Impact of Oophorectomy on Survival and Improving Nutritional Status in Ovarian Metastasis from Colorectal Adenocarcinoma.

INTRODUCTION: Ovarian metastasis of colorectal cancer is known to have a poor prognosis. This study aimed to elucidate the characteristics of patients who underwent oophorectomy for ovarian metastasis from colorectal cancer. METHODS: This retrospective study included 16 patients who underwent oophorectomy for colorectal cancer metastasis to the ovary from January 2004 to December 2017. Improvement in patient's symptoms and pre- and postoperative changes in various nutritional and inflammatory indicators were assessed. Survival analysis and identification of prognostic factors were conducted with a median follow-up of 40.7 (5-109) months. RESULTS: Of 16 patients, 12 had (75%) synchronous and 4 (25%) had metachronous metastasis. Fourteen patients were symptomatic but symptoms resolved postoperatively. Thirteen patients (81.3%) had ascites and 5 (31.3%) had pleural effusion on preoperative computed tomography that disappeared after surgery in all cases. The median value of prognostic nutritional factor was significantly increased postoperatively (36.0 [preoperatively] vs. 47.5, p < 0.0001). The median (interquartile range) values for lymphocyte-C-reactive protein ratio were 715.2 (110-2,607) preoperatively and 6,095.2 (1,612.3-14,431.8) postoperatively (p = 0.0214). The median survival of the entire cohort was 60.4 months. The 3-year survival rates for R0 + R1 and R2 cases were 83% and 24% (p = 0.018), respectively. Univariate analysis showed that R2 resection and low postoperative lymphocyte-C-reactive protein ratio were associated with poor prognosis. CONCLUSIONS: Oophorectomy for ovarian metastasis from colorectal cancers was safely performed. It improved the patients' symptoms and nutritional status and may result in improved prognosis.

Short-term outcomes of laparoscopic and robotic distal gastrectomy for gastric cancer: Real-world evidence from a large-scale inpatient database in Japan.

BACKGROUND AND OBJECTIVES: Robotic distal gastrectomy (RDG) has been widely performed throughout Japan since it became insured in 2018. This study aimed to evaluate the short-term outcomes of RDG and laparoscopic distal gastrectomy (LDG) for gastric cancer using real-world data. METHODS: A total of 4161 patients who underwent LDG (n = 3173) or RDG (n = 988) for gastric cancer between April 2018 and October 2022 were identified through the Japanese Diagnosis Procedure Combination Database, which covers 42 national university hospitals. The primary outcome was postoperative in-hospital mortality rate. The secondary outcomes were postoperative complication rates, time to diet resumption, and postoperative length of stay (LOS). RESULTS: In-hospital mortality and postoperative complication rates in the RDG group were comparable with those in the LDG group (0.1% vs. 0.0%, p = 1.000, and 8.7% vs. 8.2%, p = 0.693, respectively). RDG was associated with a longer duration of anesthesia (325 vs. 262 min, p < 0.001), similar time to diet resumption (3 vs. 3 days, p < 0.001), and shorter postoperative LOS (10 vs. 11 days, p < 0.001) compared with LDG. CONCLUSIONS: RDG was performed safely and provided shorter postoperative LOS, since it became covered by insurance in Japan.

ARL4C is associated with epithelial-to-mesenchymal transition in colorectal cancer.

BACKGROUND: ADP-ribosylation factor-like protein 4 C (ARL4C) is a member of the ARF small GTP-binding protein subfamily. The ARL4C gene is highly expressed in colorectal cancer (CRC). ARL4C protein promotes cell motility, invasion, and proliferation. METHODS: We investigated the characteristics of ARL4C by comparing its expression at the invasion front and relationships with clinicopathological data using RNAscope, a highly sensitive RNA in situ method. RESULTS: In all cases, ARL4C expression was observed in cancer stromal cells and cancer cells. ARL4C expression in cancer cells was localized at the invasion front. In cancer stromal cells, ARL4C expression was significantly stronger in cases with high-grade tumor budding than in cases with low-grade tumor budding (P = 0.0002). Additionally, ARL4C expression was significantly increased in patients with high histological grade compared with those with low histological grade (P = 0.0227). Furthermore, ARL4C expression was significantly stronger in lesions with the epithelial-to-mesenchymal transition (EMT) phenotype compared with the non-EMT phenotype (P = 0.0289). In CRC cells, ARL4C expression was significantly stronger in cells that had the EMT phenotype compared with those with a non-EMT phenotype (P = 0.0366). ARL4C expression was significantly higher in cancer stromal cells than in CRC cells (P < 0.0001). CONCLUSION: Our analysis reinforces the possibility that ARL4C expression worsens the prognosis of patients with CRC. Further elucidation of the function of ARL4C is desired.

Lymphocyte-to-Monocyte Ratio Is a Predictive Biomarker of Response to Treatment with Nivolumab for Gastric Cancer.

INTRODUCTION: Patients with unresectable or recurrent gastric cancer who have an objective response (OR) to nivolumab monotherapy are expected to have a good long-term prognosis. However, the OR rate for nivolumab treatment is low at 11%, and there is a need for biomarkers to predict the treatment response. This study aimed to analyze the significance of systemic inflammation-related variables and clinicopathologic characteristics as predictive markers of response to nivolumab monotherapy in patients with advanced gastric cancer. METHODS: In this retrospective cohort study, we enrolled 71 consecutive patients who received nivolumab monotherapy for unresectable or recurrent gastric cancer. Receiver operating characteristic curve analysis was performed to determine the cutoff values of systemic inflammation-related variables, predictors of treatment response, and other prognostic factors related to nivolumab therapy. We focused on systemic inflammation-related variables measured before nivolumab induction and 2 weeks after its first administration and performed multivariate analysis to assess whether they could be used as prognostic factors. RESULTS: Multivariate analysis revealed that a lymphocyte-to-monocyte ratio (LMR) of ≤3.28 after 2 weeks of initial nivolumab treatment (2wLMR) is a statistically significant predictor of treatment response (p = 0.012). The progression-free survival (PFS) rate of patients with liver metastasis was significantly worse than that of the other patients (1-year PFS: 0.0 vs. 24.4%, respectively; p = 0.005). The overall survival (OS) of patients with a low 2wLMR was significantly longer than that in patients with a high 2wLMR (1-year OS: 37.4 vs. 18.9%, respectively; p = 0.022). CONCLUSIONS: Thus, the 2wLMR could be a useful biomarker to predict response to nivolumab treatment and the prognosis of unresectable and recurrent gastric cancer.

Impact of barometric pressure on adhesive small bowel obstruction: a retrospective study.

BACKGROUND: Adhesive small bowel obstruction (ASBO) is one of the most common causes of postoperative morbidity. According to Boyle's law, decreased barometric pressure expands the volume of intestinal gas. We aimed to elucidate the relationship between barometric pressure and ASBO. METHODS: We divided 215 admissions of 120 patients with ASBO into three groups: the fasting group, which responded to fasting (n = 51); the decompression group, which was successfully treated with gastrointestinal decompression (n = 104); and the surgery group which required emergency or elective surgery to treat ASBO (n = 60). We compared and examined clinical backgrounds, findings on admission, and barometric pressure during the peri-onset period (29 days: from 14 days before to 14 days after the onset of ASBO). RESULTS: There were significant differences among the three groups regarding gender, history of ASBO, hospital length of stay, and barometric pressure on the onset day of ASBO. Barometric pressure on the onset day was significantly higher in the fasting group than in the decompression group (p = 0.005). During pre-onset day 5 to post-onset day 2, fluctuations in the barometric pressure in the fasting and decompression groups showed reciprocal changes with a symmetrical axis overlapping the median barometric pressure in Matsumoto City; the fluctuations tapered over time after onset. In the fasting group, the barometric pressure on the onset day was significantly higher than that on pre-onset days 14, 11, 7, 4, 3, and 2; post-onset days 3 and 10; and the median pressure in Matsumoto City. Conversely, in the decompression group, the barometric pressure on the onset day was lower than that on pre-onset days 14, 5-2; post-onset days 1, 2, 7, 8, 11, 13, and 14; and the median pressure in Matsumoto City. In the surgery group, the barometric pressure on the onset day was equivalent to those on the other days. CONCLUSIONS: ASBO with response to conservative treatment is vulnerable to barometric pressure. Additionally, ASBO that is successfully treated with fasting and decompression is associated with a different barometric pressure on the onset day and reciprocal fluctuations in the barometric pressure during the peri-onset period.

Fascin1 suppresses RIG-I-like receptor signaling and interferon-ß production by associating with IκB kinase ϵ (IKKϵ) in colon cancer.

Fascin1 is an actin-bundling protein involved in cancer cell migration and has recently been shown also to have roles in virus-mediated immune cell responses. Because viral infection has been shown to activate immune cells and to induce interferon-ß expression in human cancer cells, we evaluated the effects of fascin1 on virus-dependent signaling via the membrane- and actin-associated protein RIG-I (retinoic acid-inducible gene I) in colon cancer cells. We knocked down fascin1 expression with shRNA retrovirally transduced into a DLD-1 colon cancer and L929 fibroblast-like cell lines and used luciferase reporter assays and co-immunoprecipitation to identify fascin1 targets. We found that intracellular poly(I·C) transfection to mimic viral infection enhances the RIG-I/MDA5 (melanoma differentiation-associated gene 5)-mediated dimerization of interferon regulatory factor 3 (IRF-3). The transfection also significantly increased the expression levels of IRF-7, interferon-ß, and interferon-inducible cytokine IP-10 in fascin1-deleted cells compared with controls while significantly suppressing cell growth, migration, and invasion. We also found that fascin1 constitutively interacts with IκB kinase ϵ (IKKϵ) in the RIG-I signaling pathway. In summary, we have identified fascin1 as a suppressor of the RIG-I signaling pathway associating with IκB kinase ϵ in DLD-1 colon cancer cells to suppress immune responses to viral infection.

[Two Cases of Fournier's Gangrene That Occurred during Chemotherapy for Rectal Cancer].

Two cases of Fournier's gangrene occurred during chemotherapy for advanced rectal cancer. Patients were treated using surgical debridement and antibiotic therapy. Case 1: A 66-year-old man had advanced rectal cancer with para-aortic and inguinal lymph node metastases. He received a sigmoid colostomy and chemotherapy(capecitabine, oxaliplatin, bevacizumab). Due to progression of the rectal mass, we performed radiotherapy(30 Gy)and chemotherapy(irinotecan, S-1, bevacizumab). After 14 days, he was hospitalized with a diagnosis of Fournier's gangrene with anal pain and fever. Case 2: A 63-year-old man had mucinous rectal carcinoma with sacrum invasion. He received a sigmoid colostomy and chemotherapy. Sixteen days after regorafenib therapy, as a fifth-line of chemotherapy, he was hospitalized with a diagnosis of Fournier's gangrene with hip pain, swollen perineum, and fever. There have been no reports of Fournier's gangrene occurring during chemotherapy for rectal cancer. We report 2 cases with a review of literature.

Interleukin-6 Stromal Expression is Correlated with Epithelial-Mesenchymal Transition at Tumor Budding in Colorectal Cancer.

Background. Tumor budding is a poor prognostic factor in colorectal adenocarcinoma, but the underlying mechanism remains unclear. Interleukin-6 (IL6) is one of the main cytokines produced by cancer-associated fibroblasts. IL6 is linked with cancer progression and poor prognosis by activating cancer cells and modifying the cancer microenvironment. However, little is known about the expression of IL6 in tumor budding and its association with tumor budding in colorectal adenocarcinoma. Methods. The clinicopathological and prognostic significance of IL6 in tumor budding was examined using a tissue microarray consisting of 36 patient samples of tumor budding in colorectal adenocarcinoma. IL6 mRNA was detected by RNAscope. Patients were stratified into negative and positive IL6 expression groups. Results. IL6 expression was overwhelmingly observed in cancer stroma but was negligible in cancer cells. Tumor budding grade was higher in the IL6-positive group in cancer stroma than in the IL6-negative group (P = .0161), while the IL6-positive group significantly exhibited the epithelial-mesenchymal transition phenotype compared with the IL6-negative group in cancer stroma (P = .0301). There was no significant difference in overall survival between colorectal adenocarcinoma patients in the IL6-positive and -negative groups in cancer stroma. Conclusion. Tumor budding may be affected by IL6 expression, and IL6 expression in cancer stroma at tumor budding may be an important prognostic marker.

ASC-associated inflammation promotes cecal tumorigenesis in aryl hydrocarbon receptor-deficient mice.

The aryl hydrocarbon receptor (AhR) plays a suppressive role in cecal carcinogenesis by CUL4B/AhR-mediated ubiquitylation and degradation of ß-catenin, which is activated by xenobiotics and natural ligands. AhR-deficient (AhR(-)(/-)) mice develop cecal tumors with severe inflammation. To elucidate whether the tumors develop autonomously in AhR(-/-) mice due to impaired ß-catenin degradation or in association with accelerated inflammation, we performed two kinds of experiments using germ-free (GF) AhR(-/-) mice and compound mutant mice lacking genes for AhR and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which plays an essential role in caspase-1 activation in inflammasomes. Both GF AhR(-/-) and AhR(-/-)•ASC(-/-) mice showed considerably reduced tumor development compared with that in AhR(-/-) mice albeit in a 'cancer-prone' state with aberrant ß-catenin accumulation. Blocking of the interleukin (IL)-1ß signaling pathway by treatment with a caspase-1 inhibitor, YVAD, reduced cecal tumorigenesis in AhR(-/-) mice. Signal transducers and activators of transcription 3 (STAT3) activation was detected in the cecal epithelium of the AhR(-/-) mice due to enhanced IL-6 production. An inhibitor of the STAT3 signaling pathway, AG490 suppressed the tumor formation. ASC-mediated inflammation was also found to play a critical role in tumor development in Apc(Min/+) mice, a mouse model of familial adenomatous polyposis. Collectively, these results revealed an important role of the bacteria-triggered or ASC-mediated inflammation signaling pathway in the intestinal tumorigenesis of mice and suggest a possible chemical therapeutic intervention, including AhR ligands and inhibitors of the inflammation pathway.

Goblet cell adenocarcinoma of the appendix: A case report of three cases.

INTRODUCTION AND IMPORTANCE: Appendiceal goblet cell adenocarcinoma is in 0.3-0.9 % of appendectomy specimens. There is still controversy regarding whether surgery with dissection or additional resection is necessary for goblet cell adenocarcinoma and whether adjuvant chemotherapy is practical. We present three cases of goblet cell adenocarcinomas. CASE PRESENTATION: Case 1: A 30-year-old woman was diagnosed with appendicitis and underwent appendicectomy. Histopathological evaluation revealed a malignant neoplasm with goblet-like cells and tumour infiltration into the subserosa. The patient underwent laparoscopic ileocecal resection, and the main lymph nodes at the root of the feeding vessels were removed. Case 2: A 50-year-old man was diagnosed with appendicitis and underwent appendicectomy. Histopathological evaluation revealed a malignant neoplasm with goblet-like cells; malignant cells were found at the surgical resection margins. The patient underwent laparoscopic ileocolic resection. Case 3: A 60-year-old man undergoing treatment for malignant melanoma. He was diagnosed with appendicitis associated with an appendiceal tumour, and emergency laparoscopic caecal resection was performed and diagnosed as goblet cell adenocarcinoma. We decided to prioritize treatment for malignant melanoma, and the patient is under follow-up for goblet cell adenocarcinoma and no metastasis was detected. CLINICAL DISCUSSION: We performed additional resection in two case of goblet cell adenocarcinoma. Diagnosing appendiceal goblet cell adenocarcinoma is difficult, and the prognosis of patients with positive lymph nodes is poor. Surgical treatment should be considered for the advanced stages of this disease. CONCLUSION: Goblet cell adenocarcinoma, diagnosed after appendectomy, additional resection including lymph node dissection may provide a long-term prognosis.

High expression of LGR6 is a poor prognostic factor in esophageal carcinoma.

BACKGROUND: Leucine-rich repeat-containing G-protein-coupled receptor 6 (LGR6) promotes carcinogenesis and progression in some cancer types. However, there are few reports of LGR6 expression in esophageal squamous cell carcinoma (ESCC). LGR6 expression and clinicopathological features in ESCC were investigated by RNAscope, a highly sensitive RNA in situ hybridization method. METHODS: Appropriate tumors were selected from 41 cases of ESCC from which tissue microarrays were generated, and LGR6 expression was identified by RNAscope. RESULTS: Thirty-seven patients had LGR6 expression. High LGR6 expression was observed in 17 cases and low LGR6 expression in 24 cases. LGR6 expression was significantly higher in high histological grade ESCC than in low histological grade ESCC (P = 0.0023). ESCC patients who received neoadjuvant chemotherapy had significantly higher LGR6 expression than those without neoadjuvant chemotherapy (P = 0.0109). Furthermore, high LGR6 expression showed a poorer prognosis than low LGR6 expression (log-rank test, P = 0.0365). CONCLUSIONS: LGR6 may be a prognostic factor and a potential new therapeutic target in ESCC.

Importance of intraoperative indocyanine green imaging in the management of non-occlusive mesenteric ischemia: a case report.

BACKGROUND: Non-obstructive intestinal ischemia (NOMI) is caused by intestinal vascular spasm and has a poor prognosis if not diagnosed and treated early. Indocyanine green (ICG) fluorescence imaging has been reported to be useful for the intraoperative assessment of the extent of intestinal resection required for NOMI. Few reports have described massive intestinal bleeding after conservative management of NOMI. We report a case of NOMI with massive postoperative bleeding from the site of an ICG contrast defect found before the initial surgery. CASE PRESENTATION: A 47-year-old woman with hemodialysis-dependent chronic kidney disease presented complaining of severe abdominal pain. A computed tomography scan showed portal gas and dilation of the small intestine, leading to a diagnosis of NOMI and subsequent emergency surgery. At the time of initial surgery, the contrast effect of ICG was slightly reduced, showing a granular distribution in the ascending colon to cecum (fine grain pattern) and significantly reduced in parts of the terminal ileum except around blood vessels (perivascular pattern). However, there was no obvious gross necrosis of the serosal surface, and the intestinal tract was not resected. The acute postoperative course was uneventful; however, the patient went into shock on the 24th postoperative day due to massive, small intestinal bleeding, and emergency surgery was performed. The bleeding originated from the section of the ileum that had complete loss of ICG contrast effect before the initial surgery. A right hemicolectomy with the terminal ileum resection was performed, and an ileo-transverse anastomosis was performed. The second post-operative course was uneventful. CONCLUSIONS: We report a case of delayed hemorrhage of the ileum shown to have poor blood flow on ICG imaging at the initial surgery. Intraoperative ICG fluorescence imaging is useful in assessing the degree of intestinal ischemia for NOMI. When patients with NOMI are followed up without surgery, complications such as bleeding should be noted.

Transmesenteric approach for laparoscopic endoscopic cooperative surgery for a duodenal adenoma located in the third portion of the duodenum.

We report our experience in a patient with adenoma located in the horizontal part of the duodenum, which was effectively treated with the transmesenteric laparoscopic endoscopic cooperative surgery (LECS) approach. This approach, which entails incising the mesentery of the colon, simplified laparoscopic access to the horizontal part of the duodenum, which was minimally mobilized. Thus, the bulb and descending part of the duodenum were fixed to the retroperitoneum, facilitating stable handling of the endoscope and enabled safe and effective excision of an adenoma located in the horizontal part of the duodenum. This approach enabled safe and effective excision of an adenoma located in the horizontal part of the duodenum. The advantages of this method include a secure field of view, lower probability of damage to large vessels, and minimizing the defect to the intestine caused by the incision.

Comparison of Short-term Outcomes Between Esophageal Bypass Surgery and Self-expanding Stent Insertion in Esophageal Cancer: A Propensity Score-matched Analysis Using a Large-scale Inpatient Database.

BACKGROUND: Advanced esophageal cancer is occasionally accompanied by difficulty swallowing owing to esophageal stenosis or tracheoesophageal fistula formation. Esophageal bypass surgery and stent insertion are considered feasible palliative management options. The aim of this study was to evaluate the short-term outcomes of these palliative treatments. MATERIALS AND METHODS: Patient data were obtained from a large-scale inpatient database of 42 National University Hospitals in Japan. Patients with advanced esophageal cancer who underwent esophageal bypass surgery or stent insertion between April 2016 and March 2021 were included in this study. One-to-one propensity score matching of patients who underwent bypass surgery or stent insertion was performed. The primary outcomes were time to diet resumption and length of hospital stay after surgery. The secondary outcome was the incidence of postoperative complications. RESULTS: In 43 propensity score-matched pairs, the incidence of postoperative respiratory complications was significantly higher in the bypass group than in the stent group (32.6% vs. 9.3%, P = 0.008). Postoperative length of hospital stay was longer in the bypass group than in the stent group (24 vs. 10 d, P < 0.001). Logistic regression analysis revealed that stent insertion was associated with a decreased risk of respiratory complications (odds ratio 0.077, P < 0.007). Among patients who underwent the interventions (bypass surgery or stent insertion) and subsequently underwent anticancer therapy (chemotherapy/radiotherapy) during hospitalization, the interval between the intervention and anticancer therapy was longer in the bypass group than in the stent group (25 vs. 7 d, P = 0.003). CONCLUSIONS: Esophageal stent insertion provides better short-term outcomes than bypass surgery in patients with advanced unresectable esophageal cancer.

Gastric glomus tumor resection using laparoscopic endoscopic cooperative surgery: A case report.

Gastric glomus tumors are rare submucosal mesenchymal neoplasms that are difficult to diagnose preoperatively. We present a case of a 60-year-old woman who was diagnosed with a gastric glomus tumor using endoscopic ultrasonography-guided fine-needle aspiration biopsy. The tumor was successfully resected with laparoscopic endoscopic cooperative surgery (LECS). LECS could be an effective method for the resection of gastric glomus tumors.

MEK inhibitor and anti-EGFR antibody overcome sotorasib resistance signals and enhance its antitumor effect in colorectal cancer cells.

The Kirsten rat sarcoma (KRAS) oncogene was "undruggable" until sotorasib, a KRASG12C selective inhibitor, was developed with promising efficacy. However, inhibition of mutant KRAS in colorectal cancer cells (CRC) is ineffective due to feedback activation of MEK/ERK downstream of KRAS. In this study, we screened for combination therapies of simultaneous inhibition to overcome sotorasib resistance using our previously developed Mix Culture Assay. We evaluated whether there was an additive effect of sotorasib administered alone and in combination with two or three drugs: trametinib, a MEK inhibitor, and cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody. The MAPK pathway was reactivated in KRASG12C-mutated cell lines treated with sotorasib alone. Treatment with KRAS and MEK inhibitors suppressed the reactivation of the MAPK pathway, but upregulated EGFR expression. However, the addition of cetuximab to this combination suppressed EGFR reactivation. This three-drug combination therapy resulted in significant growth inhibition in vitro and in vivo. Our data suggest that reactive feedback may play a key role in the resistance signal in CRC. Simultaneously inhibiting KRAS, MEK, and EGFR is a potentially promising strategy for patients with KRASG12C-mutated CRC.

Cetuximab Enhances the Efficacy of MRTX1133, a Novel KRASG12D Inhibitor, in Colorectal Cancer Treatment.

BACKGROUND/AIM: Kirsten Rat Sarcoma viral oncogene homolog (KRAS) has remained undruggable for decades. KRAS has predominantly been used to evaluate the applicability of anti-Epidermal Growth Factor Receptor (EGFR) antibody drugs. However, various KRAS inhibitors have recently emerged. Unfortunately, KRAS inhibitors have not been effective against colorectal cancer. Therefore, this study aimed to determine the effects of MRTX1133, a novel KRASG12D inhibitor, in combination with an anti-EGFR antibody, cetuximab, on signal transduction and cell proliferation. MATERIALS AND METHODS: The KRASG12D-mutated LS513 and KRAS wild-type CACO-2 human colon cancer cell lines were utilized. The KRASG12D mutation was stably transduced into the CACO-2 cells using a retrovirus. We evaluated the effects of the drugs using the CCK-8 assay and assessed the activity of proteins related to the MAPK pathway using western blotting. RESULTS: We demonstrated that the administration of MRTX1133, a novel KRASG12D inhibitor, to KRASG12D-mutated colorectal cancer cells led to feedback activation of the ERK pathway via EGFR activation, inducing drug resistance. Intriguingly, when MRTX1133 was used in combination with cetuximab, KRASG12D-mutant colorectal cancer growth was effectively inhibited, both in vitro and in vivo. CONCLUSION: The combination of MRTX1133 and cetuximab serves as a potential and promising therapeutic approach for colorectal cancer with KRASG12D mutation. KRASG12D is a frequent genetic mutation not only in colorectal cancer, but also in pancreatic and lung cancer, and the results of this study open new avenues for potential treatment of many cancer patients.

Hereditary diffuse gastric cancer in a Japanese family with CDH1 mutation three case reports.

BACKGROUND: Germline pathogenic variants in the E-cadherin gene CDH1 cause hereditary diffuse gastric cancer (HDGC), which is an autosomal dominant cancer syndrome, accounting for 1-3% of all gastric cancers. HDGC harboring a CDH 1 variant is extremely rare in Japan. METHOD: In this study we report the clinical courses of three cases with HDGC from a single Japanese family. RESULTS: The proband exhibited advanced and metastatic gastric cancer, and was found to have a previously reported heterozygous frameshift variant in CDH1 (NM_004360.3:c.1009_1010del:p.Ser337Phefs*12). Five at-risk relatives underwent presymptomatic molecular testing after careful genetic counseling, and three were molecularly diagnosed as positive for the variant. Esophagogastroduodenoscopy was performed in these relatives revealing abnormal small pale mucosal patches, small ulcerative lesion and no abnormal findings. Moreover, random and targeted biopsies were compatible with pathological diagnosis of HDGC in the three cases, all of which underwent total prophylactic gastrectomy. CONCLUSION: It is critical for the assessment and management of HDGC patients to be actively offered a multidisciplinary and familial-oriented approach. Notably, genetic screening in suspected individuals and familial members is a determining piece for a higher detection rate and the identification of clinical relevant mutations in both low and high-incidence gastric cancer countries.

RhoA G17E/Vav1 Signaling Induces Cancer Invasion via Matrix Metalloproteinase-9 in Gastric Cancer.

BACKGROUND: RAS homolog family member A (RhoA), a member of the Rho family of small GTPases, and Vav1, a guanine nucleotide exchange factor for Rho family GTPases, have been reported to activate pathways related to the actin cytoskeleton and regulation of cell shape, attachment, and motility. The interaction between these molecules in lymphoma is involved in malignant signaling, but its function in epithelial malignancy is unknown. Here, we investigated the malignant signal of mutant RhoA in gastric cancer and demonstrated the potential of RhoA G17E/Vav1 as a therapeutic target for diffuse gastric cancer. METHODS: The RhoA mutants R5W, G17E, and Y42C were retrovirally transduced into the gastric cancer cell line MKN74. The stably transduced cells were used for morphology, proliferation, and migration/invasion assays in vitro. MKN74 cells stably transduced with ectopic wild-type RhoA and mutant RhoA (G17E) were used in a peritoneal xenograft assay. RESULTS: The RhoA mutations G17E and Y42C induced morphological changes in MKN74. G17E induced Vav1 expression at the mRNA and protein levels and promoted the migration and invasion of MKN74. An RNA interference assay of Vav1 revealed that RhoA G17E enhanced cancer cell invasion via Vav1. Furthermore, immunoprecipitation revealed that Vav1 and RhoA G17E specifically bind and function together through matrix metalloproteinase -9. In a peritoneal xenograft model of nude mice, RhoA G17E promoted peritoneal dissemination, whereas Vav1 knockdown suppressed it. CONCLUSION: Overall, our findings indicate that RhoA G17E is associated with Vav1 and promoted cancer invasion via matrix metalloproteinase -9 in gastric cancer cells. Thus, RhoA G17E/Vav1 signaling in diffuse gastric cancer may be a useful therapeutic target.