Tumor microenvironment characteristics association with clinical outcome in patients with resected intestinal-type gastric cancer.

BACKGROUND: Tumor microenvironment (TME) characteristics including tumor stroma ratio (TSR), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs) were examined in resected gastric cancer. These TME features have been shown to indicate metastatic potential in colon cancer, and intestinal-type gastric cancer (IGC) has pathological similarities with that malignancy. METHODS: TSR, TB, and TILs were quantified in routine histological sections from 493 patients with IGC who underwent radical resection at 2 university hospitals in China from 2010 to 2016. TME variables were dichotomized as follows: TSR (50%), TILs (median), TB per international guidelines (4 buds/0.785mm2), and platelet-lymphocyte ratio (PLR) per survival ROC. Association of TME features with patient clinicopathological characteristics, time-to-recurrence (TTR), and cancer-specific-survival (CSS) were examined using univariate and multivariate analysis, including a relative contribution analysis by Cox regression. RESULTS: Patients whose tumors showed high TSR or high TB or low TILs were each significantly associated with increased T and N stage, higher histological grade, and poorer TTR and CSS at 5 years. Only TSR and N stage were independently associated with TTR and CSS after adjustment for covariates. PLR was only independently associated with TTR after adjustment for covariates. Among the variables examined, only TSR was significantly associated with both TTR (HR 1.72, 95% CI, 1.14-2.60, P = .01) and CSS (HR 1.62, 95% CI, 1.05-2.51, P = .03) multivariately. Relative contribution to TTR revealed that the top 3 contributors were N stage (45.1%), TSR (22.5%), and PLR (12.9%), while the top 3 contributors to CSS were N stage (59.9%), TSR (14.7%), and PLR (10.9%). CONCLUSIONS: Among the examined TME features, TSR was the most robust for prognostication and was significantly associated with both TTR and CSS. Furthermore, the relative contribution of TSR to patient TTR and CSS was second only to nodal status.

Intestinal-Type Adenocarcinoma in Head and Neck: Dissecting Oncogenic Gene Alterations Through Whole Transcriptome and Exome Analysis.

Adenocarcinomas of the nasal/paranasal sinuses are uncommon, but intestinal-type adenocarcinomas (ITACs) are important. Due to the rarity of these tumors, their molecular profile is not well known. To further investigate the molecular profile and find potential oncogenic drivers, we compared the whole transcriptome and exome of ITACs at different anatomic locations in the head and neck. Twenty-one head and neck adenocarcinomas were used in this study, divided into 10 sinonasal adenocarcinomas (SNT) and 11 extrasinonasal (T) head and neck adenocarcinomas according to anatomic location and histology. Tumor samples along with normal mucosa were microdissected from formalin-fixed, paraffin-embedded samples, and RNA and DNA were subjected to whole-transcriptome and -exome shotgun sequencing. Analysis of ITACs at sinonasal locations showed 410 subtype-specific differentially expressed (DE) genes and noncoding transcripts compared with the group of other anatomic locations, with 2909 subtype-specific DE genes. The groups shared 872 genes, with 17 highly different or opposing DE genes. Whole-exome mutation analysis revealed the gene MLL3 (KMT2C) to be exhibiting the most frequent loss-of-function mutations in all adenocarcinomas investigated. The results suggest that the head and neck ITACs investigated were mainly caused by loss-of-function mutations in MLL3 that disabled chromatin methylation and remodeling of all MLL3-targeted enhancers in the tumors. This changed the activity of multiple genes/gene clusters, supporting oncogenicity mostly via pathways of signaling, dedifferentiation, proliferation, migration, and immune and inflammatory deregulation, indicating a truly epigenetic event as the root cause for the heterogenous diversity of these enteric types of cancer. The data of this study form the basis for understanding cell fate determination and cellular homeostasis in the normal respiratory mucosa at different anatomic sites and show the contribution of different mucosal components to the etiology/molecular pathology of ITAC.

Gastric dysplastic lesions in Helicobacter pylori-naïve stomach: Foveolar-type adenoma and intestinal-type dysplasia.

Reports of Helicobacter pylori (Hp)-naïve gastric neoplasm (HpNGN) cases have been rapidly increasing due to the recent increase in the Hp-naïve population in Japan. Most HpNGNs exhibit the gastric immunophenotype and a low malignant potential regardless of histological type. Especially, foveolar-type gastric adenoma (FGA) and intestinal-type gastric dysplasia (IGD) rarely progress to invasive carcinoma. FGA is a foveolar epithelial neoplasm that occurs in the fundic gland (oxyntic gland) mucosa and is classified as the flat type or raspberry type (FGA-RA). The flat type is a large, whitish flatly elevated lesion while FGA-RA is a small reddish polyp. Genomically, the flat type is characterized by APC and KRAS gene mutations and FGA-RA by a common single nucleotide variant in the KLF4 gene. This KLF4 single-nucleotide variant reportedly induces gastric foveolar epithelial tumorigenesis and activates both cell proliferation and apoptosis, leading to its slow-growing nature. IGD consists of an intestinalized epithelial dysplasia that develops in the pyloric gland mucosa, characterized as a superficial depressed lesion surrounded by raised mucosa showing a gastritis-like appearance. Immunohistochemically, it exhibits an intestinal or gastrointestinal phenotype and, frequently, p53 overexpression. Thus, IGD shows unique characteristics in HpNGNs and a potential multistep tumorigenic process.

Mutations in Helicobacter pylori infected patients with chronic gastritis, intestinal type of gastric cancer and familial gastric cancer.

BACKGROUND: Development of sequential changes of mucous leading to gastric cancer and familial cases of gastric cancer of intestinal type is widely connected with Helicobacter pylori infections. In this study we analysed variants of genes involved in cancerogenesis and inflammatory processes of intestines in patients infected with H.pylori. Our goal was to test whether mutations in these genes predestinate to development of gastric cancer, and whether there is a genetic factor that makes it more likely for infections with H.pylori to cause gastric cancer. As infections with H. pylori are relatively common, discovering such genetic predispositions could be used for establishing risk-groups and for planning treatments. METHODS: Our studies cover analysis of variants in genes involved in cancerogenesis: TP53 (rs11540652, rs587782329, COSM10771), MSH2 (rs193922376), MLH1 (rs63750217), and inflammatory processes of intestine: NOD2 (rs2066847, rs2066842), IL1A (rs1800587) and IL1B (rs1143634) from H.pylori-infected patients. RESULTS: Mutations were more common in the group of patients with gastric cancer of intestinal type and familial cases of gastric cancer in comparison with patients with chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia or gastric cancer (p-value = 0.00824), with the prevalence of p53 mutations in patients with familial gastric cancer vs. patients with other changes of mucosa (p-value = 0.000049). Additionally, gastric cancer patients have mainly genotype TT or CT of the rs2066842 variant of the NOD2 gene. CONCLUSIONS: The lack of statistically significant changes of other interleukin genes involved in inflammatory processes may suggest the presence of H.pylori infection as a potential trigger for the development of the inflammatory process of the mucosa, leading through microbiota dysbiosis to the development of enteric gastric cancer. Mutations in analysed genes correlated with more severe mucosal changes, with a much more frequent presence of TP53 gene mutations, with a limited presence of other mutations in the familial history of gastric cancer.

Choice of surgery in intestinal-type adenocarcinoma of the sinonasal tract: a long-term comparative study.

PURPOSE: Intestinal-type adenocarcinoma (ITAC) is a rare sinonasal malignancy. Curative treatment requires multidisciplinary approach, with surgical options consist of the endonasal endoscopic approach (EEA) and external surgery (EXTS). Here, we provide the post-operative and survival results from a single-center long-term follow-up. METHODS: We report long-term follow-up of 92 ITAC cases treated between 1998 and 2018, treated with EEA (n = 40) or EXTS (n = 52). Survival estimates, post-operative complications and duration of hospitalization were compared between surgical modalities. RESULTS: Baseline characteristics were similar. A higher number of T4b tumors (16%), and subsequently more tumoral invasion (39%), was present in patients undergoing EXTS compared to EEA (3% and 18%, respectively). No difference in Barnes histology subtypes was noticed. Patients undergoing EEA had a shorter post-operative hospitalization stay versus EXTS (4 versus 7 days). Use of EEA was associated to improved disease-specific survival (DSS; 11.4 versus 4.4 years; HREEA = 0.53), especially for patients with T3-4a tumors (11.4 versus 3.0 years; HREEA = 0.41). Patients with T3-4 stage, tumoral invasion, positive surgical margins, mucinous or mixed histology, and prolonged post-operative hospital stay showed poor local relapse-free, disease-free, overall, and DSS. CONCLUSIONS: Long-term follow-up in locally advanced ITAC demonstrates that resection by EEA is correlated with improved DSS compared to EXTS, especially for T3-4 tumors. No significant differences between both treatment modalities was observed regarding per- and post-operative complications, although hospitalization in patients undergoing EEA was shorter than for patients treated with EXTS. These results confirm that EEA should remain the preferred surgical procedure in operable cases of sinonasal ITAC.

Non-intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses: an analysis of clinical characteristics and prognosis.

BACKGROUND: Non­intestinal adenocarcinoma of the nasal cavity and paranasal sinuses (non­ITAC) is a heterogeneous tumour that has rarely been reported in previous studies. We compared and analysed the symptoms, radiographic and pathological features, treatment methods, and prognosis of patients with low-grade (G1) and high-grade (G3) tumours. METHODS: This was a retrospective study included 22 patients with pathologically confirmed non-ITAC of the nasal cavity and paranasal sinuses who were treated between January 2008 and December 2021 at a single centre. Of these, 11 patients had G1 tumours, and 11 patients had G3 tumours. Clinicopathological features, treatment methods, and survival outcomes were analysed. RESULTS: The median follow-up period was 48.5 months. Nasal congestion was the most common initial symptom, and the nasal cavity was the most frequently involved site. For G1 tumours, the main treatment was simple surgery, 1 and 3­year overall survival (OS) rates were 100 and 88.9%, while the 1 and 3­year local control (LC) rates were 100 and 100%, respectively. For G3 tumours, the main treatments were surgery combined with radiotherapy and/or chemotherapy,1 and 3­year OS rates were 72.7 and 72.7%, while the 1 and 3­year LC rates were 100 and 90.91%, respectively. G3 tumours was associated with significantly shorter overall survival than G1 tumours (P = 0.035). Patients with stage III-IV showed shorter overall survival compared to stage I-II patients (P = 0.035). CONCLUSIONS: Non-ITAC of the nasal cavity and paranasal sinuses may frequently occur in the nasal cavity. The main treatment modality is surgery, supplemented by radiotherapy and chemotherapy. Pathological grade and tumour stage were poor prognostic factors for the disease.

Identification of Serum Biomarkers to Monitor Therapeutic Response in Intestinal-Type Gastric Cancer.

There are a limited number of clinically useful serum biomarkers to predict tumor onset or treatment response in gastric cancer (GC). For this reason, we explored the serum proteome of the gp130Y757F murine model of intestinal-type gastric cancer (IGC). We identified 30 proteins with significantly elevated expression in early gp130Y757F IGC and 12 proteins that were significantly elevated in late gp130Y757F IGC compared to age- and gender-matched wild-type mice. Within these signatures, there was an overlap of 10 proteins commonly elevated in both early- and late-stage disease. These results highlight the potential to identify serum biomarkers of disease stage. Since IGC in the gp130Y757F model can be reversed following therapeutic inhibition of Interleukin (IL)-11, we explored whether the protein signatures we identified could be used to monitor tumor regression. We compared two different therapeutic modalities and found 5 proteins to be uniquely differentially expressed between control animals and animals halfway through treatment, with 10 differentially expressed at the end of treatment. Our findings highlight the potential to identify reliable biomarkers to track IGC tumor regression in response to treatment.

Primary Vaginal Mucinous Adenocarcinoma of Intestinal Type-Clinical, Radiological and Morphological Aspects.

Background and Objectives: Neoplasms of the vagina are rare and account for 1-2% of all tumors of the female reproductive system. Primary neoplasms of the vagina are most often carcinomas originating from squamous or glandular epithelium. Of the primary glandular tumors, clear cell, endometrioid, and serous adenocarcinomas are the most common types, while mucinous and mesonephric types are very rare. Mucinous adenocarcinoma is histologically subclassified into endocervical and intestinal types. We add to the existing literature another case of an extremely rare gynecological neoplasm-primary vaginal mucinous adenocarcinoma (PVMAC) intestinal type associated with vaginal villous adenoma with high-grade dysplasia. We discuss the clinical, radiological and morphological features of this rare entity. Materials and Methods: We report a case of a 59-year-old woman with PVMAC intestinal type associated with vaginal villous adenoma with high-grade dysplasia. The patient was evaluated with a gynecological exam, and biopsy, curettage and tumor excision were performed. The positron emission tomography-computed tomography (PET/CT) scan, at the level of the pelvis, supported the primary location of the disease. Histological and immunohistochemical methods were applied. Results: The gynecological examination of the vagina revealed an exophytic polypoid mass with a diameter of 3 cm, located on the posterior wall, in the area of introitus vaginae. The PET/CT scan revealed a hypermetabolic malignant formation involving the vagina and anal canal, without evidence of pelvic and inguinal lymphadenopathy, and also, it excluded disease at sites other than the vagina. The histological and immunohistochemical investigations, as well as the clinical and radiological data, lent support to the diagnosis "primary vaginal mucinous adenocarcinoma intestinal type". Conclusions: PVMAC intestinal type is a rare gynecological pathology, which presents a serious challenge for oncogynecologists, radiologists and pathologists.

Comparison of clinical and pathological features between early-stage gastric-type and intestinal-type differentiated adenocarcinoma: a retrospective study.

BACKGROUND: The clinicopathological features and endoscopic characteristics under magnifying endoscopy with narrow band imaging (ME-NBI) between early-stage gastric-type differentiated adenocarcinoma (GDA) and intestinal-type differentiated adenocarcinoma (IDA) remain controversial. METHODS: Early gastric adenocarcinomas that underwent endoscopic submucosal dissection (ESD) in Nanjing Drum Tower Hospital between August 2017 and August 2021 were included in the present study. GDA cases and IDA cases were selected based on morphology and immunohistochemistry staining of CD10, MUC2, MUC5AC, and MUC6. Clinicopathological data and endoscopic findings in ME-NBI were compared between GDAs and IDAs. RESULTS: The mucin phenotypes of 657 gastric cancers were gastric (n = 307), intestinal (n = 109), mixed (n = 181) and unclassified (n = 60). No significant difference was observed in terms of gender, age, tumor size, gross type, tumor location, background mucosa, lymphatic invasion, and vascular invasion between patients with GDA and IDA. GDA cases were associated with deeper invasion than IDA cases (p = 0.007). In ME-NBI, GDAs were more likely to exhibit an intralobular loop patten, whereas IDAs were more likely to exhibit a fine network pattern. In addition, the proportion of none-curative resection in GDAs was significantly higher than that in IDAs (p = 0.007). CONCLUSION: The mucin phenotype of differentiated early gastric adenocarcinoma has clinical significance. GDA was associated with less endoscopically resectability than IDA.

Clinical factors associated with noncurative endoscopic submucosal dissection for the expanded indication of intestinal-type early gastric cancer: Post hoc analysis of a multi-institutional, single-arm, confirmatory trial (JCOG0607).

OBJECTIVES: The multi-institutional, single-arm, confirmatory trial JCOG0607 showed excellent efficacy of endoscopic submucosal dissection (ESD) for the expanded indication of intramucosal intestinal-type early gastric cancer (EGC), which consists of two groups: lesions >2 cm if clinical finding of ulcer (cUL)-negative, or those ≤3 cm if cUL-positive because of the expected low risk of lymph node metastasis. However, the proportion of noncurative resections (NCR) requiring additional surgery was high (32.4%). This post hoc analysis aimed to explore the clinical factors associated with NCR. METHODS: As the expanded indication includes two different groups, we explored the clinical factors associated with NCR separately in cUL-negative (>2 cm) and cUL-positive (≤3 cm) groups using the log-linear model. RESULTS: Two hundred and sixty cUL-negative and 206 cUL-positive EGCs were analyzed. The proportions of NCR were 33.8% in the cUL-negative group and 29.6% in the cUL-positive group. A multivariable analysis demonstrated that moderately differentiated predominant histology diagnosed in pretreatment biopsy (risk ratio [RR] 1.93, 95% confidence interval [CI] 1.34-2.77, P < 0.001) and lesion in the upper stomach (RR 1.75, 95% CI 1.03-2.96, P = 0.038) in the cUL-negative EGCs, and tumor size >2 cm (RR 1.78, 95% CI 1.22-2.58, P = 0.003) and female sex (RR 1.62, 95% CI 1.07-2.44, P = 0.021) in the cUL-positive EGCs were independent factors associated with NCR. CONCLUSIONS: Clinical risk factors associated with NCR were different between cUL-negative and cUL-positive EGCs. To avoid NCR, we need to take these factors into account when deciding expanded indications for ESD.

Signaling Pathways mTOR and ERK as Therapeutic Targets in Sinonasal Intestinal-Type Adenocarcinoma.

Despite advances in surgery and radiotherapy, the overall prognosis of sinonasal intestinal-type adenocarcinoma (ITAC) is poor, and new treatment options are needed. Recent studies have indicated alterations in cellular signaling pathways that may serve as targets for modern inhibitors. Our aim was to evaluate the frequency of mTOR and ERK pathway upregulation in a retrospective series of 139 ITAC and to test the efficacy and mechanism of action of candidate targeted inhibitors in cell line ITAC-3. An immunohistochemical analysis on p-AKT, p-mTOR, p-S6, p-4E-BP1, and p-ERK indicated, respectively, a 68% and 57% mTOR and ERK pathway activation. In vitro studies using low doses of mTOR inhibitor everolimus and ERK inhibitor selumetinib showed significant growth inhibition as monotherapy and especially as combined therapy. This effect was accompanied by the downregulation of mTOR and ERK protein expression. Our data open a new and promising possibility for personalized treatment of ITAC patients.

Tumors of the Nose and Paranasal Sinuses: Promoting Factors and Molecular Mechanisms-A Systematic Review.

Sinonasal neoplasms are uncommon diseases, characterized by heterogeneous biological behavior, which frequently results in challenges in differential diagnosis and treatment choice. The aim of this review was to examine the pathogenesis and molecular mechanisms underlying the regulation of tumor initiation and growth, in order to better define diagnostic and therapeutic strategies as well as the prognostic impact of these rare neoplasms. A systematic review according to Preferred Reporting Items for Systematic Review and Meta-Analysis criteria was conducted between September and November 2022. The authors considered the three main histological patterns of sinonasal tumors, namely Squamous Cell Carcinoma, Intestinal-Type Adenocarcinoma, and Olfactory Neuroblastoma. In total, 246 articles were eventually included in the analysis. The genetic and epigenetic changes underlying the oncogenic process were discussed, through a qualitative synthesis of the included studies. The identification of a comprehensive model of carcinogenesis for each sinonasal cancer subtype is needed, in order to pave the way toward tailored treatment approaches and improve survival for this rare and challenging group of cancers.

Molecular Biomarkers in Sinonasal Cancers: New Frontiers in Diagnosis and Treatment.

PURPOSE OF REVIEW: Sinonasal tumors are rare and heterogeneous diseases which pose challenges in diagnosis and treatment. Despite significant progress made in surgical, oncological, and radiotherapy fields, their prognosis still remains poor. Therefore, alternative strategies should be studied in order to refine diagnosis and improve patient care. RECENT FINDINGS: In recent years, in-depth molecular studies have identified new biological markers, such as genetic abnormalities and epigenetic variations, which have allowed to refine diagnosis and predict prognosis. As a consequence, new histological entities have been described and specific subgroup stratifications within the well-known histotypes have been made possible. These discoveries have expanded indications for immunotherapy and targeted therapies in order to reduce tumor spread, thus representing a valuable implementation of standard treatments. Recent findings in molecular biology have paved the way for better understanding and managing such rare and aggressive tumors. Although further efforts need to be made in this direction, expectations are promising.

Intestinal-type adenocarcinoma presenting as a female periurethral mass.

BACKGROUND: The periurethral mass in the female is a rare clinical entity and most of the lesions are benign. We present an unusual case of a periurethral mass found to be intestinal-type adenocarcinoma which has not been previously reported in the literature. CASE PRESENTATION: A 58-year-old woman was referred to our hospital with acute urinary retention. She complained of frequency, urgency and progressive obstructive urinary symptoms for the last 3 months. A pelvic magnetic resonance imaging scan showed a soft tissue mass of 5 × 4 cm surrounding the entire urethra. A needle biopsy was done and revealed adenocarcinoma with intestinal-type features. The tumor was removed by a simultaneous laparoscopic abdominal and transperineal approach. The pathological results showed a positive surgical margin and urethra and vagina wall invasion. The neoplastic cells were positive for CK20, CDX-2, CerbB-2, MSH2, MSH6, MLH1, PMS2 and P53. The patient received adjuvant systemic chemotherapy comprising S-1 and oxaliplatin. Follow-up with pelvic MRI 6 months after surgery showed no signs of local recurrence. CONCLUSIONS: We have reported the first case of the primary periurethral adenocarcinoma of intestinal type. There are currently no standardized protocols for the diagnosis, clinical course, and treatment of this rare tumor. This case study can aid decision-making regarding the diagnosis and treatment of this tumor.

The use of histopathological subtyping in patients with ampullary cancer: a nationwide analysis.

BACKGROUND: Recent guidelines advise to subtype adenocarcinoma at the ampulla and papilla of Vater (here: ampullary cancer) as intestinal, pancreatobiliary, and mixed, because this has consequences for both prognosis and treatment. This nationwide study aimed to investigate how often histopathological subtyping is performed in daily clinical practice in patients with ampullary cancer. METHODS: Pathology reports of all patients with ampullary cancer were retrieved from the Dutch nationwide pathology database (PALGA, 1991-2020). Reports were assessed for the presence and methods used for the classification of these tumors into intestinal, pancreatobiliary, and mixed subtypes. The use of immunohistochemical markers was recorded. RESULTS: Overall, 5246 patients with ampullary cancer were included. In 1030 (19.6%) patients, a distinction between intestinal, pancreatobiliary, and mixed subtypes was made. Use of subtyping increased from 3% in 1991-1993 to 37% in 2018-2020. In 274 of the 1030 (26.6%) patients, immunohistochemistry was used to make this distinction. A gradual increase in the use of various immunohistochemical markers was seen over time since 2008, with cytokeratin 7, cytokeratin 20, and CDX2 being the most common. Staining of DPC4/SMAD4 was increasingly used since 2012. CONCLUSION: Despite recent improvements in the use of subtyping in ampullary cancer, the distinction between intestinal, pancreatobiliary, and mixed subtypes is only made in a minority of patients. Nationwide efforts are required to standardize the pathological distinction of the various subtypes of ampullary cancer.

Applications of Co2 laser in endoscopic surgery for sinonasal neoplasms.

OBJECTIVE: The aim of the study is to assess safety, effectiveness, and potential advantages of CO2 fiber laser during endoscopic endonasal surgery for the resection of sinonasal neoplasms. We present text, images, and videos to show our experience with this new device recently introduced in endoscopic endonasal surgery and as a potential tool for educational purpose. METHODS: Six patients affected by benign or malignant sinonasal tumors who underwent endoscopic resection between January and May 2021 were enrolled in the study. Surgical approach was conducted via standardized centripetal endonasal technique. During the surgery we evaluated instrument ergonomics, quality in section on both healthy tissue and tumor, coagulation, and bleeding control from major vessels. RESULTS: In our experience, CO2 fiber laser has proved to have good ergonomics, as well as to be a safe and effective tool for the resection of both neoplastic and healthy tissues. Cauterization was efficient only in vessels with average diameter lower than 1 cm. Prolonged procedural time, costs, and necessity of learning-curve and expertise are possible drawbacks. CONCLUSION: Co2-fiber laser is an effective tool which can aid the surgeon during endoscopic endonasal approach to sinonasal neoplasms.

Telomere lengths in Barrett's esophagus as a precancerous lesion.

BACKGROUND: We have reported that precancerous conditions and lesions invariably have shorter telomeres and associated chromosomal instability relative to normal tissue. METHODS: Using the Q-FISH method and our original software, Tissue Telo, we estimated telomere lengths in cardiac- and intestinal-type mucosae in 48 cases of Barrett's esophagus (short-segment (SS) n = 18; long-segment (LS) n = 30). RESULTS: There were no significant differences in telomere length between the cardiac and intestinal types in any of the 48 cases, suggesting that the presence or absence of goblet cells in the columnar segments is unrelated to telomere-dependent chromosomal instability in Barrett's esophagus. In LS Barrett's esophagus, telomeres were shorter in cardiac-type than in intestinal-type mucosa, suggesting that the former may play a more important role than the latter as a precancerous lesion in LS. Telomeres in cardiac-type mucosa were longer in SS than in LS, supporting the possibility that cardiac-type LS may pose a higher risk as a precancerous lesion than cardiac-type SS. CONCLUSIONS: Although it has been considered that Barrett's carcinoma arises only from intestinal-type mucosa, our present findings support previous histogenetic studies suggesting that cardiac-type mucosa is more important as a precancerous condition in Barrett's esophagus than anticipated.

Intestinal phenotype is maintained by Atoh1 in the cancer region of intraductal papillary mucinous neoplasm.

Intraductal papillary mucinous neoplasm (IPMN) is a precancerous lesion of pancreatic cancer. Although there are 4 types of IPMN, among which intestinal-type IPMN is likely to progress into invasive cancer known as colloid carcinoma, no information regarding the involvement of the intestinal phenotype in the carcinogenesis of IPMN exists. The present study was conducted to explore how the intestinal differentiation system is maintained during the tumor progression of intestinal-type IPMN using surgical resection specimens. Results showed that Atoh1, a critical transcriptional factor for intestinal differentiation toward the secretory lineages of intestinal epithelial cells, was expressed in an invasive-grade IPMN. To determine the function of Atoh1 in pancreatic cancer, we generated a pancreatic ductal adenocarcinoma (PDAC) cell line overexpressing Atoh1. In a xenograft model, we successfully induced an IPMN phenotype in PDAC cells via Atoh1 induction. Finally, for the first time, we discovered that GPA33 is expressed in intestinal-type IPMN, thereby suggesting a novel target for cancer therapy. In conclusion, the intestinal differentiation system might be maintained during tumor progression of intestinal-type IPMN. Further analysis of the function of Atoh1 in IPMN might be useful for understanding the molecular mechanism underlying the malignant potential during the tumor progression of IPMN.

3D endoscopic endonasal craniectomy for intestinal type adeno-carcinoma (ITAC) of the nasal cavity.

BACKGROUND: The aim of this study was to describe the potential advantages of the 3D endoscope-assisted craniectomy for tumor of the nasal cavity. METHODS: A 77-year-old man with a 6 month history of persistent progressive right nasal obstruction and iposmia is reported. Physical examination, including nasal endoscopy, revealed a large mass within the right nasal cavity. He had no associated symptoms such as visual complaints, paresthesia, and facial pain. He worked as a carpenter. Further imaging by CT and MRI revealed a large, expansive nasal-ethmoid lesion that almost completely occupies the right nasal cavity with partial extension posterior to the choana, extensive erosion of the ethmoid. Medially marks the nasal septum with deviation to the left. Laterally it marks the medial wall of the maxillary sinus and at the top it is in contact with the cribriform plate which seems to be interrupted in the right parasagittal seat at the 3rd anterior of the olfactory cleft. Histopathological analysis of the specimen was consistent with sinonasal adenocarcinoma, intestinal type (ITAC) cT4aN0 ([1]). RESULTS: Patient was taken up for surgery by transnasal 3D endoscopic approach for excision of tumor with repair of the skull base defect, using Karl Storz IMAGE1 S D3-Link™ and 4-mm TIPCAM®. The mass could be dissected free of the dura and the entire specimen was removed completely and sent for histopthological examination. We followed our 8 main surgical steps: 1) Tumor disassembling; 2) Nasal septum removal; 3) Centripetal bilateral ethmoidectomy and sphenoidotomy; 4) Draf III frontal sinusotomy 5) Anterior and posterior ethmoidal artery closure 6) Skull base removal; 7) Intracranial work; 8) Reconstruction time. A 4 × 2.3 cm skull base defect was repaired using triple layer of fascia lata (Intracranial intradural, intracranial extradural and extracranial) and was sealed using tissue glue (TisselR). Post-operative recovery was uneventful, pack were removed on 3rd postoperative day and patient was discharged on the 7th post-operative day. After 2 years of follow up, the patient is free of disease. CONCLUSION: We describe 3D endoscopic transnasal craniectomy for Intestinal Type Adeno-Carcinoma (ITAC) of the nasal cavity as a feasible technique for the surgical management of sino-nasal tumors ([2].) Our experience with this approach has been outstanding. We firmly believe that in the first three steps of the procedure the 3D endoscope is not necessary because it extends the surgical time and induce eyestrain of the main surgeon. Nevertheless, 3D endoscope gives the major advantage during the skull base removal and the intracranial work. It offers an optimal vision and better perception of depth with safe manipulation of the instruments avoiding injuries to healthy tissue ([3]). Furthermore, 3D images offer better understanding of the relationship between anatomical landmarks, helping the didactic learning curve of our residents.

Identification of cancer stem cell-related biomarkers in intestinal-type and diffuse-type gastric cancer by stemness index and weighted correlation network analysis.

BACKGROUND: Cancer stem cells (CSCs) play an important role in drug resistance, recurrence, and metastasis of tumors. Considering the heterogeneity of tumors, this study aimed to explore the key genes regulating stem cells in intestinal-type and diffuse-type gastric cancer. METHODS: RNA-seq data and related clinical information were downloaded from The Cancer Genome Atlas (TCGA). WGCNA was used to clustered differentially expressed genes with similar expression profiles to form modules. Furtherly, based on the mRNA expression-based stemness index (mRNAsi), significant modules and key genes were identified. Next, the expression of key genes was further verified by the Oncomine database. RESULTS: MRNAsi scores of GC were significantly higher than that of normal tissue. Additionally, mRNAsi scores of intestinal-type GC (IGC) were significantly higher than that of diffuse-type GC (DGC). WGCNA showed that the blue module of IGC and the brown module of DGC were both the most significantly associated with mRNAsi. We screened out 16 and 43 key genes for IGC and DGC and found that these genes were closely related, respectively. Functional analysis showed the relationship between the key genes confirmed in the Oncomine database and the fate of cells. CONCLUSIONS: In this study, 16 and 43 genes related to the characteristics of CSCs were identified in IGC and DGC, respectively. These genes were both associated with cell cycle, which could serve as therapeutic targets for the inhibition of stem cells from both types of GC.