The nuclear-localized GHR is involved in the cell proliferation of gastric cancer, and pegvisomant may be an important potential drug to inhibit the proliferation of gastric cancer cells.

Under normal physiological conditions, growth hormones (GH) play an important role in body growth and metabolism. A recent study showed that GH has important biological effects on gastric cancer (GC) both in vitro and in vivo. However, the biological properties of GH/GHR (GHR, growth hormone receptor) in GC cells have not been fully elucidated. To this end, we systemically studied the biological properties of GH in GC cells and found that GH/GHR was transported into the nuclei of GC cells. Furthermore, we investigated the functions of nuclear GHR and its potential mechanisms of action. We found that nuclear-localized GHR was closely related to the proliferation of GC cells. In addition, we systematically studied the effect of a GHR inhibitor (pegvisomant) on GC in vivo and in vitro, and the results showed that pegvisomant can not only inhibit the proliferation of GC cells but also inhibit the nuclear localization of GHR, suggesting that pegvisomant may be a dual-effect antagonist. Current research indicates that GHR may be a potential target for the treatment of GC.

LINC01857 promotes the proliferation, migration, and invasion of gastric cancer cells via regulating miR-4731-5p/HOXC6.

The great importance of long non-coding RNAs (lncRNAs) in tumorigenesis has been acknowledged gradually. LINC01857 is previously reported to be highly expressed in gastric cancer (GC), while the regulatory mechanism of LINC01857 in GC is largely unknown. In this study, we detected high expression of LINC01857 from the GC microarray GSE109476. Additionally, LINC01857 expression is remarkably upregulated in GC cell lines (AGS, MKN-45, HGC-27, and SGC-7901) compared with the normal gastric mucosal cell line GES-1. Functionally, LINC01857 knockdown suppressed the proliferation, migration, invasion, and epithelial-mesenchymal transformation (EMT) of GC cells, while LINC01857 overexpression promoted the proliferation, migration, invasion, and EMT of GC cells. Furthermore, our data demonstrate that LINC01857 targeted miR-4731-5p and subsequently increased the expression of HOXC6 in GC. Rescue experiments showed that miR-4731-5p inhibition and HOXC6 overexpression could reverse the biological behavior of GC cells induced by LINC01857 knockdown. In conclusion, we demonstrated that LINC01857 sponged miR-4731-5p to promote the expression of HOXC6 and eventually acts as an oncogene in GC.

Upregulation of exonuclease 1 caused by homology-dependent repair confers cisplatin resistance to gastric cancer cells.

The homology-dependent repair (HDR) pathway is involved in deoxyribonucleic acid (DNA) damage response (DDR), which is crucial to cancer cell survival after treatment with DNA damage agents, including cisplatin (CDDP). Here, we explored the interactions between exonuclease 1 (EXO1), a core gene in the HDR pathway, and CDDP resistance in gastric cancer (GC). Using bioinformatics analysis, we identified the HDR pathway as the most amplified pathway in DDR in GC. In addition, EXO1 was the core gene in the HDR pathway and showed the most significant amplification in GC. The amplification of EXO1 resulted in higher EXO1 expression in cancerous tissues, with malignant prognostic effects. Moreover, we upregulated or downregulated EXO1 in GC cells to examine its effects on the cell malignant phenotype and CDDP resistance in vitro and in vivo. The depletion of EXO1 inhibited cell proliferatory, migratory, and invasive activities, and provided apoptosis resistance to GC cells. EXO1 expression was elevated in CDDP-resistant cells. Ectopic expression of EXO1 increased the resistance of GC cells to CDDP, while downregulation of EXO1 increased the sensitivity of GC cells. Taken together, our study indicates that the HDR pathway is an important player in CDDP resistance in GC through the regulation of EXO1.

[The autopsy of Napoleon Bonaparte: Anatomo-pathological assessment for the bicentenary of the death of Napoleon I on the island of Saint Helena in 1821]. / L'autopsie de Napoléon Bonaparte. Mise au point anatomo-pathologique pour le bicentenaire de la mort de Napoléon Ier sur l'île de Sainte-Hélène en 1821.

Napoleon Bonaparte died on 5 May 1821 on the island of St Helena after almost six years of exile. The next day, Dr Francesco Antommarchi, a Corsican doctor chosen by the Bonaparte family to treat the exiled emperor, performed the autopsy in the presence of sixteen people, including seven British doctors. Two hundred years after the event of 6 May 1821, the cause of Napoleon's death is still a mystery. Various hypotheses, such as arsenic intoxication, cardiac arrhythmia or, more recently, anaemia caused by gastrointestinal haemorrhage associated with chronic gastritis, have been put forward in the medical-historical literature. The main reasons for all these debates and misunderstandings are the presence of several autopsy reports, their often unscientific interpretation, as well as a certain taste for mystery. However, from a scientific point of view, the question arises as to whether autopsy reports are really conclusive as to the real cause of death. Thus, on the occasion of the bicentenary of Napoleon I's death in St. Helena, an international group of anatomo-pathologists specialising in digestive pathology set themselves the goal of analysing Napoleon I's autopsy reports according to their level of medical evidence (high, moderate and low). The autopsy reports of 1821 support the hypothesis of advanced malignant neoplasia of the stomach associated with gastric haemorrhage as the immediate cause of Napoleon I's death on 5 May 1821.

circ-NOTCH1 acts as a sponge of miR-637 and affects the expression of its target gene Apelin to regulate gastric cancer cell growth.

Gastric cancer (GC) is a major cause of cancer-related deaths worldwide, and has a low survival rate, low cure rate, high recurrence rate, and poor prognosis. Recent studies have indicated that circular RNAs (circRNAs) have important functions in the occurrence and progression of GC. Studies on circ-NOTCH1, which was shown to be highly expressed in GC, have indicated that miR-637 binds to circ-NOTCH1 at multiple sites, and a dual-luciferase reporter gene assay further confirmed that miR-637 indeed targeted circ-NOTCH1 and Apelin. Circ-NOTCH1 and Apelin are highly expressed in GC cells and tissues, whereas the expression of miR-637 is reduced. Circ-NOTCH1 and miR-637 do not regulate each other's expression levels, but circ-NOTCH1significantly upregulates the expression of the miR-637 target gene Apelin, whereas miR-637 inhibites the expression of Apelin. Examination of GC cells showed that circ-NOTCH1 enhances cell proliferation and invasiveness, and reduces cell apoptosis; these effects were reversed by miR-637, which could terminate the above effects of circ-NOTCH1. When co-transfected with the circ-NOTCH1 overexpression plasmid and Apelin siRNAs, there were no obvious changes to the levels of cell proliferation, apoptosis, or invasiveness. Therefore, in GC cells, circ-NOTCH1 inhibits the transcriptional activity of miR-637, thereby upregulating the expression of its target gene Apelin and regulating cell proliferation, apoptosis, and invasiveness. This finding provides more experimental evidence for the function of circRNA in GC.

Inhibition of autophagy improves resistance and enhances sensitivity of gastric cancer cells to cisplatin.

Autophagy plays critical roles in tumorigenesis, while the effects of autophagy on chemoresistance of cancer cells had great disparity. This study aims to explore the impacts of autophagy on the sensitivity and resistance of gastric cancer cells to cisplatin (DDP). We firstly demonstrated that there was stronger autophagy activity in gastric cancer SGC-7901 cells than that in DDP-resisting SGC-7901/DDP cells. Then, we discovered that inhibiting autophagy by chloroquine (CQ) significantly enhanced the proliferation-inhibiting and apoptosis-inducing effects of DDP to SGC-7901 and SGC-7901/DDP cells. Moreover, CQ could partially reverse the resistance of SGC-7901/DDP cells to DDP in a concentration-dependent manner. However, the autophagy inducer everolimus (RAD001) had no obvious effects on the sensitivity of gastric cells to DDP. Mechanistically, we demonstrated that CQ might enhance the sensitivity of SGC-7901cells and improve the resistance of SGC-7901/DDP cells to DDP through inhibiting the mTORC1 pathway, especially to SGC-7901/DDP cells. Additionally, we found interfering Beclin-1 using Beclin-1 shRNA also enhanced the proliferation-inhibiting and apoptosis-inducing effects of DDP on gastric cancer cells by inhibiting phosphorylation of Akt. Our study shows that inhibiting autophagy could improve the chemoresistance and enhanced sensitivity of gastric cancer cells to DDP and provide a rationale for the administration of cisplatin combined with CQ for treating patients with gastric cancer.

[Hereditary gastric cancer: Challenges for the pathologist in 2020]. / Les cancers gastriques héréditaires: rôle du pathologiste en 2020.

Gastric cancer is the third most common cancer worldwide. The majority of gastric cancers are sporadic but familial clustering is seen in more than 10% of cases. This manuscript is divided into two parts. The first part is dedicated to the non-syndromic hereditary gastric cancer, particularly the hereditary diffuse gastric cancer (HDGC) and other gastric polyposes including the recently described GAPPS (Gastric adenocarcinoma and proximal polyposis of the stomach). The second part concerns the syndromic gastric cancer, namely the HNPCC syndrome (Hereditary Non Polyposis Colorectal Cancer) occurring as part of a genetic predisposition syndrome to cancer. Recent advances in oncogenetics and next generation sequencing technology have enabled the identification of new entities. This enhancement in knowledge regarding inherited syndromes predisposing to gastric cancer has consequently improved the management of patients and their families. In this context, pathologists play a major role in identifying particular morphologic entities prompting genetic investigation. The aim of this manuscript is to provide an update on the current knowledge about hereditary gastric cancer.

MiR-129-5p suppresses gastric cancer cell invasion and proliferation by inhibiting COL1A1.

Gastric cancer (GC) is one of the most lethal cancers worldwide. In this study, we aimed to explore the role of miR-129-5p, a newly identified miR-129 member, in GC cells as well as the potential mechanism of action. The results of reverse transcription - qualitative polymerase chain reaction (RT-qPCR) and Western Blot showed that miR-129 was downregulated in GC cells compared with normal ones. Using MTT, colony formation, wound healing assay, and a Transwell assay, we evaluated the proliferation, migration, and invasion abilities of transfected cells, and confirmed miR-129-5p as a tumor suppressor in GC. After a microarray analysis comparing different gene expressions in miR-129-5p transfected SGC-7901 cells, COL1A1 was selected for biggest fold-change and potential target of miR-129-5p predicted by TargetScan. Measured by RT-qPCR and Western blot, COL1A1 turned out to be upregulated in GC tissues and cells. We further confirmed the targeting relationship between miR-129-5p and COL1A1 by dual luciferase assay. By manipulating the expression of COL1A1 in SGC-7901 cells, cell proliferation, migration, and invasion were examined and the tumor-promoting function of COL1A1 was validated. Moreover, co-transfection of miR-129-5p mimics and COL1A1 attenuated the tumor-promoting effects induced by a single-transfection of COL1A1, and miR-129-5p inhibitor counteracted the tumor-suppressing effects of COL1A1 siRNA. Collectively, the data demonstrate the important functions of the miR-129-5p-COL1A1 axis in GC: miR-129-5p suppresses GC cell proliferation, migration, and invasion, by selectively inhibiting COL1A1. This study provides new therapeutic targets for the clinical treatment of GC.

[Lymphedema of the lower limbs: Initial manifestation of gastric linitis plastica]. / Lymphœdème des membres inférieurs révélant une linite gastrique.

BACKGROUND: Primary lymphedemas are constitutional abnormalities of the lymphatic system. Secondary lymphedemas occur after damage to the lymphatic system, mainly after cancer treatments or tumour mass compression. There are many other causes, including filariasis, which is nonetheless very rare in France. PATIENTS AND METHODS: A 52-year-old man presented with a two-month history of increased size of the left leg. He was asymptomatic and in good general condition. Clinical examination revealed non-pitting lymphedema and ipsilateral hydrocele without loco-regional compressive lymph node. Initial extensive explorations were unremarkable. Lymphoscintigraphy revealed low tracer fixation in the left leg. The symptoms continued to worsen, with exacerbation and bilateralization of the lymphedema. Two months later, axillary lymph nodes appeared corresponding to metastasis from a signet-ring cell carcinoma. Despite two lines of chemotherapy, the patient died 8 months later due to multiple metastatic disease. DISCUSSION: Our case is remarkable because the lymphedema was not related to extrinsic compression and was the first symptom of gastric cancer. In the absence of compression, endo-lymphatic micro-metastases could constitute the causative process. Acquired lymphedema of the lower limbs must be recognized as a potential early symptom of gastric carcinoma and should therefore prompt further investigations.

Transcript level of AKR1C3 is down-regulated in gastric cancer.

Steroid hormones have been shown to play a role in gastric carcinogenesis. Large amounts of steroid hormones are locally produced in the peripheral tissues of both genders. Type 5 of 17ß-hydroxysteroid dehydrogenase, encoded by the AKR1C3 gene, plays a pivotal role in both androgen and estrogen metabolism, and its expression was found to be deregulated in different cancers. In this study we measured AKR1C3 transcript and protein levels in nontumoral and primary tumoral gastric tissues, and evaluated their association with some clinicopathological features of gastric cancer (GC). We found decreased levels of AKR1C3 transcript (p < 0.0001) and protein (p = 0.0021) in GC tissues compared with the adjacent, apparently histopathologically normal, mucosa. Lower levels of AKR1C3 transcript were observed in diffuse and intestinal types of GC, whereas AKR1C3 protein levels were decreased in tumors with multisite localization, in diffuse histological type, T3, T4, and G3 grades. We also determined the effect of the histone deacetylase inhibitor sodium butyrate (NaBu) on AKR1C3 expression in EPG 85-257 and HGC-27 GC cell lines. We found that NaBu elevates the levels of both AKR1C3 transcript and protein in the cell lines we investigated. Together, our results suggest that decreased expression of AKR1C3 may be involved in development of GC and can be restored by NaBu.

[Hereditary gastric cancer syndromes and their association with specific histological subtypes]. / Prédispositions génétiques au cancer gastrique et leur association au type histologique.

About 5% of gastric cancers are associated with hereditary cancer syndromes. Histology is paramount in this context, as major susceptibility genes are associated with specific subtypes. Germline pathogenic variants in CDH1 and CTNNA1 cause Hereditary Diffuse Gastric Cancer (HDGC). Major advances have been made in the past ten years regarding HDGC. Penetrance estimates for diffuse cancer are now lower than previously thought, at 30-40%. Surveillance upper gastrointestinal endoscopy is now an acceptable alternative to prophylactic total gastrectomy. Indeed, its sensitivity in detecting advanced disease is satisfactory assuming it is performed by an expert and according to a specific protocol. The risk of intestinal-type gastric cancer is increased in patients with Lynch syndrome, although it is much lower than the risk of colorectal and endometrial cancer. Intestinal-type gastric cancers are also observed in excess in patients with hereditary polyposis, the main one being APC-associated familial adenomatous polyposis. The main and most clinically relevant manifestations in patients with polyposes remain colorectal and duodenal polyps and carcinomas, well ahead of gastric cancer. Finally, recent data point towards increased gastric cancer risk in hereditary breast and ovarian cancer.

[Perioperative treatment for resectable esogastric adenocarcinoma]. / Traitements péri-opératoires des adénocarcinomes œsogastriques localisés.

Gastric cancer is the 6th most common cancer in the world. Gastric adenocarcinomas can be divided into two groups: gastroesophageal junction adenocarcinomas and distal gastric adenocarcinomas, with different risk factors and potentially different therapeutic strategies. Therapeutic strategy for esogastric adenocarcinoma is multimodal. Gastric adenocarcinomas are managed with surgery and peri-operative chemotherapy. Gastroesophageal junction adenocarcinomas can either be treated surgically after neoadjuvant chemoradiotherapy or in the same way than gastric adenocarcinomas. There is currently no evidence of superiority of either treatment strategy. Recently, nivolumab has been validated as an adjuvant therapy for patients with esophageal cancer who received preoperative chemoradiotherapy and had residual tumor on the surgical specimen. In the absence of preoperative treatment, adjuvant chemoradiotherapy or chemotherapy should be discussed on a patient-by-patient basis. Currently, there is not indication for targeted therapies, nor for adapting postoperative treatment according to the response to preoperative treatment. The only validated indication for immunotherapy is as adjuvant treatment of esophageal cancer, but many studies are ongoing and may change practices in the future. The objective of this review is to synthesize the literature concerning the management of localized esogastric adenocarcinoma.

[Immunotherapy in advanced gastric cancer]. / Immunothérapie dans le traitement du cancer gastrique métastatique.

Metastatic gastroesophageal adenocarcinoma is a disease with a poor prognosis whose survival did not exceed twelve months until recently. Long limited to conventional cytotoxic chemotherapy protocols, the therapeutic arsenal has been expanded in recent years with the advent of new molecules. In this evolving therapeutic landscape, immunotherapy has also been developed in metastatic gastric cancer. After initial therapeutic trials with mixed or even negative results, immunotherapy was able to make a breakthrough with the checkmate 649 phase III trial demonstrating a significant survival improvement by adding nivolumab to a first-line chemotherapy by XELOX or FOLFOX. The survival benefit provided by nivolumab was greater for patients with tumor CPS≥5 (or even ≥10), whereas it was almost inexistant for tumor CPS<5 (or even<10). Based on this study, a UE approval was obtained from EMA for tumors with a CPS≥5. For HER2-positive metastatic gastric cancer, promising results have been obtained by combination of chemotherapy with anti-HER2 and immunotherapy, and these therapeutic approaches are currently assessed in phase III trials. The variation in the therapeutic response obtained by immunotherapy supposes the existence of molecular subgroups more or less sensitive to these immune checkpoint inhibitors. Some biomarkers have been identified as predictors of response to immunotherapy, such as microsatellite instability, which is probably the most robust of them, but also tumor mutational burden, lymphoplasmacytic infiltration, or EBV tumor positive.

Unrecognized digestive toxicities of radiation therapy.

The aim of this article is to review unrecognized toxicities resulting from radiation therapy of digestive neoplasms. Due to their precocious occurrence, acute toxicities are well-known by radiation oncologist, and their treatment well-established. Thus, acute toxicities will not be described in this review. We will focus on incidence, diagnosis, and management of late and uncommon toxicities occurring in the digestive tract and digestive organs. Prevention, by respecting healthy tissues constraints, is the main tool to reduce incidence of those rare complications. Nonetheless, once installed, late toxicities remain a major burden in terms of quality of life and can even be life threatening. Hence, information and education about their diagnosis and management is important.

Efficacy and safety of trastuzumab in combination with oxaliplatin and fluorouracil-based chemotherapy for patients with HER2-positive metastatic gastric and gastro-oesophageal junction adenocarcinoma patients: a retrospective study.

BACKGROUND: Trastuzumab with 5-fluorouracil (5-FU) and cisplatin offers prolonged survival in patients with HER2-overexpressing advanced gastric cancer (AGC) and advanced gastro-oesophageal junction cancer (AGOJ). Oxaliplatin in combination with intravenous 5-FU plus leucovorin (LV; modified [m]FOLFOX6) or capecitabine (XELOX) improves tolerability compared with 5-FU/cisplatin regimen. There are few data available on the efficacy and safety of trastuzumab-oxaliplatin-based chemotherapy in previously untreated HER2-positive AGC and AGOJ patients. METHODS: Clinical data were retrospectively analysed in patients receiving trastuzumab plus mFOLFOX6 or XELOX as first-line therapy between July 2009 and December 2012. Eligible patients had histologically proven AGC or AGOJ, HER2 overexpression, and no prior chemotherapy for metastatic disease. RESULTS: Thirty-four patients met the eligibility criteria. Median age was 63 years, 79% of patients had ECOG PS score of 0-1, and all had metastatic disease. Median duration of treatment was 7.5 months. Overall response rate was 41% (95% CI: 25-56). Median progression-free survival and overall survival were 9.0 months (95% CI: 5.6-12) and 17.3 months (95% CI: 13.5-32.3), respectively. Tolerability was acceptable. The most frequent grade 3-4 toxicities were neutropenia (8.8%) and neuropathy (17.6%). CONCLUSION: mFOLFOX6-trastuzumab combination is an efficient regimen with an acceptable safety profile for AGC and AGOJ patients. These results warrant further prospective study.