Sustained Clinical Complete Response after Discontinuation of Trastuzumab-deruxetecan Due to Interstitial Pneumonia for HER2-positive Gastric adenocarcinoma with Enteroblastic Differentiation (GAED): A Case Report.

Trastuzumab deruxtecan (T-DXd) has demonstrated remarkable efficacy as a third- or later-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric and gastroesophageal junction adenocarcinomas. However, it may cause pneumonitis, and its efficacy in rare histologies such as gastric adenocarcinoma with enteroblastic differentiation (GAED) remains unclear. A 74-year-old woman with unresectable HER2-positive GAED and lung metastasis received T-DXd as a fifth-line chemotherapy. Treatment was discontinued after 15 cycles owing to drug-induced pneumonitis; however, the patient achieved a sustained complete response for 14 months without subsequent chemotherapy or the exacerbation of pneumonitis. T-DXd was effective in HER2-positive GAED.

Satellite double-stranded RNA induces mesenchymal transition in pancreatic cancer by regulating alternative splicing.

Human satellite II (HSATII), composed of tandem repeats in pericentromeric regions, is aberrantly transcribed in epithelial cancers, particularly pancreatic cancer. Dysregulation of repetitive elements in cancer tissues can facilitate incidental dsRNA formation; however, it remains controversial whether dsRNAs play tumor-promoting or tumor-suppressing roles during cancer progression. Therefore, we focused on the double-stranded formation of HSATII RNA and explored its molecular function. The overexpression of double-stranded HSATII (dsHSATII) RNA promoted mesenchymal-like morphological changes and enhanced the invasiveness of pancreatic cancer cells. We identified an RNA-binding protein, spermatid perinuclear RNA-binding protein (STRBP), which preferentially binds to dsHSATII RNA rather than single-stranded HSATII RNA. The mesenchymal transition of dsHSATII-expressing cells was rescued by STRBP overexpression. Mechanistically, STRBP is involved in the alternative splicing of genes associated with epithelial-mesenchymal transition (EMT). We also confirmed that isoform switching of CLSTN1, driven by dsHSATII overexpression or STRBP depletion, induced EMT-like morphological changes. These findings reveal a novel tumor-promoting function of dsHSATII RNA, inducing EMT-like changes and cell invasiveness, thus enhancing our understanding of the biological significance of aberrant expression of satellite arrays in malignant tumors.

Brown slits for colorectal adenoma crypts on conventional magnifying endoscopy with narrow band imaging using the X1 system.

BACKGROUND: Accurate diagnosis of colorectal premalignant polyps, including adenomas, is vital in clinical practice. AIM: To investigate the diagnostic yields of novel findings of brown slits for adenomas. METHODS: Patients who underwent colonoscopy at the Toyoshima Endoscopy Clinic were enrolled. Polyps sized ≥ 5 mm suspected of adenomas or clinically significant serrated polyps were included in the study. We defined the surface structures of colorectal polyps, which were brown curves inside and along the tubular glands identified using a combination of a new X1 system (Olympus Corporation) and a conventional magnifying colonoscope with non-staining narrow band imaging (NBI), as brown slits. The brown slits corresponded to slit-like lumens on endocytoscopy and histological crypt openings of an adenoma. We evaluated the diagnostic performance of brown slits for adenoma. RESULTS: A total of 108 Lesions from 62 patients were eligible. The average age was 60.4 years and 41.9% were male. The mean polyp size was 7.45 ± 2.83 mm. Fifty-seven lesions were positive for brown slits. Histopathological diagnosis comprised 59 low-grade tubular adenomas, 16 sessile serrated lesions, and 33 hyperplastic polyps. Among 59 adenomas, 56 (94.9%) were positive for brown slits. Among 16 sessile serrated lesions, 0 (0%) was positive for brown slits. Among 33 hyperplastic polyps, 1 (3.0%) was positive for brown slits. The sensitivity, specificity, and accuracy of brown slits for adenoma were 94.9%, 98.0%, and 96.3%, respectively. The positive predictive value and negative predictive value of brown slits for adenoma were also excellent for 98.2%, and 94.1%, respectively. CONCLUSION: Brown slits on conventional magnifying endoscopy with non-staining NBI using the X1 system were useful for diagnosing colorectal adenoma. The new endoscopy system could be examined using new standards.

Texture and color enhancement imaging in magnifying endoscopic evaluation of colorectal adenomas.

BACKGROUND: Olympus Corporation has developed texture and color enhancement imaging (TXI) as a novel image-enhancing endoscopic technique. AIM: To investigate the effectiveness of TXI in identifying colorectal adenomas using magnifying observation. METHODS: Colorectal adenomas were observed by magnified endoscopy using white light imaging (WLI), TXI, narrow band imaging (NBI), and chromoendoscopy (CE). This study adopted mode 1 of TXI. Adenomas were confirmed by histological examination. TXI visibility was compared with the visibility of WLI, NBI, and CE for tumor margin, and vessel and surface patterns of the Japan NBI expert team (JNET) classification. Three expert endoscopists and three non-expert endoscopists evaluated the visibility scores, which were classified as 1, 2, 3, and 4. RESULTS: Sixty-one consecutive adenomas were evaluated. The visibility score for tumor margin of TXI (3.47 ± 0.79) was significantly higher than that of WLI (2.86 ± 1.02, P < 0.001), but lower than that of NBI (3.76 ± 0.52, P < 0.001), regardless of the endoscopist's expertise. TXI (3.05 ± 0.79) had a higher visibility score for the vessel pattern of JNET classification than WLI (2.17 ± 0.90, P < 0.001) and CE (2.47 ± 0.87, P < 0.001), but lower visibility score than NBI (3.79 ± 0.47, P < 0.001), regardless of the experience of endoscopists. For the visibility score for the surface pattern of JNET classification, TXI (2.89 ± 0.85) was superior to WLI (1.95 ± 0.79, P < 0.01) and CE (2.75 ± 0.90, P = 0.002), but inferior to NBI (3.67 ± 0.55, P < 0.001). CONCLUSION: TXI provided higher visibility than WLI, lower than NBI, and comparable to or higher than CE in the magnified observation of colorectal adenomas.

Consistency between the endoscopic Kyoto classification and pathological updated Sydney system for gastritis: A cross-sectional study.

BACKGROUND: Two methods are used to evaluate gastritis: the updated Sydney system (USS) with pathology and Kyoto classification, a new endoscopy-based diagnostic criterion for which evidence is accumulating. However, the consistency of their results is unclear. This study investigated the consistency of their results. METHODS: Patients who underwent esophagogastroduodenoscopy and were evaluated for Helicobacter pylori infection for the first time were eligible. The association between corpus and antral USS scores (neutrophil activity, chronic inflammation, atrophy, and intestinal metaplasia) and Kyoto classification scores (atrophy, intestinal metaplasia, enlarged folds, nodularity, and diffuse redness) was assessed. RESULTS: Seven-hundred-seventeen patients (mean age, 49.2 years; female sex, 57.9%; 450 H. pylori-positive and 267 H. pylori-negative patients) were enrolled. All endoscopic gastritis cases in the Kyoto classification were associated with high corpus and antral USS scores for neutrophil activity and chronic inflammation. A subanalysis was performed for H. pylori-positive patients. Regarding atrophy and intestinal metaplasia, endoscopic findings were associated with USS scores. Enlarged folds, nodularity, and diffuse redness were associated with high corpus USS scores for neutrophil activity and chronic inflammation, but with low antral USS scores for atrophy and intestinal metaplasia. The Kyoto classification scores were also associated with the pathological topographic distribution of neutrophil activity and intestinal metaplasia. CONCLUSIONS: Among H. pylori-positive individuals, endoscopic and pathological diagnoses were consistent with atrophy and intestinal metaplasia. Enlarged folds, nodularity, and diffuse redness were associated with pathological inflammation (neutrophil activity and chronic inflammation) of the corpus; however, they were inversely associated with pathological atrophy and intestinal metaplasia. The endoscopy-based Kyoto classification of gastritis partially reflects pathology.

Clinical usefulness of a deep learning-based system as the first screening on small-bowel capsule endoscopy reading.

BACKGROUND AND AIM: To examine whether our convolutional neural network (CNN) system based on deep learning can reduce the reading time of endoscopists without oversight of abnormalities in the capsule-endoscopy reading process. METHODS: Twenty videos of the entire small-bowel capsule endoscopy procedure were prepared, each of which included 0-5 lesions of small-bowel mucosal breaks (erosions or ulcerations). At another institute, two reading processes were compared: (A) endoscopist-alone readings and (B) endoscopist readings after the first screening by the proposed CNN. In process B, endoscopists read only images detected by CNN. Two experts and four trainees independently read 20 videos each (10 for process A and 10 for process B). Outcomes were reading time and detection rate of mucosal breaks by endoscopists. Gold standard was findings at the original institute by two experts. RESULTS: Mean reading time of small-bowel sections by endoscopists was significantly shorter during process B (expert, 3.1 min; trainee, 5.2 min) compared to process A (expert, 12.2 min; trainee, 20.7 min) (P < 0.001). For 37 mucosal breaks, detection rate by endoscopists did not significantly decrease in process B (expert, 87%; trainee, 55%) compared to process A (expert, 84%; trainee, 47%). Experts detected all eight large lesions (>5 mm), but trainees could not, even when supported by the CNN. CONCLUSIONS: Our CNN-based system for capsule endoscopy videos reduced the reading time of endoscopists without decreasing the detection rate of mucosal breaks. However, the reading level of endoscopists should be considered when using the system.

Detection of circulating colorectal cancer cells by a custom microfluid system before and after endoscopic metallic stent placement.

Although the detection of circulating tumor cells (CTCs) should be crucial for future personalized medicine, no efficient and flexible methods have been established. The current study established a polymeric custom-made chip for capturing CTCs with a high efficiency and flexibility. As an example of clinical application, the effects of self-expandable metallic stent (SEMS) placement on the release of cancer cells into the blood of patients with colorectal cancer and bowel obstruction were analyzed. This was assessed as the placement of SEMS may cause mechanical damage and physical force to malignant tissue, increasing the risk of cancer cell release into the bloodstream. The present study examined the number of CTCs using a custom-made chip, before, at 24 h after and at 4 days after SEMS placement in patients with colorectal cancer. The results revealed that, among the 13 patients examined, the number of CTCs was increased in three cases at 24 h after SEMS placement. However, this increase was temporary. The number of CTCs also decreased at 4 days after stent placement in most cases. The CTC chip of the current study detected the number of CD133-positive cancer stem-like cells, which did not change, even in the patient whose total number of CTCs temporarily increased. The results indicated that this custom-made microfluid system can efficiently and flexibly detect CTCs, demonstrating its potential for obtaining information during the management of patients with cancer.

Expression of circular RNA CDR1­AS in colon cancer cells increases cell surface PD­L1 protein levels.

The expression of CDR1­AS, a representative circular RNA, is closely linked with poor prognosis in gastrointestinal cancers, such as colon, liver, and pancreatic cancers. Although it is well known that CDR1­AS antagonizes microRNA­7 function through its sequence similarities in the brain, its biological function and link with the malignant potential of cancer cells remain unclear, partly due to the difficulties of ectopic expression of circular RNAs. In the present study, SW620, a colon cancer cell line that stably expresses CDR1­AS RNA circularized, was established using the laccase 2 gene cassette, and its biological function associated with malignant behavior was determined. In contrast to previous studies, cell growth or invasion ability was not altered by CDR1­AS expression. However, the expression levels of CMTM4 and CMTM6, which were recently recognized as critical regulators of PD­L1 protein expression at the cell surface, were significantly increased. Accordingly, the cell surface PD­L1 protein levels were increased in CDR1­AS­expressing cells. Notably, the effects were not canceled out by overexpressing microRNA­7, indicating that the increase in cell surface PD­L1 in CDR1­AS­expressing cells was not dependent on microRNA­7 function. These results indicated that expression of this circular RNA in cancer cells may lead to poor prognosis by increasing cell surface PD­L1 levels through microRNA­7­independent mechanisms.

A new method for insertion of long intestinal tube for small bowel obstruction: Nonendoscopic over-the-wire method via short nasogastric tube.

It is often difficult to insert a long intestinal tube (LT) in patients with small bowel obstruction (SBO). We developed a novel technique for inserting an LT without endoscopy called nonendoscopic over-the-wire method via short nasogastric tube (NEWSt). We evaluated the efficacy and safety of NEWSt.We performed a retrospective study of patients who underwent LT insertion for SBO without any indications of strangulation with either NEWSt (n = 16) or endoscopy (n = 17) between November 2011 and February 2015 at our hospital. Univariate analysis was used to assess the success rate of LT placement beyond the duodenojejunal flexure, time required for the procedure, clinical outcomes, and adverse events.The success rate was 100% in both groups. Procedure time was numerically, but not statistically, shorter in the NEWSt group compared with the endoscopy group (24 ±â€Š13 vs 30 ±â€Š13 min; P = 0.174). There were no statistically significant differences between the 2 groups in terms of surgery rate (31% vs 12%; P = 0.225), fasting period (11.3 ±â€Š6.3 vs 9.9 ±â€Š4.5 days; P = 0.482), hospital stay (26.4 ±â€Š22.1 vs 18.7 ±â€Š7.0 days; P = 0.194), and recurrence rate (19% vs 24%; P = 1.0). No serious adverse event was observed in the NEWSt group, whereas serious aspiration pneumonia was observed in 2 patients after LT insertion in the endoscopy group.Without endoscopy, NEWSt enabled the high success rate and the short procedure time for the LT insertion. Prospective, randomized controlled trials are needed.

The death effector domain-containing DEDD forms a complex with Akt and Hsp90, and supports their stability.

Insulin secretion and glucose transport are the major mechanisms to balance glucose homeostasis. Recently, we found that the death effector domain-containing DEDD inhibits cyclin-dependent kinase-1 (Cdk1) function, thereby preventing Cdk1-dependent inhibitory phosphorylation of S6 kinase-1 (S6K1), downstream of phosphatidylinositol 3-kinase (PI3K), which overall results in maintenance of S6K1 activity. Here we newly show that DEDD forms a complex with Akt and heat-shock protein 90 (Hsp90), and supports the stability of both proteins. Hence, in DEDD(-/-) mice, Akt protein levels are diminished in skeletal muscles and adipose tissues, which interferes with the translocation of glucose-transporter 4 (GLUT4) upon insulin stimulation, leading to inefficient incorporation of glucose in these organs. Interestingly, as for the activation of S6K1, suppression of Cdk1 is involved in the stabilization of Akt protein by DEDD, since diminishment of Cdk1 in DEDD(-/-) cells via siRNA expression or treatment with a Cdk1-inhibitor, increases both Akt and Hsp90 protein levels. Such multifaceted involvement of DEDD in glucose homeostasis by supporting both insulin secretion (via maintenance of S6K1 activity) and glucose uptake (via stabilizing Akt protein), may suggest an association of DEDD-deficiency with the pathogenesis of type 2 diabetes mellitus.