Calcipotriol abrogates cancer-associated fibroblast-derived IL-8-mediated oxaliplatin resistance in gastric cancer cells via blocking PI3K/Akt signaling.

Activation of vitamin D receptor (VDR) in cancer-associated fibroblasts (CAFs) has been implicated in hesitating tumor progression and chemoresistance of several human malignancies. Yet, the role of VDR in CAF-induced chemotherapy resistance of gastric cancer (GC) cells remains elusive. In this study we first conducted immunohistochemistry analysis on tissue microarrays including 88 pairs of GC and normal mucosa samples, and provided clinical evidence that VDR was mainly expressed in gastric mucous cells but almost invisible in CAFs, and VDR expression was negatively correlated with malignant clinical phenotype and advanced stages, low VDR expression confers to poor overall survival rate of patients with GC. In a co-culture system of primary CAFs and cancer cells, we showed that treatment of HGC-27 and AGS GC cells with VDR ligand calcipotriol (Cal, 500 nM) significantly inhibited CAF-induced oxaliplatin resistance. By using RNA-sequencing and Human Cytokine Antibody Array, we demonstrated that IL-8 secretion from CAFs induced oxaliplatin resistance via activating the PI3K/AKT pathway in GC, whereas Cal treatment greatly attenuated the tumor-supportive effect of CAF-derived IL-8 on GC cells. Taken together, this study verifies the specific localization of VDR in GC tissues and demonstrates that activation of VDR abrogates CAF-derived IL-8-mediated oxaliplatin resistance in GC via blocking PI3K/Akt signaling, suggesting vitamin D supplementation as a potential strategy of enhancing the anti-tumor effect of chemotherapy in GC.

Clinicopathologic features and prognostic value of KRAS, NRAS and BRAF mutations and DNA mismatch repair status: A single-center retrospective study of 1,834 Chinese patients with Stage I-IV colorectal cancer.

Mutations of KRAS, NRAS, BRAF and DNA mismatch repair (MMR) status have become an important part of the assessment of patients with colorectal cancer (CRC), while respective clinicopathologic features and prognostic significance in specific stages and related detection strategies remain unclear. We retrospectively analyzed clinicopathologic features and prognosis of 1,834 patients with Stage I-IV colorectal adenocarcinoma. Mutations in KRAS, NRAS and BRAF and DNA MMR status were determined. The mutation rates of KRAS, NRAS and BRAF were 46.4, 3.2 and 3.5%, respectively, and the mismatch repair gene deletion (dMMR) rate was 5.6%. In a multivariate analysis, female, advanced age, tumor type histology, mucinous carcinoma and positive tumor deposits were associated with a high KRAS mutation rate. A high BRAF mutation rate was associated with female, poor differentiation, lymphovascular invasion and positive tumor deposits. Factors associated with high dMMR rates included low age, large tumor size, poor differentiation, Stages I-III. Tumor site was independently associated with KRAS mutation, BRAF mutation and dMMR. KRAS and BRAF mutations were independent risk factors for shorter overall survival (OS) in Stage IV tumors but not in Stage I-III tumors. NRAS mutation was an independent risk factor for shorter OS in Stage I-II tumors. dMMR was independently associated with longer OS in Stage III tumors.

Pituitary tumor-transforming gene-1 serves as an independent prognostic biomarker for gastric cancer.

BACKGROUND: Pituitary tumor-transforming gene-1 (PTTG1) is a transcription factor that can affect transcriptional activity, angiogenesis, and cell senescence. We examined PTTG1 mRNA and protein expression in gastric cancer (GC) cell lines and tissues to determine its value as a biomarker for GC diagnosis and therapy. METHODS: PTTG1 mRNA expression from 78 GC cases and paired adjacent normal mucosa (PCR cohort) as well as from five gastric cell lines was assessed using qRT-PCR. Nuclear and cytoplasmic RNA were extracted from two gastric cell lines to determine PTTG1 mRNA localization. PTTG1 protein expression from 98 GC cases, their paired adjacent normal mucosa, and 23 gastric intraepithelial neoplasia (GIN) cases was examined using immunohistochemistry (IHC cohort). The correlation between PTTG1 mRNA and protein expression and GC clinicopathological parameters was analyzed. RESULTS: PTTG1 mRNA expression in GC tissues and cell lines was significantly increased compared with adjacent normal gastric mucosa and normal gastric mucous cell lines (p < 0.05). PTTG1 expression was nuclear and cytoplasmic, with higher cytoplasmic expression. PTTG1 immunostaining significantly differed in GC (95.66 ± 20.65), GIN (84.00 ± 34.16), and normal adjacent mucosa (28 ± 22.25) (p < 0.001). Multivariate Cox regression analysis revealed that PTTG1 mRNA and protein expression are independent prognostic factors for GC patient survival. CONCLUSION: Our results suggest that PTTG1 is a promising target for GC diagnosis and therapy.

Reciprocal repression between TUSC7 and miR-23b in gastric cancer.

Recently, long noncoding RNAs (lncRNAs) were demonstrated to play important regulatory roles in biological processes and cancer biology. However, the overall pathophysiological contribution of lncRNAs to gastric cancer (GC) remains largely unknown. In this study, differentially expressed lncRNAs in GC and paired adjacent normal tissue samples were identified by microarray and were validated using quantitative real-time polymerase chain reaction (qRT-PCR). One particular lncRNA, tumour suppressor candidate 7 (TUSC7), was analyzed in sequential large cohorts, and the Kaplan-Meier method with the log-rank test for comparisons was used to analyse the survival data. The results indicated that TUSC7 was downregulated in GC samples and was an independent prognostic indicator of disease-free survival (DFS) and disease-specific survival (DSS) in GC patients. Applying loss-of-function and gain-of-function approaches, we determined that TUSC7 suppressed tumour cell growth in vitro and in vivo. Furthermore, we showed that TUSC7 was a direct transcriptional target of p53 via interaction of p53 with the putative p53-response element in the upstream region of TUSC7. Finally, we demonstrated reciprocal repression between TUSC7 and miR-23b; in contrast to TUSC7, miR-23b promoted cell growth. The results indicated that TUSC7 is a p53-regulated tumour suppressor that acts in part by repressing miR-23b and that TUSC7 may be a key regulatory hub in GC.

Circulating CUDR, LSINCT-5 and PTENP1 long noncoding RNAs in sera distinguish patients with gastric cancer from healthy controls.

The examination of circulating nucleic acids (CNAs) is an emerging noninvasive diagnostic technique. However, it is unclear if serum long noncoding RNAs (lncRNAs) represent a novel marker to detect gastric cancer (GC). In this study, we measured 39 candidate cancer-associated lncRNAs by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) in sera from 110 patients with GC, 106 age- and sex-matched healthy subjects and 15 patients with gastric peptic ulcer, markers were validated and assessed by RT-qPCR. The correlation of the expression levels of the candidate serum lncRNAs with clinical parameters of GC patients was performed. A three-lncRNA signature, including CUDR, LSINCT-5 and PTENP1, was identified that may be potential diagnostic marker for GC. The areas under the receiver operating characteristic (ROC) curve for this serum three-lncRNA signature were 0.920 and 0.829 for the two sets of serum samples. Moreover, a risk model for the serum three-lncRNA signature demonstrated that healthy samples can be distinguished from early GC samples. Three-lncRNA signature in serum was identified as diagnostic marker for GC. This work may facilitate the detection of GC and serve as the basis for further studies of the clinical value of serum lncRNAs in maintaining surveillance and forecasting prognosis.

Down-regulation of ncRAN, a long non-coding RNA, contributes to colorectal cancer cell migration and invasion and predicts poor overall survival for colorectal cancer patients.

Accumulating evidence has indicated that long non-coding RNAs (lncRNAs) play critical roles in regulating cellular processes, such as cell growth and apoptosis, as well as cancer progression and metastasis. ncRAN (non-coding RNA expressed in aggressive neuroblastoma) was previously shown to be dramatically up-regulated and associated with poor prognosis in human neuroblastoma. This lncRNA also plays an important role in bladder cancer growth and invasion. Colorectal cancer (CRC) progression typically follows a complex cascade from primary malignancy to distant metastasis, but whether the aberrant expression of ncRAN in CRC is associated with malignancy, metastasis or prognosis remains unknown. In this study, we demonstrated that ncRAN expression is significantly down-regulated in tumor tissue and CRC cell lines compared with adjacent normal tissue and a normal intestinal mucous cell line. Reduced expression of ncRAN was detected in poorly differentiated or undifferentiated tumors and in tumors with liver metastases. Kaplan-Meier analysis indicated that patients with lower ncRAN expression have a worse overall survival. Moreover, multivariate analysis revealed that decreased expression of ncRAN is an independent predictor of overall survival. Our experimental data indicated that ncRAN mediates the in vitro migration and invasion of CRC cells. Together, these results suggest that ncRAN might represent a novel prognostic indicator, a biomarker for the early detection of metastasis and a target for gene therapy in CRC.

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023.

The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.

[Role of arginase-1 expression in distinguishing hepatocellular carcinoma from non-hepatocellular tumors].

OBJECTIVE: To study the role of arginase-1 (Arg-1) expression in differential diagnosis of hepatocellular carcinoma (HCC), Arg-1 staining pattern in clear cell neoplasm (HCC and non-HCC) and Arg-1 expression in non-hepatocellular tumors. METHODS: Seventy-eight cases of HCC (including 8 cases of clear cell type and 70 cases of non- clear cell type) and 246 cases of non-hepatocellular neoplasms (including 29 cases of metastatic tumors such as breast cancer, nasopharyngeal carcinoma and neuroendocrine carcinoma, 77 cases of tumors with clear cell changes such as malignant melanoma, clear cell renal cell carcinoma and alveolar soft part sarcoma, and 140 cases of other types of tumors such as ovarian endometrioid adenocarcinoma, pituitary tumor and thyroid papillary carcinoma) were studied.Immunohistochemical study for Arg-1 was performed on the paraffin-embedded tumor tissue. RESULTS: In HCC, Arg-1 demonstrated both cytoplasmic and nuclear staining, with an overall sensitivity of 96.2% (75/78).In well, moderately and poorly differentiated HCC, the sensitivity was 15/15, 100% (41/41) and 86.4% (19/22), respectively. That was in contrast to negative staining for Arg-1 in all the 29 cases of metastatic tumors studied. The sensitivity, specificity, positive predictive value and negative predictive value of Arg-1 in distinguishing HCC from metastatic tumors was 96.2%, 100%, 100% and 90.6%, respectively. Cytoplasmic and membranous staining was observed in clear cell type of HCC. The overall sensitivity of Arg-1 expression in the 77 cases of tumors with clear cell changes was 14.3% (11/77), including 8/15 for malignant melanoma, 2/4 for ovarian clear cell carcinoma and 1/1 gall bladder adenocarcinoma with clear cell component.In malignant melanoma and ovarian clear cell carcinoma, only cytoplasmic staining was demonstrated. There was no expression of Arg-1 in the 140 cases of other tumor types studied. CONCLUSIONS: Arg-1 is a sensitive and specific marker for HCC.It is a potentially useful immunohistochemical marker in distinguishing HCC from metastatic tumors. Though also expressed in malignant melanoma and ovarian clear cell carcinoma, Arg-1 shows a different staining pattern as compared with that in HCC.

Histomorphological and molecular genetic characterization of different intratumoral regions and matched metastatic lymph nodes of colorectal cancer with heterogenous mismatch repair protein expression.

PURPOSE: To better understand the clinicopathological characteristics and molecular alterations in different intratumoral components of colorectal cancer (CRC) with heterogeneity of mismatch repair (MMR) protein expression and microsatellite instability (MSI) status. METHODS: The histopathological features, MSI status, and other molecular alterations were analyzed in separately microdissected intratumoral regions and matched metastatic lymph nodes in four cases with intratumoral heterogenous MMR expression screened from 500 CRC patients, using PCR-based MSI testing, MLH1 promoter methylation, and targeted next-generation sequencing (NGS). RESULTS: High microsatellite instability (MSI-H) was identified in MLH1/PMS2-deficient regions in Cases 1 to 3 and in MSH2/MSH6-deficient regions in Case 4, while microsatellite stability (MSS) was detected in all the intratumoral regions and metastatic lymph nodes with proficient MMR expression (pMMR). Intratumoral heterogeneity of MLH1 promoter methylation and/or other common driving gene mutations of CRC, such as KRAS and PIK3CA mutations, was identified in all four CRCs. Further, three cases (75%) showed heterogeneous histomorphological features in intratumoral components and metastatic lymph nodes (Cases 1, 2, and 4), and the corresponding metastatic lymph nodes showed moderate differentiation with MSS/pMMR (Cases 2 and 3). CONCLUSIONS: Intratumoral heterogeneous MSI status is highly correlated with intratumoral histomorphological heterogeneity, which is also an important clue for the intratumoral heterogeneity of drive gene mutations in CRC. Thus, it is essential to detect MMR protein expression and other gene mutations in metastases before treatment, especially for CRCs with intratumoral heterogenous MMR protein expression or heterogenous histomorphological features.

[Myxoid dermatofibrosarcoma protuberans: a clinicopathologic analysis of 16 cases].

OBJECTIVE: To study the clinicopathologic features and differential diagnosis of myxoid dermafibrosarcoma protuberans (DFSP). METHODS: The clinical and pathologic features of 16 cases of myxoid DFSP were reviewed. RESULTS: There were altogether 15 males and 1 female. The age of the patients ranged from 11 to 73 years (mean = 47 years and median = 48 years). The commonest site of involvement was trunk (number = 11), followed by shoulder (number = 2), head and neck (number = 2), and extremity (number = 1). Similar to conventional DFSP, most patients presented with a slowly enlarging subcutaneous nodule which showed a rapid recent growth in some cases. Amongst the 16 cases studied, 12 occurred de novo and 4 represented local recurrence. The tumors ranged from 2 to 10 cm in greatest dimension (mean = 5 cm and median = 4 cm). Histologically, they were poorly circumscribed and located in the dermis, with focal infiltration into the underlying subcutaneous tissue. Seven cases were purely myxoid and composed of spindly and stellate cells with delicate arborizing vascular meshwork. The remaining 9 cases were predominantly myxoid (> 50%), with 5 cases containing cellular areas resembling conventional DFSP and 4 cases showing fibrosarcomatous transformation. In addition, foci of giant cell fibroblastoma-like areas were noted in 1 case. Immunohistochemical study showed that the tumors cells were positive for CD34. The staining was weak in the myxoid areas, as compared with conventional DFSP. Of the 4 recurrent cases, one patient developed lung metastases. CONCLUSIONS: Myxoid DFSP represents a rare variant of DFSP and may pose important diagnostic pitfalls. It is especially so if the tumor purely consists of myxoid element. Familiarity with the histologic features helps to avoid misdiagnosis.

[Plexiform angiomyxoid myofibroblastic tumor of stomach].

OBJECTIVE: To study the clinicopathologic features, immunophenotype and differential diagnosis of plexiform angiomyxoid myofibroblastic tumor (PAMT) of the stomach. METHODS: The clinical and pathologic findings of 3 cases of PAMT in the gastric antrum were retrospectively analyzed. Immunohistochemical study was carried out and the literature was reviewed. RESULTS: The age of patients ranged from 31 to 47 years. The male-to-female ratio was 1:2. The clinical presentation included epigastric pain and distension. Endoscopically, the tumor mass protruded into the gastric cavity at the antrum and ranged from 4.5 cm to 8.0 cm in greatest dimension. One of the tumors studied was associated with surface ulceration. Histologically, the tumors were located in the gastric wall. They were composed of bland spindle cells and small vessels arranged in a plexiform or nodular pattern within a myxoid stroma. Immunohistochemical study showed that the spindle cells were consistently positive for smooth muscle actin and muscle-specific actin. There was focal staining for h-caldesmon, desmin in case 3 and focal positive for epithelial membrane antigen, CAM5.2 in case 1. Further, CD10 and progesterone receptor were positive in case 3. CONCLUSIONS: PAMT represents a rare novel mesenchymal tumor of the stomach, with a propensity of gastric antral involvement. The distinctive pathologic features help to differentiate this entity from other benign and malignant tumors.

[KRAS and BRAF gene mutations in correlation with clinicopathologic features of colorectal carcinoma in Chinese].

OBJECTIVE: To retrospectively analyze KRAS and BRAF gene mutation features in Chinese colorectal cancer (CRC) and their clinicopathologic relationship. METHODS: 557 colorectal cancer cases were collected, including 325 colon cancer and 232 rectal cancer. PCR amplification and DNA sequencing were used to detect mutations in exon 2 of KRAS gene and exon 15 of BRAF gene mutation. RESULTS: (1) KRAS mutation was found in 40.4% (225/557) colorectal cancer. The most common mutation locations were in codon 12(79.1%, 178/225) and codon 13 (20.4%, 46/225). The most common mutation types were GGT > GAT (G12D) (37.8%, 85/225), GGT > GTT(G12V) (20.0%, 45/225) in codon 12 and GGC > GAC (G13D) in codon 13 (19.6%, 44/225). These three point mutations accounted 77.3% (174/225) in total KRAS gene mutation cases. All cases showed only one of point mutation types. (2) Among 557 CRC cases, KRAS mutation was significantly higher in female (46.2%, 92/199) than in man (37.2%, 133/358; P < 0.05). KRAS gene codon 13 mutation was higher in right colon cancer (11.3%, 12/106) than that in left colon cancer (4.8%, 6/124), but it didn't show any statistical significance (P > 0.05). (3) BRAF gene mutation was 5.1% (10/197) in colorectal cancer and 8/10 were the point mutation of GTG > GAG (V600E). Eight colorectal cancer cases with GTG > GAG (V600E) were not showing KRAS gene mutation. Both two cases with mutation on codon 600 (GTG > ATG, V600M) and codon 606 (GGG > AGT, G606S) showed codon 12 mutation of KRAS gene. (4) BRAF (V600E) gene mutation was higher in female (8.5%, 6/71) than that in male (1.6%, 2/126; P = 0.05); BRAF mutation in colon cancer (8.3%, 6/72) was higher than that in rectum cancer (2.1%, 2/94), but hadn't statistical significance (P > 0.05). CONCLUSIONS: (1) Codon 12, 13 in KRAS gene and codon 600 in BRAF gene are the most common mutation points in Chinese colorectal cancer. KRAS and BRAF mutations are mutually exclusive. (2) KRAS and BRAF gene mutation is higher in female than that in male, suggesting that RAS-RAF-MAPK signal pathway is probably related to hormones directly or indirectly. (3) There is a trend that codon 13 mutation in KRAS and codon 600 mutation in BRAF in right colon cancer are higher than that in left colon cancer, respectively, however, which needs more cases to be further verified.

[Detection of chromosomal translocations involving ALK gene in anaplastic large cell lymphoma by fluorescence in-situ hybridization and its clinical significance].

OBJECTIVE: To investigate clinicopathologic features and clinical value of the chromosomal translocation involving anaplastic lymphoma kinase (ALK) in anaplastic large cell lymphoma (ALCL) by fluorescence in situ hybridization (FISH). METHODS: A total of 55 cases, including 45 cases of ALCL and 10 reactive lymphoid hyperplasia, were collected during 1999 to 2006 in the Department of Pathology, Fudan University Shanghai Cancer Center, and Xinhua Hospital Affiliated to Shanghai Jiaotong University. All cases were studied by FISH using dual color break apart probes of ALK for detection of chromosomal translocation, compared with the previous results of immunohistochemistry (IHC) and reverse-transcriptase polymerase chain reaction (RT-PCR) for the detection of ALK aberrations. RESULTS: The result of FISH showed that the clear red and green fluorescence signals were detected in 38 cases of ALCL, in which conspicuous split signals were observed in tumor cells in 24 cases (63.2%), suggesting the rearrangement of the ALK locus, with multiple copies of ALK gene in one case. In addition, the rearrangement of the ALK locus was not identified in 14 of 38 cases (36.8%); and the FISH results were unable to be evaluated in 7 cases, because no fluorescent signals involving ALK gene were found or signals were too weak to be analyzed. The concordance for the detection ALK aberrations in ALCL between FISH and RT-PCR, FISH and IHC were both statistically significant (P < 0.01). Chromosomal translocation involving ALK gene was not found in all 10 cases of reactive lymphoid hyperplasia. CONCLUSIONS: ALCL is an entity of lymphoma characterized by special clinical presentation, morphology, and ALK aberrations. FISH is helpful for detection of the chromosomal translocations involving ALK in ALCL, however, the detection efficiency by FISH may be affected by storage time of the paraffin-embedded tissue; and therefore combined detection with IHC and RT-PCR could complement each other and help for differential diagnosis of ALK(+)ALCL from ALK(-)ALCL.

Comprehensive molecular characterization and identification of prognostic signature in stomach adenocarcinoma on the basis of energy-metabolism-related genes.

BACKGROUND: Stomach adenocarcinoma (STAD) is a leading cause of cancer deaths, but its molecular and prognostic characteristics has never been fully illustrated. AIM: To describe a molecular evaluation of primary STAD and develop new therapies and identify promising prognostic signatures. METHODS: We describe a comprehensive molecular evaluation of primary STAD based on comprehensive analysis of energy-metabolism-related gene (EMRG) expression profiles. RESULTS: On the basis of 86 EMRGs that were significantly associated to patients' progression-free survival (PFS), we propose a molecular classification dividing gastric cancer into two subtypes: Cluster 1, most of which are young patients and display more immune and stromal cell components in tumor microenvironment and lower tumor priority; and Cluster 2, which show early stages and better PFS. Moreover, we construct a 6-gene signature that can classify the prognostic risk of patients after a three-phase training test and validation process. Compared with patients with low-risk score, patients with high-risk score had shorter overall survival. Furthermore, calibration and DCA analysis plots indicate the excellent predictive performance of the 6-gene signature, and which present higher robustness and clinical usability compared with three previous reported prognostic gene signatures. According to gene set enrichment analysis, gene sets related to the high-risk group were participated in the ECM receptor interaction and hedgehog signaling pathway. CONCLUSION: Identification of the EMRG-based molecular subtypes and prognostic gene model provides a roadmap for patient stratification and trials of targeted therapies.

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2021.

There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub-specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow-up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non-metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third-line to the first-line of treatment for different patient groups with detailed notes are provided.

Malignant Gastrointestinal Neuroectodermal Tumor: Clinicopathologic, Immunohistochemical, and Molecular Analysis of 19 Cases.

A malignant gastrointestinal neuroectodermal tumor (GNET) is rare, and it is therefore yet to be completely understood. This study aimed to present the clinicopathologic features of GNET, including treatment information. We included 19 patients with GNET with a mean tumor size of 4.2 cm. The most common site of tumor origin was the small intestine (57.9%), followed by the stomach (15.8%), colon (10.5%), ileocecal junction (5.3%), lower esophagus (5.3%), and anal canal (5.3%). Microscopically, the tumors were composed of epithelioid cells with eosinophilic or clear cytoplasm arranged in nest, sheet-like, papillary, or pseudoalveolar patterns and/or spindle tumor cells with eosinophilic cytoplasm arranged in a fascicular pattern. Immunohistochemically, the tumor cells stained positively for S100 (19/19,100%), SOX10 (14/15, 93.3%), vimentin (17/17, 100%), synaptophysin (Syn) (7/17, 41.2%), CD56 (4/13, 30.8%), CD99 (1/5, 20%), and CD117 (1/15, 6.7%), and negatively for HMB45, Melan A, DOG1, CD34, AE1/AE3, CAM5.2, chromogranin A, smooth muscle actin, and desmin. In total, 14/15 (93.3%) cases showed split Ewing sarcoma breakpoint region 1 gene (EWSR1) signals consistent with a chromosomal translocation involving EWSR1. Within a mean follow-up of 29.7 months (range: 3 to 63 mo), 2/15 (13.3%) patients died of disease, 5 (33.3%) were alive with disease, and 8 (53.3%) had no evidence of disease. Two and 1 patients showed partial response to apatinib and anlotinib, respectively. In conclusion, GNET has distinctive morphologic, immunohistochemical, and molecular genetic features and should be distinguished from other gastrointestinal tract malignancies. Apatinib and anlotinib might be effective for the treatment of advanced GNET and could prolong patient survival.

Intravascular large B-cell lymphoma with cutaneous manifestations: a clinicopathologic, immunophenotypic and molecular study of three cases.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is an extremely rare type of malignant lymphoma characterized by exclusive or predominant growth of neoplastic cells within the lumen of blood vessels. Cases in the literature predominantly involve the skin and central nervous system, with special emphasis on the 'cutaneous variant'. METHODS: Three cases of IVLBCL with cutaneous manifestations, including two systemic IVLBCL and one cutaneous variant, were described in this study. In all cases, clinical presentation and follow-up data were meticulously evaluated and immunophenotypic and molecular studies were performed. RESULTS: All three cases displayed the B-cell phenotype and showed monoclonality with immunoglobulin heavy chain gene rearrangement. Bcl2 was expressed in the two systemic IVLBCL cases with fatal outcomes. The third patient with the 'cutaneous variant' achieved complete remission and a longer survival time of 15 months after chemotherapy. CONCLUSIONS: Skin manifestations and neurological findings, although to different degrees, are important clues to the diagnosis of IVLBCL. As most IVLBCL are grouped into the post-germinal center B-cell subtype of diffuse large B-cell lymphoma, Bcl2 expression may be correlated with a worse prognosis in IVLBCL. The cutaneous variant of IVLBCL has a significantly better outcome than that of systemic IVLBCL.

[Prevalence of API2-MALT1 fusion gene in gastrointestinal mucosa-associated lymphoid tissue lymphomas and diffuse large B cell lymphomas].

OBJECTIVE: To investigate the difference of the prevalence of t(11;18)(q21;q21)/API2-MALT1 fusion gene between gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B cell lymphoma (DLBCL). METHODS: A total of 57 cases gastrointestinal MALT lymphomas (38 gastric and 19 intestinal lymphomas), 32 DLBCL (28 gastric and 4 intestinal lymphomas) and 7 cases gastric DLBCL accompanied MALT lymphoma were collected from the Cancer Hospital of Fudan University. API2-MALT1 fusion gene was detected by fluorescent in situ hybridization (FISH) using both dual fusion translocation and break apart probes. RESULTS: Among gastrointestinal MALT lymphomas, API2-MALT1 fusion gene was found in 12 of 57 cases (21.1%, 10 gastric and 2 intestinal lymphomas). In contrast, the fusion gene was not found in all 32 DLBCL and 7 gastric DLBCL with MALT lymphoma component. There was statistical significant difference between two groups (chi(2) = 9.383, P = 0.001). CONCLUSIONS: API2-MALT1 fusion gene is a distinctive genetic aberration in MALT lymphomas, and is not present in DLBCL. The findings suggest that gastrointestinal tract MALT lymphomas with API2-MALT1 fusion gene may not transform into DLBCL, which may represent primary lymphoma or transformed API2-MALT1 negative MALT lymphomas.

Solitary rectal ulcer syndrome complicating sessile serrated adenoma/polyps: A case report and review of literature.

Solitary rectal ulcer syndrome (SRUS) is a rare benign condition, which can mimic many other diseases because of their similarities in clinical, endoscopic and histological features. Sessile serrated adenoma/polyp (SSA/p) is a premalignant lesion in the colon and rectum. The misdiagnosis of SSA/p in SRUS patients has been noted, but the case of SRUS arising secondarily to SSA/p has been rarely reported. We herein report the case of a 59-year-old man who presented with an ulcerative nodular lesion in the rectum, accompanied by the symptoms of blood and mucus in the feces, diarrhea and constipation. Magnetic resonance imagining revealed thickening of the rectal mucosa-submucosa. Histologically, the lesion was characterized by the hyperplastic lamina propria and diffusely serrated crypts. Further immunohistochemical staining showed the loss of HES1 and MLH1 expression in the epithelial cells in the serrated area. The patient with SRUS had histological changes of SSA/p, suggesting a potential of tumor transformation in certain cases. SRUS uncommonly accompanied by serrated lesions should at least be considered by pathologists and clinicians.

E2F1 induces LSINCT5 transcriptional activity and promotes gastric cancer progression by affecting the epithelial-mesenchymal transition.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been shown to play important regulatory roles in human cancer. We previously verified that the lncRNA long stress-induced noncoding transcript 5 (LSINCT5) is overexpressed in gastric cancer (GC) cells and closely correlated with cell proliferation and patient prognosis. However, whether aberrant LSINCT5 expression has an important effect on GC progression is unclear, and the potential mechanisms remain unknown. In GC, E2F1 expression is also aberrant, but the biological functions of E2F1 are controversial, and the correlation between E2F1 and lncRNAs remains unknown. MATERIALS AND METHODS: Expression of LSINCT5 was analyzed in metastatic GC tissues compared with nonmetastatic tissues using quantitative real-time PCR (qRT-PCR) assays. Gain and loss of function approaches were used to investigate the biological role of LSINCT5 in GC cell migration and invasion. A computational screen of LSINCT5 promoter was conducted to search for transcription factor-binding sites. LSINCT5 promoter activities were examined by ChIP and luciferase reporter assays. qRT-PCR and western blotting assays were performed to detect the expression of multiple EMT markers in cells in which LSINCT5 was overexpressed or knocked down. RESULTS: An integrated quantitative analysis revealed that LSINCT5 was significantly over-expressed in metastatic GC tissues. Forced LSINCT5 expression promoted cell migration and invasion, whereas loss of LSINCT5 function decreased cell migration and invasion. Mechanistic investigations showed that LSINCT5 is a direct transcriptional target of E2F1. Moreover, LSINCT5 overexpression was found to play an important role in the epithelial-to-mesenchymal transition by regulating the expression of E-cadherin, N-cadherin, vimentin, and matrix metalloproteinase-2. CONCLUSION: These data suggest that E2F1-mediated activation of LSINCT5, a regulator of cell migration and invasion, constitute the mechanistic link between the E2F1-mediated pathway and lncRNA that regulates cell migration and invasion. Thus, LSINCT5 may be a target for new GC therapies.