Is CT Radiomics Superior to Morphological Evaluation for pN0 Characterization? A Pilot Study in Colon Cancer.

The aim of this study was to compare CT radiomics and morphological features when assessing benign lymph nodes (LNs) in colon cancer (CC). This retrospective study included 100 CC patients (test cohort) who underwent a preoperative CT examination and were diagnosed as pN0 after surgery. Regional LNs were scored with a morphological Likert scale (NODE-SCORE) and divided into two groups: low likelihood (LLM: 0-2 points) and high likelihood (HLM: 3-7 points) of malignancy. The T-test and the Mann-Whitney test were used to compare 107 radiomic features extracted from the two groups. Radiomic features were also extracted from primary lesions (PLs), and the receiver operating characteristic (ROC) was used to test a LN/PL ratio when assessing the LN's status identified with radiomics and with the NODE-SCORE. An amount of 337 LNs were divided into 167 with LLM and 170 with HLM. Radiomics showed 15/107 features, with a significant difference (p < 0.02) between the two groups. The comparison of selected features between 81 PLs and the corresponding LNs showed all significant differences (p < 0.0001). According to the LN/PL ratio, the selected features recognized a higher number of LNs than the NODE-SCORE (p < 0.001). On validation of the cohort of 20 patients (10 pN0, 10 pN2), significant ROC curves were obtained for LN/PL busyness (AUC = 0.91; 0.69-0.99; 95% C.I.; and p < 0.001) and for LN/PL dependence entropy (AUC = 0.76; 0.52-0.92; 95% C.I.; and p = 0.03). The radiomics ratio between CC and LNs is more accurate for noninvasively discriminating benign LNs compared to CT morphological features.

Diagnostic and Therapeutic Management of Primary Orbital Neuroendocrine Tumors (NETs): Systematic Literature Review and Clinical Case Presentation.

BACKGROUND: The ocular involvement of neuroendocrine neoplasms (NENs) is uncommon and mainly represented by metastases from gastrointestinal and lung neuroendocrine tumors. Primary orbital NENs are even less common and their diagnostic and therapeutic management is a challenge. METHODS: A systematic review of the literature was conducted from 1966 to September 2023 on PubMed to identify articles on orbital NENs and to summarize their clinical-pathological features, diagnosis and therapeutic management. Furthermore, we presented a case of a locally advanced retro-orbital primary neuroendocrine tumor that was referred to the certified Center of Excellence of Sant'Andrea Hospital, La Sapienza University of Rome, Italy. RESULTS: The final analysis included 63 records on orbital NENs and 11 records focused on primary orbital NENs. The localization was mostly unilateral and in the right orbit; proptosis or exophthalmos represented the initial symptoms. The diagnostic work-up and therapeutic management was discussed and a diagnostic algorithm for the suspicion of primary orbital NENs was proposed. CONCLUSIONS: A multidisciplinary approach is required for the management of primary orbital NENs, emphasizing the importance of early referral to dedicated centers for prompt differential diagnosis, tailored treatment, and an improved quality of life and survival.

Real-Time Evaluation of Thyroid Cytology Using New Digital Microscopy Allows for Sample Adequacy Assessment, Morphological Classification, and Supports Molecular Analysis.

Thyroid cytological examination, a key tool in preoperative thyroid nodule evaluation, is specific and accurate; some drawbacks are due to inadequate or indeterminate cytological reports and there is a need for an innovative approach overcoming the limits of traditional cytological diagnostics. Fluorescence laser confocal microscopes (FCM) is a new optical technique for allowing immediate digital imaging of fresh unfixed tissues and real-time assessment of sample adequacy and diagnostic evaluation for small biopsies and cytological samples. Currently, there are no data about the use of FCMs in the field of thyroid nodular pathology. The aims of this study were to test FCM technology for evaluating the adequacy of FNA samples at the time of the procedure and to assess the level of concordance between FCM cytological evaluations, paired conventional cytology, and final surgical histology. The secondary aim was to define the integrity of nucleic acids after FCM evaluation through NGS molecular analysis. Sample adequacy was correctly stated. Comparing FCM evaluation with the final histology, all cases resulting in malignant or suspicious for malignancy at FCM, were confirmed to be carcinomas (PPV 100%). In conclusion, we describe a successful application of FCM in thyroid preoperative cytological evaluation, with advantages in immediate adequacy assessment and diagnostic information, while preserving cellular specimens for permanent morphology and molecular analysis, thus improving timely and accurate patient management.

Utility of histopathological revision in the management of gastro-entero-pancreatic neuroendocrine neoplasia.

BACKGROUND: Histological evaluation and grading assessment are key points in the diagnostic work-up of gastroentero-pancreatic neuroendocrine neoplasms (GEP-NENs). AIM: To analyze the impact of histopathological revision on the clinical management of patients with GEP-NEN. MATERIALS AND METHODS: Patients referred to our Center of Excellence between 2015 and 2021 were included in this study. Immunohistochemical slides at the time of initial diagnosis were reviewed to assess tumor morphology, diagnostic immunohistochemistry, and Ki67. RESULTS: 101 patients were evaluated, with 65 (64.4%) gastrointestinal, 25 (24.7%) pancreatic, and 11 (10.9%) occult neoplastic lesions suspected to be of GEP origin. The main changes resulting from the revision were: first Ki-67 assessment in 15.8% of patients, Ki-67 change in 59.2% of patients and grading modification in 23.5% of patients. An additional immunohistochemical evaluation was performed in 78 (77.2%) patients, leading to a confirmation of GEP origin in 10 of 11 (90.9%) of unknown primary site neoplastic lesions and an exclusion of NEN diagnosis in 2 (2%) patients. After histopathological revision, a significant modification in clinical management was proposed in 42 (41.6%) patients. CONCLUSIONS: Histopathological revision in a referral NEN center is strongly advised in newly diagnosed GEP-NENs to properly plan prognostic stratification and therapeutic choice.

Incidence and Predictors of Gastric Neoplastic Lesions in Corpus-Restricted Atrophic Gastritis: A Single-Center Cohort Study.

INTRODUCTION: Corpus-restricted atrophic gastritis is a chronic inflammatory disorder leading to possible development of type 1 neuroendocrine tumors (T1gNET), intraepithelial neoplasia (IEN), and gastric cancer (GC). We aimed to assess occurrence and predictors of gastric neoplastic lesions in patients with corpus-restricted atrophic gastritis at long-term follow-up. METHODS: A prospective single-center cohort of patients with corpus-restricted atrophic gastritis adhering to endoscopic-histological surveillance was considered. Follow-up gastroscopies were scheduled according to the management of epithelial precancerous conditions and lesions of the stomach guidelines. In case of new/worsening of known symptoms, gastroscopy was anticipated. Cox regression analyses and Kaplan-Meier survival curves were obtained. RESULTS: Two hundred seventy-five patients with corpus-restricted atrophic gastritis (72.0% female, median age 61 [23-84] years) were included. At a median follow-up of 5 (1-17) years, the annual incidence rate person-year was 0.5%, 0.6%, 2.8%, and 3.9% for GC/high-grade IEN, low-grade IEN, T1gNET, and all gastric neoplastic lesions, respectively. All patients showed at baseline operative link for gastritis assessment (OLGA)-2, except 2 low-grade (LG) IEN patients and 1 T1gNET patient with OLGA-1. Age older than 60 years (hazard ratio [HR] 4.7), intestinal metaplasia without pseudopyloric metaplasia (HR 4.3), and pernicious anemia (HR 4.3) were associated with higher risk for GC/HG-IEN or LG-IEN development and shorter mean survival time for progression (13.4, 13.2, and 11.1, respectively, vs 14.7 years, P = 0.01). Pernicious anemia was an independent risk factor for T1gNET (HR 2.2) and associated with a shorter mean survival time for progression (11.7 vs 13.6 years, P = 0.04) as well as severe corpus atrophy (12.8 vs 13.6 years, P = 0.03). DISCUSSION: Patients with corpus-restricted atrophic gastritis are at increased risk for GC and T1gNET despite low-risk OLGA scores, and those aged older than 60 years with corpus intestinal metaplasia or pernicious anemia seem to display a high-risk scenario.

The Day-To-Day Practice of MMR and MSI Assessment in Colorectal Adenocarcinoma: What We Know and What We Still Need to Explore.

BACKGROUND: The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination. MMR protein status is identified using immunohistochemistry. Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR. In colorectal cancer (CRC), MMR/MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy. SUMMARY: In this Review, we describe the challenges the practicing pathologist may face in relation to the assessment of MMR/MSI status and any open issues which still need to be addressed, focusing on pre-analytic issues, pitfalls in the interpretation, and technical aspects of the different assays. KEY MESSAGES: The current methods of detecting dMMR/MSI status have been optimized for CRCs, and whether these techniques can be applied to all tumor and specimen types is still not fully understood. Following the Food and Drug Administration (FDA), tissue/site agnostic drug approval of pembrolizumab for advanced/metastatic MSI tumors, MMR/MSI status in gastrointestinal tract is a common request from the oncologist. In this setting, several issues still need to be addressed, including criteria for sample adequacy.

The role of CXCL12 axis in pancreatic cancer: New biomarkers and potential targets.

Introduction: Chemokines are small, secreted peptides involved in the mediation of the immune cell recruitment. Chemokines have been implicated in several diseases including autoimmune diseases, viral infections and also played a critical role in the genesis and development of several malignant tumors. CXCL12 is a homeostatic CXC chemokine involved in the process of proliferation, and tumor spread. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors, that is still lacking effective therapies and with a dramatically poor prognosis. Method: We conducted a scientific literature search on Pubmed and Google Scholar including retrospective, prospective studies and reviews focused on the current research elucidating the emerging role of CXCL12 and its receptors CXCR4 - CXCR7 in the pathogenesis of pancreatic cancer. Results: Considering the mechanism of immunomodulation of the CXCL12-CXCR4-CXCR7 axis, as well as the potential interaction with the microenvironment in the PDAC, several combined therapeutic approaches have been studied and developed, to overcome the "cold" immunological setting of PDAC, like combining CXCL12 axis inhibitors with anti PD-1/PDL1 drugs. Conclusion: Understanding the role of this chemokine's axis in disease initiation and progression may provide the basis for developing new potential biomarkers as well as therapeutic targets for related pancreatic cancers.

Clear cell carcinoma of the stomach: a rare tumor variant imparting poor prognosis.

INTRODUCTION: Clear cell gastric cancer (CCGC) represents an extremely rare variant of adenocarcinoma of the stomach. It can be mistaken for a clear cell metastatic lesion arising from other anatomic parts, especially renal cell carcinoma. PATIENTS AND METHODS: We describe the case of a 66-year-old woman who was operated for a pyloric adenocarcinoma which resulted to be a CCGC at definitive histology. Moreover, we offer a systematic review of the current pertinent literature on CCGC. RESULTS: Our case represents the 160th example of CCGC. Clear cell aspect is due to the intracytoplasmic accumulation of glycogen in most cases, followed by mucin, lipid or water; the reason of the underlying biochemical process is still unclear. Paralleling other epithelial clear cell malignancies (as ovarian, bladder, urothelial or pancreatic cancers), also CCGC shows a more aggressive clinical behavior over conventional neoplastic counterparts. CONCLUSIONS: Differently from clear cell carcinomas involving other organs, CCGC has been rarely investigated by the literature. Since, compared to non clear cell cancers, this particular phenotype of gastric cancer appears to be associated with poorer prognosis, further studies are needed in order to corroborate its real adverse prognostic significance and standardize the correct management and treatment.

Somatic NGS Analysis of DNA Damage Response (DDR) Genes ATM, MRE11A, RAD50, NBN, and ATR in Locally Advanced Rectal Cancer Treated with Neoadjuvant Chemo-Radiotherapy.

BACKGROUND: Neoadjuvant chemo-radiotherapy (nCRT) represents the standard of care for locally advanced rectal cancer (LARC); however, there exists no biomarker that can predict the cancer's response to treatment as less than 20% of patients experience pathological complete response (pCR). Ionizing radiations induce double strand breaks (DSBs) and trigger a DNA damage response (DDR) involving ATM, ATR, and the MRN complex (MRE11, Rad50, and NBS1). In this study, we performed an extensive mutational analysis of the genes involved in the DDR pathway in LARC patients who have undergone nCRT. METHODS: 13 LARC patients with pCR and 11 LARC patients with partial response (pPR) were investigated using a NGS dedicated panel, designed for formalin-fixed paraffin-embedded (FFPE) samples, containing ATR, ATM, and MRE11-RAD50-NBN genes. The identified variants were classified according to guidelines' recommendations. RESULTS: Eight non-benign variants, six of which were observed in 3 (23%) out of 13 pCR patients, were identified. In particular, a pCR patient carried out a pathogenetic frameshift mutation in exon 21 of the RAD50 gene. The two remaining non-benign missense variants were found in 2 (18%) out of 11 patients in the pPR group. CONCLUSIONS: Our data show that the genes involved in the Homologous Recombination (HR) pathway are rarely mutated in LARC; however, given the identification of a missense mutation in RAD 50 in one case of pCR, it could be worth exploring its potential role as a biomarker in larger series.

MiR-378a-3p Acts as a Tumor Suppressor in Colorectal Cancer Stem-Like Cells and Affects the Expression of MALAT1 and NEAT1 lncRNAs.

MiR-378a-3p plays a critical role in carcinogenesis acting as a tumor suppressor, promoting apoptosis and cell cycle arrest and reducing invasion and drug resistance in several human cancers, including colorectal cancer (CRC), where its expression is significantly associated with histological classification and prognosis. In this study, we investigated the biological and cellular processes affected by miR-378a-3p in the context of CRC carcinogenesis. In agreement with the literature, miR-378a-3p is downregulated in our cohort of CRC patients as well as, in 15 patient-derived colorectal cancer stem-like cell (CRC-SC) lines and 8 CRC cell lines, compared to normal mucosae. Restoration of miR-378a-3p restrains tumorigenic properties of CRC and CRC-SC lines, as well as, significantly reduces tumor growth in two CRC-SC xenograft mouse models. We reported that miR-378a-3p modulates the expression of the lncRNAs MALAT1 and NEAT1. Their expression is inversely correlated with that of miR-378a-3p in patient-derived CRC-SC lines. Silencing of miR-378a-3p targets, MALAT1 and NEAT1, significantly impairs tumorigenic properties of CRC-SCs, supporting the critical role of miR-378a-3p in CRC carcinogenesis as a tumor-suppressor factor by establishing a finely tuned crosstalk with lncRNAs MALAT1 and NEAT1.

Endoscopic diagnosis of gastric intestinal metaplasia in patients with autoimmune gastritis using narrow-band imaging: does pseudopyloric metaplasia muddy the waters?

Background and study aims In autoimmune atrophic gastritis (AAG), associated with intestinal (IM) and/or pseudopyloric metaplasia (PPM), endoscopic surveillance is recommended for gastric cancer risk mainly linked to IM. Endoscopic Grading of Gastric Intestinal Metaplasia (EGGIM) reliably identifies IM, but has not been assessed in AAG. We aimed to assess the performance of EGGIM (index test) versus histology (reference test) of corpus IM in AAG. Patients and methods This was a cross-sectional study of 210 AAG patients undergoing surveillance gastroscopy with narrow-band imaging (NBI): corpus IM scored according to EGGIM, histology according to updated Sydney system, and morphological criteria. Results NBI identified corpus IM in 88.6 % of AAG patients: EGGIM were 0, 1, 2, 3, 4 in 11.4 %, 0.5 %, 33.3 %, 1.9 %, and 52.9 %, respectively. Histology identified corpus IM in 78.1 % and PPM in 79.5 % of patients. PPM was present with IM in 57.6 % and without IM in 21.9 % patients, 20.5 % had IM without PPM. EGGIM, compared to histology, correctly classified 76.2 % of patients, showing high sensitivity (91.5 %, 95 %CI 86.1-95.3). EGGIM correctly classified 93 % of patients with IM without PPM, 90.9 % with both metaplasias, and 21.7 % with PPM without IM yielding low specificity (21.7 %, 95 %CI 10.9-36.4). Conclusions In AAG, EGGIM showed high accuracy and sensitivity identifying > 90 % of patients with histological corpus IM. EGGIM overestimated IM when PPM without IM was present, yielding low specificity. These findings raise the question of whether in AAG, PPM and IM may display similar endoscopic features on NBI.

The Potential Role of Genomic Signature in Stage II Relapsed Colorectal Cancer (CRC) Patients: A Mono-Institutional Study.

Purpose: The absolute benefit of adjuvant chemotherapy in stage II CRC is only 3-4%. The identification of biomarkers through molecular profiling could identify patients who will more benefit from adjuvant chemotherapy. Patients and Methods: This retrospective analysis examined tissue blocks from 17 patients affected by relapsed stage II CRC, whose comprehensive genomic profiling of tumors was conducted through next-generation sequencing (NGS) via Roche-FoundationOne®. Results: Mutations were found in APC (76.5%), TP53 (58.8%) and KRAS (52.9%). Only KRAS wild-type samples showed FBXW7. APC frameshift mutations and MLH1 splice variant were conversely significant correlated (7% v 93%, P = 0.014). The median number of gene mutations reported was 6 (range 2-14). The TP53 mutation was associated most frequently with lung metastasis (P = 0.07) and high tumor budding (P = 0.03). Despite no statistical significance, lung recurrence, LVI/Pni, MSI and more than 6 genetic mutations were correlated to worse DFS and OS. Patients carried co-mutations of TP53-FBXW7 reported the worse DFS (4 v 14 months) and OS (4 v 65 months) compared to the other patients. Conclusion: According to the present analysis, the setting of relapsed CRC emerges as one of the fields of greatest utility for NGS, looking at personalized cancer care.

In Elderly Anemic Patients without Endoscopic Signs of Bleeding Are Duodenal Biopsies Always Necessary to Rule Out Celiac Disease?

Iron-deficiency anemia in the elderly may be due to numerous gastrointestinal conditions. Anemia is frequent in celiac disease (CD); however, the use of routine duodenal biopsies, independently of age or serology, is debated. To determine the diagnostic yield of routine duodenal biopsies in adult and elderly patients with no bleeding anemia, a cross-sectional study analyzing 7968 gastroscopies (2017−2020) was performed; 744 were for anemia and 275 were excluded (GI bleeding or without duodenal biopsies). Of the 469 included patients, clinical, endoscopic, and histological features were analyzed in groups with or without histopathological changes in the duodenal mucosa (DM). Univariate/multivariate analyses were performed. Of the 469 patients, 41 (8.7%) had DM histopathological changes, 12 (2.6%) had CD, 26 (5.5%) had duodenal intraepithelial lymphocytosis (DIL), and 3 had (0.6%) other conditions. They were younger compared to patients with normal DM. DM histopathology was significantly inversely correlated with age group, with prevalences of 27%, 20%, 12.5%, 10%, and 2.5%, in the <40−50, 51−60, 61−70, 71−80, and >80-year age groups, respectively (p = 0.0010). Logistic-regression models showed that anemic patients aged >60, >70, or >80 years with endoscopically normal DM had a progressively three- to four-fold higher probability of having normal duodenal histology. In adults, anemic patients without bleeding, age and endoscopically normal DM are predictors of normal DM histology. In >70-year anemic patients, negligible DM pathology was found. The results suggest that routine duodenal biopsies are questionable in elderly anemic patients

Prevalence of Segmental Colitis Associated with Colonic Diverticulosis in a Prospective Cohort of Patients Who Underwent Colonoscopy in a Tertiary Center.

In patients with colonic diverticulosis, the prevalence of segmental colitis associated with diverticulosis (SCAD) is debated. The aim of this study was to assess the prevalence of SCAD in consecutive patients with diverticulosis in a single tertiary center. Over a six-month period, consecutive adult patients with colonic diverticulosis were included. Patients with endoscopic signs of interdiverticular mucosal inflammation (erythema, friability, and ulcerations) were considered suspected SCAD and underwent multiple biopsy samplings to confirm diagnosis. Clinical features were collected from diverticulosis and suspected SCAD patients. In total, 367 (26.5%) of 1383 patients who underwent colonoscopy presented diverticulosis. Among diverticulosis patients, 4.3% (n = 16) presented macroscopic signs of interdiverticular mucosal inflammation and were identified as suspected SCAD. Compared to that of patients with diverticulosis, the age of suspected SCAD patients was significantly lower (60 ± 12.9 years (41.0-86.0) vs. 70 ± 10.6 years (38.0-93.0)) (p = 0.047). Among patients with suspected SCAD, one patient received a new diagnosis of Crohn's disease, one had spirochetosis infection, and one presented drug-induced colitis. The remaining patients with suspected SCAD (n = 13) were not confirmed by histology. This observational study suggests that SCAD diagnosis is a challenge in clinical practice due to the heterogeneity of endoscopic findings and lack of stated histological criteria.

Management of type-I gastric neuroendocrine neoplasms: A 10-years prospective single centre study.

BACKGROUND: This study aimed to evaluate the outcome of patients with type 1 gastric neuroendocrine neoplasia (T1gNENs) treated with different endoscopic approaches. METHODS: Patients were managed with endoscopic surveillance at regular intervals. Resection was performed by forceps or cold snare in tumours < 10 mm, otherwise mucosal resection (EMR) or submucosal dissection (ESD) were done. RESULTS: 127 T1gNENs, detected in 80 patients, were included. 87.4% of them were <5 mm, whereas 8.7% were 6-10 mm, 3.1% were 11-20 mm, and 0.8% was >20 mm. Ki67 <3%% was found in 85.8% tumours, whereas it was 3%-20% in the remaining 14.2% lesions. Noninterventional management (surveillance without radical resection) was performed in 15 patients (18.7%) with T1gNENs <5 mm. None of them underwent disease progression during follow-up. among the 65 patients treated by radical endoscopic resection, 37 patients (56.9%) had disease recurrence. 48.5% T1gNENs were removed by forceps, 16.8% by cold snare, 31.7% by EMR and 3% by ESD. The recurrence rate was similar among the different endoscopic techniques used. CONCLUSIONS: The management of T1gNENs may be planned based on tumour size. T1gNENs < 5 mm for which the initial removal is not radical could be followed up by noninterventional endoscopic surveillance.

The Ultrastructural Analysis of Human Colorectal Cancer Stem Cell-Derived Spheroids and Their Mouse Xenograft Shows That the Same Cells Types Have Different Ratios.

Spheroids from primary colorectal cancer cells and their mice xenografts have emerged as useful preclinical models for cancer research as they replicate tumor features more faithfully as compared to cell lines. While 3D models provide a reliable system for drug discovery and testing, their structural complexity represents a challenge and their structure-function relationships are only partly understood. Here, we present a comparative ultrastructural and flow citometric analysis of patient colorectal cancer-derived spheroids and their mice xenografts. Ultrastructural observations highlighted that multicellular spheroids and their xenografts contain the same cancer cell types but with different ratios, specifically multicellular spheroids were enriched in cells with a stem-like phenotype, while xenografts had an increased amount of lipid droplets-containing cells. The flow cytometric analysis for stem cell marker and activity showed enrichment of stem-like cells presence and activity in spheroids while xenografts had the inverse response. Our results evidence the effects on cancer cells of different in vitro and in vivo microenvironments. Those differences have to be paid into account in designing innovative experimental models for personalized drug testing.

Pseudopyloric Metaplasia Is Not Associated With the Development of Gastric Cancer.

INTRODUCTION: Corpus atrophic gastritis (CAG) is associated with intestinal metaplasia (IM) and pseudopyloric metaplasia (PPM). Prospective data on corpus mucosa PPM and its link to the development of gastric cancer (GC) are lacking. This study aimed to investigate the relationship between the presence of corpus mucosa PPM at baseline and the development of GC at follow-up in patients with CAG. METHODS: A longitudinal cohort study was conducted on patients with consecutive CAG adhering to endoscopic-histological surveillance. Patients were stratified for the presence/absence of corpus PPM without concomitant corpus IM at baseline, and the occurrence of gastric neoplastic lesions at the longest available follow-up was assessed. RESULTS: A total of 292 patients with CAG with a follow-up of 4.2 (3-17) years were included. At baseline, corpus PPM without corpus IM was diagnosed in 62 patients (21.2%). At the follow-up, GC was detected in 5 patients (1.7%) and gastric dysplasia (GD) in 4 patients (1.4%). In all these 9 patients with GC/GD at the follow-up, corpus IM was present at baseline and follow-up. Age <50 years (odds ratio [OR] 2.5), absence of pernicious anemia (OR 4.3), and absence of severe corpus atrophy (OR 2.3) were associated with corpus PPM without corpus IM. DISCUSSION: At the 4.2-year follow-up, in patients with CAG characterized at baseline with corpus PPM without corpus IM, GC or GD was not observed because these lesions were consistently associated with corpus IM. Corpus PPM without corpus IM was associated with younger age, absence of pernicious anemia, and severe corpus atrophy, suggesting a lower stage of disease progression. Corpus PPM alone seems not to be associated with GC, whose development seems to require the presence of corpus IM as a necessary step.

Gastric microbiota composition in patients with corpus atrophic gastritis.

BACKGROUND: In corpus atrophic gastritis (CAG), hypochlorhydria makes plausible the overgrowth of intragastric bacteria, whose role in gastric carcinogenesis is under debate. AIMS: To characterize the antrum/corpus composition of the gastric bacterial microbiota in CAG patients compared to controls without CAG. METHODS: A cross-sectional monocentric study on consecutive patients with known histological diagnosis of CAG undergoing gastroscopy for gastric cancer surveillance and patients without CAG undergoing gastroscopy for dyspepsia or anemia (108 biopsies from 55 patients, median age 61.5). Genomic DNA from one antral and one corpus biopsy from each case (n = 23) and control (n = 32) was extracted. Gastric microbiota was assessed by sequencing hypervariable regions of the 16SrRNA gene. RESULTS: Bacterial abundance and diversity were significantly lower in CAG cases than in controls (p < 0.001). Firmicutes were more frequent in cases, Bacteroidetes and Fusobacteria in controls (p < 0.0001). Streptococcaceae were more abundant in cases (p < 0.0001), Prevotellaceae in controls (p < 0.0001). The genus Streptococcus was positively correlated with severe OLGA/OLGIM stages linked to a higher risk of gastric cancer. CONCLUSION: Gastric bacterial microbiota in CAG showed a reduced abundance and complexity but was characterized by higher colonization of Firmicutes, in particular Streptococcus, increased in subjects with severe atrophy/metaplasia stages at higher risk of gastric cancer.

Histological growth patterns and molecular analysis of resected colorectal lung metastases.

Lung is the site of metastasis in about 15-25 % of colorectal cancer (CRC) patients. Lung metastasectomy of CRC represents a standard therapy in patients with resectable metastases. In this study we investigated both histological patterns of metastases and mutations in MAPkinase pathway genes and their relationship to prognosis. The study included 74 patients that underwent metastasectomy of colorectal lung metastasis (CLM). In patients that underwent surgical resection of more than one metastasis in the same operation the largest was chosen. In patients that had undergone multiple lung metastasectomy only the sample from the first metastasectomy was included. Histologically metastases were scored according to amount and distribution of necrosis and fibrosis and three patterns were identified: "pattern A", metastasis with extensive, confluent central necrosis surrounded by a rim of neoplastic glands; "pattern B", metastasis characterized by a proliferation of neoplastic glands in a dense stroma with focal necrosis mainly intraglandular; "pattern C", metastasis with a mixed A and B morphology. In all samples direct sequencing of exon 2 of KRAS and NRAS genes and exon 15 of BRAF genes was carried out.Histological patterns weren't related to metastasis size or other clinical features however pattern C metastases showed a significant worst disease free survival (DFS). KRAS mutations were observed in 39 % of patients. Mutations in KRAS codon 13 resulted significantly associated with synchronous metastasis and poor prognosis. No mutations were identified in exon 2 NRAS gene whilst 1.4 % harboured a mutation in BRAF. To our knowledge this is the first study that investigates in a large series of CLM histological growth patterns, molecular alterations and their relationship to prognosis. Our data suggest a prognostic role in CLM of KRAS specific mutations and histopathological patterns.

Isolated intestinal Ganglioneuromatosis: case report and literature review.

BACKGROUND: Intestinal Ganglioneuromatosis (IG) is a rare disorder of the enteric nervous system. In pediatric age it is often associated with genetic syndromes such as Neurofibromatosis 1 (NF1), multiple endocrine neoplasia type 2B (MEN2B) and Cowden syndrome (PTEN mutation), and ganglioneuromas (GNs) may be sometimes the first sign of the disease. Isolated GNs are rare and sporadic. Clinical symptom vary and depend on the size and on the location of the GNs. This disorder affects intestinal motility and it, consequently, causes changes in bowel habits, abdominal pain, occlusive symptoms and rarely lower gastrointestinal bleeding secondary to ulceration of the intestinal mucosa. On the other hand, patients can remain asymptomatic for many years. CASE PRESENTATION: We describe a 9-year-old boy referred to our emergency department for right lower quadrant abdominal pain. No familial history for gastrointestinal disorders. No history of fever or weight loss. At physical examination, he had diffused abdominal pain. Abdominal ultrasonography showed a hypoechoic formation measuring 41.8 mm by 35 mm in the right lower quadrant of the abdomen. Routine blood tests were normal, but fecal occult blood test was positive. Abdominal TC confirmed the hypodense formation, of about 5 cm in transverse diameter, in the right hypochondrium that apparently invaginated in the caecum-last ileal loop. Colonoscopy showed in the cecum an invaginated polypoid lesion of the terminal ileal loop. Laparoscopic resection of the polypoid lesion was performed. Histological diagnosis of the large neoplasm observed in the terminal ileum was diffuse ganglioneuromatosis. NF1, RET and PTEN gene tests resulted negative for specific mutations. At the 1 year follow-up, the patient presented good general condition and blood tests, fecal occult blood test, esophagogastroduodenoscopy, colonoscopy and MR-enterography were negative. CONCLUSIONS: Only few cases are reported in literature of IG in pediatric age. Although rare, the present case suggests that this disorder must be taken in consideration in every patient with GI symptoms such as abdominal pain, constipation, lower intestinal bleeding, in order to avoid a delayed diagnosis.