sequence-binding protein 2 (SATB2) is a transcription factor expressed by colonic cryptic epithelium and epithelial neoplasms of the lower gastrointestinal (GI) tract, as well as by small bowel adenocarcinomas (SBAs), though at a lower rate. Nevertheless, up to now, only small SBA series, often including a very limited number of Crohn’s disease-associated SBAs (CrD-SBAs) and celiac disease-associated SBAs (CD-SBA), have been investigated for SATB2 expression. We evaluated the expression of SATB2 and other GI phenotypic markers (cytokeratin (CK) 7 and CK20, caudal type homeobox 2 (CDX2) and alpha-methylacyl-CoA racemase (AMACR)), as well as mismatch repair (MMR) proteins, in 100 SBAs, encompassing 34 CrD-SBAs, 28 CD-SBAs and 38 sporadic cases (Spo-SBAs). Any mutual association and correlation with other clinico-pathologic features, including patient prognosis, were searched. Twenty (20%) SATB2-positive SBAs (4 CrD-SBAs, 7 CD-SBAs and 9 Spo-SBAs) were identified. The prevalence of SATB2 positivity was lower in CrD-SBA (12%) in comparison with both CD-SBAs (25%) and Spo-SBAs (24%). Interestingly, six SBAs (two CD-SBAs and four Spo-SBAs) displayed a full colorectal carcinoma (CRC)-like immunoprofile (CK7−/CK20+/CDX2+/AMACR+/SATB2+); none of them was a CrD-SBA. No association between SATB2 expression and MMR status was observed. Although SATB2-positive SBA patients showed a more favorable outcome in comparison with SATB2-negative ones, the difference did not reach statistical significance. When cancers were stratified according to CK7/CK20 expression patterns, we found that CK7−/CK20- SBAs were enriched with MMR-deficient cases (71%) and patients with CK7−/CK20− or CK7−/CK20+ SBAs had a significantly better survival rate compared to those with CK7+/CK20− or CK7+/CK20+ cancers (p = 0.002). To conclude, we identified a small (6%) subset of SBAs featuring a full CRC-like immunoprofile, representing a potential diagnostic pitfall in attempts to identify the site of origin of neoplasms of unknown primary site. In contrast with data on colorectal carcinoma, SATB2 expression is not associated with MMR status in SBAs. CK patterns influence patient survival, as CK7−/CK20− cancers show better prognosis, a behavior possibly due to the high rate of MMR-deficient SBAs within this subgroup.

We read with interest the paper by Jun S [...]

Background: Growing evidence suggests that an altered microbiota composition contributes to the pathogenesis and clinical features in celiac disease (CD). We performed a comparative analysis of the gut microbiota in adulthood CD to evaluate whether: (i) dysbiosis anticipates mucosal lesions, (ii) gluten-free diet restores eubiosis, (iii) refractory CD has a peculiar microbial signature, and (iv) salivary and fecal communities overlap the mucosal one. Methods: This is a cross-sectional study where a total of 52 CD patients, including 13 active CD, 29 treated CD, 4 refractory CD, and 6 potential CD, were enrolled in a tertiary center together with 31 controls. A 16S rRNA-based amplicon metagenomics approach was applied to determine the microbiota structure and composition of salivary, duodenal mucosa, and stool samples, followed by appropriate bioinformatic analyses. Results: A reduction of both α- and β-diversity in CD, already evident in the potential form and achieving nadir in refractory CD, was evident. Taxonomically, mucosa displayed a significant abundance of Proteobacteria and an expansion of Neisseria, especially in active patients, while treated celiacs showed an intermediate profile between active disease and controls. The saliva community mirrored the mucosal one better than stool. Conclusion: Expansion of pathobiontic species anticipates villous atrophy and achieves the maximal divergence from controls in refractory CD. Gluten-free diet results in incomplete recovery. The overlapping results between mucosal and salivary samples indicate the use of saliva as a diagnostic fluid.

El Islam no desaparece de Sicilia tras la invasión normanda del siglo XI. Hombres y mujeres de cultura árabe o de religión islámica siguieron viviendo en la isla durante siglos, contribuyendo a su desarrollo artístico y cultural, influyendo en la lengua y en las tradiciones de Sicilia y, a través de ella, también en la Italia peninsular El artículo ofrece una panorámica general de la historia de dicho periodo y de su influencia en el legado cultural.

Several histopathological variants of colorectal carcinoma can be distinguished, some associated with specific molecular profiles. However, in routine practice, ninety/ninety-five percent of all large bowel tumors are diagnosed as conventional adenocarcinoma, even though they are a heterogeneous group including rare histotypes, which are often under-recognized. Indeed, colorectal cancer exhibits differences in incidence, location of tumor, pathogenesis, molecular pathways and outcome depending on histotype. The aim is therefore to review the morphological and molecular features of these rare variants of intestinal carcinomas which may hold the key to differences in prognosis and treatment.

Small bowel carcinomas (SBC) are uncommon neoplasms, whose predisposing conditions include hereditary syndromes and immune-mediated intestinal disorders including coeliac disease (CD) and Crohn’s disease (CrD). Although both CD-associated SBC (CD-SBC) and CrD-associated SBC (CrD-SBC) arise from an inflammatory background, they differ substantially in tumour cell phenotype, frequency of microsatellite instability and nuclear β-catenin expression, as well as in prognosis. For these patients, high tumour-infiltrating lymphocyte density and glandular/medullary histotype represent independent positive prognostic factors. Dysplasia adjacent to SBC is rare and characterized by intestinal phenotype and nuclear β-catenin in CD, while it is frequent and typified by gastro-pancreatobiliary marker expression and preserved membranous β-catenin in CrD. Recent evidence suggests that Epstein-Barr virus-positive dysplasia and SBC, albeit exceptional, do exist and are associated with CrD. In this review, we summarize the novel pathological and molecular insights of clinical and therapeutic interest to guide the care of CD-SBC and CrD-SBC.

Both EBV+ and MSI gastric cancers (GCs) have high lymphoid infiltration which is rare in MSS/EBV− cancers. PD-L1/PD-1 interaction leads to a down-regulated immune response and it is one of the most promising targets for gastric cancer immunotherapy. PD-L1/PD-1 and CD8 expression were immunohistochemically investigated in a series of 169 FFPE GCs, including 33 EBV+, 59 MSI and 77 MSS/EBV− cases. PD-L1 membrane immunoreactivity in more than 5% of tumor cells was present in 31/169 GCs and was associated with high levels of CD8 intraepithelial lymphocytes (TILs; p < 0.001). PD-L1+ cases were mainly poorly differentiated (71%), intestinal type (85%) and high lymphoid response (HLR; 90%) tumors. PD-L1 expression was only present in EBV⁺ (46%), MSI (24%) and rare MSS/EBV− (3%) GCs with high CD8+ TILs (p < 0.001). Despite being associated with a better prognosis both in the whole series (p < 0.05) and in the MSI subset, PD-L1 is not an independent prognostic factor. PD-L1 gene amplification was detected in 3/17 cases, including 2/7 EBV+ and 1/8 MSI GC. PD-1⁺ TILs were significantly higher in EBV⁺ than MSI and MSS/EBV− cases. PD-L1/PD-1 pathway is selectively activated in HLR GCs and could be considered an emerging therapeutic target, particularly for EBV and MSI GCs.

Anandamide (AEA) is the prominent member of the endocannabinoid family and its biological action is mediated through the binding to both type-1 (CB1) and type-2 (CB2) cannabinoid receptors (CBR). The presence of AEA and CBR in the gastrointestinal tract highlighted their pathophysiological role in several gut diseases, including celiac disease. Here, we aimed to investigate the expression of CBR at transcriptional and translational levels in the duodenal mucosa of untreated celiac patients, celiac patients on a gluten-free diet for at least 12 months and control subjects. Also biopsies from treated celiac patients cultured ex vivo with peptic-tryptic digest of gliadin were investigated. Our data show higher levels of both CB1 and CB2 receptors during active disease and normal CBR levels in treated celiac patients. In conclusion, we demonstrate an up-regulation of CB1 and CB2 mRNA and protein expression, that points to the therapeutic potential of targeting CBR in patients with celiac disease.

A novel cytoplasmic structure has been recently characterized by confocal and electron microscopy in H. pylori-infected human gastric epithelium, as an accumulation of barrel-like proteasome reactive particles colocalized with polyubiquitinated proteins, H. pylori toxins and the NOD1 receptor. This proteasome particle-rich cytoplasmic structure (PaCS), a sort of focal proteasome hyperplasia, was also detected in dysplastic cells and was found to be enriched in SHP2 and ERK proteins, known to play a role in H. pylori-mediated gastric carcinogenesis. However, no information is available on its occurrence in neoplastic growths. In this study, surgical specimens of gastric cancer and various other human epithelial neoplasms have been investigated for PaCSs by light, confocal and electron microscopy including correlative confocal and electron microscopy (CCEM). PaCSs were detected in gastric cohesive, pulmonary large cell and bronchioloalveolar, thyroid papillary, parotid gland, hepatocellular, ovarian serous papillary, uterine cervix and colon adenocarcinomas, as well as in pancreatic serous microcystic adenoma. H. pylori bodies, their virulence factors (VacA, CagA, urease, and outer membrane proteins) and the NOD1 bacterial proteoglycan receptor were selectively concentrated inside gastric cancer PaCSs, but not in PaCSs from other neoplasms which did, however, retain proteasome and polyubiquitinated proteins reactivity. No evidence of actual microbial infection was obtained in most PaCS-positive neoplasms, except for H. pylori in gastric cancer and capsulated bacteria in a colon cancer case. Particle lysis and loss of proteasome distinctive immunoreactivities were seen in some tumour cell PaCSs, possibly ending in sequestosomes or autophagic bodies. It is concluded that PaCSs are widely represented in human neoplasms and that both non-infectious and infectious factors activating the ubiquitin-proteasome system are likely to be involved in their origin. PaCS detection might help clarify the role of the ubiquitin-proteasome system in carcinogenesis.

L’autore mostra come la parola reconquista cominciò a forgiarsi nello stesso contesto e nello stesso periodo in cui nasceva la parola Spagna intesa in senso nazionale, definendo nel tempo un processo ricco di complicazioni e non sempre lineare.