Prognostic impact of clinical outcome after endoscopic gastroduodenal stent placement for malignant gastric outlet obstruction: a multicenter retrospective cohort study using a time-dependent analysis.

Background: Endoscopic gastroduodenal stent (GDS) placement is widely used as a safe and effective method to rapidly improve gastrointestinal symptoms of malignant gastric outlet obstruction (MGOO). While previous studies reported the utility of chemotherapy after GDS placement for prognosis improvement, they did not fully address the issue of immortal time bias. Objectives: To examine the association between prognosis and clinical course following endoscopic GDS placement, using a time-dependent analysis. Design: Multicenter retrospective cohort study. Methods: This study included 216 MGOO patients who underwent GDS placement between April 2010 and August 2020. Data of patient baseline characteristics, including age, gender, cancer type, performance status (PS), GDS type and length, GDS placement location, gastric outlet obstruction scoring system (GOOSS) score, and history of chemotherapy before GDS were collected. The clinical course following GDS placement was evaluated by GOOSS score, stent dysfunction, cholangitis, and chemotherapy. A Cox proportional hazards model was used to identify prognostic factors after GDS placement. Stent dysfunction, post-stent cholangitis, and post-stent chemotherapy were analyzed as time-dependent covariates. Results: Mean GOOSS scores before and after GDS were 0.7 and 2.4, respectively, with significant improvement after GDS placement (p < 0.001). The median survival time after GDS placement was 79 [95% confidence interval (CI): 68-103] days. In multivariate Cox proportional hazards model with time-dependent covariates, PS 0-1 [hazard ratio (HR): 0.55, 95% CI: 0.40-0.75; p < 0.001], ascites (HR: 1.45, 95% CI: 1.04-2.01; p = 0.028), metastasis (HR: 1.84, 95% CI: 1.31-2.58; p < 0.001), post-stent cholangitis (HR: 2.38, 95% CI: 1.37-4.15; p = 0.002), and post-stent chemotherapy (HR: 0.01, 95% CI: 0.002-0.10; p < 0.001) significantly affected prognosis after GDS placement. Conclusion: Post-stent cholangitis and tolerability to receive chemotherapy after GDS placement influenced prognosis in MGOO patients.

Successful second conversion surgery after trastuzumab deruxtecan for recurrent HER2-positive gastric cancer.

A 65-year-old woman with HER2-positive gastric cancer with multiple liver metastases underwent first conversion surgery of gastrectomy with D2 lymph nodes dissection and three liver metastases after combination therapy with capecitabine, cisplatin, and trastuzumab. Two years later, she experienced multiple liver metastases that were refractory to combination therapy with paclitaxel albumin-bound nanoparticles and ramucirumab. She participated in the DESTINY-Gastric01 trial and received tri-weekly trastuzumab deruxtecan as third-line treatment for 26 cycles. The recurrent lesions markedly shrank, and this effect continued for 19 months. We then performed partial hepatectomy for the one remaining lesion. No adjuvant chemotherapy was given, and she remains alive without recurrence 18 months after the second conversion surgery. Trastuzumab deruxtecan may generate a notable tumor response and subsequent conversion surgery could be a treatment option for HER2-positive stage IV gastric cancer.

Distinct chemotherapy-associated anti-cancer immunity by myeloid cells inhibition in murine pancreatic cancer models.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with an extremely poor prognosis. Chemotherapy, such as gemcitabine (GEM), is the only treatment for PDAC patients who are not suitable for radical surgical treatment; however, its anti-tumor efficacy is limited. In this study, we investigated the host immune system response in murine PDAC models undergoing GEM treatment. We found that PDAC tumor tissues were infiltrated with a substantial number of Gr-1+ myeloid cells and had relatively small numbers of CD4+ and CD8+ cells. In addition, there were increased numbers of myeloid cells expressing CD11b+ and Gr-1+ in peripheral blood. When mice with PDAC tumors in the intraperitoneal cavity or liver were treated with GEM, numbers of myeloid cells in tumor tissues and in peripheral blood decreased. In contrast, numbers of CD4+ or CD8+ cells increased. In peripheral blood, the numbers of CD8+ cells expressing interferon-gamma (IFN-γ) were higher in GEM-treated mice than in untreated mice. In addition, GEM treatment in combination with myeloid cell depletion further prolonged the survival of PDAC mice. The gene expression profile of peripheral blood in myeloid cell-depleted PDAC mice treated with GEM showed biological processes related to anti-cancer immunity, such as natural killer cell-mediated cytotoxicity, type I IFN signaling, and co-stimulatory signaling for T cell activation. Thus, in PDAC murine models, GEM treatment was associated with an immune response consistent with an anti-cancer effect, and depletion of myeloid-lineage cells played an important role in enhancing anti-cancer immunity associated with GEM treatment.

Immune Condition of Colorectal Cancer Patients Featured by Serum Chemokines and Gene Expressions of CD4+ Cells in Blood.

Background: Colorectal cancer (CRC), the most common malignancy worldwide, causes inflammation. We explored the inflammatory pathophysiology of CRC by assessing the peripheral blood parameters. Methods: The differences in gene expression profiles of whole blood cells and cell subpopulations between CRC patients and healthy controls were analyzed using DNA microarray. Serum cytokine/chemokine concentrations in CRC patients and healthy controls were measured via multiplex detection immunoassays. In addition, we explored correlations between the expression levels of certain genes of peripheral CD4+ cells and serum chemokine concentrations. Results: The gene expression profiles of peripheral CD4+ cells of CRC patients differed from those of healthy controls, but this was not true of CD8+ cells, CD14+ cells, CD15+ cells, or CD19+ cells. Serum IL-8 and eotaxin-1 levels were significantly elevated in CRC patients, and the levels substantially correlated with the expression levels of certain genes of CD4+ cells. Interestingly, the relationships between gene expression levels in peripheral CD4+ cells and serum IL-8 and eotaxin-1 levels resembled those of monocytes/macrophages, not T cells. Conclusions: Serum IL-8 and eotaxin-1 concentrations increased and were associated with changes in the gene expression of peripheral CD4+ cells in CRC patients.

Clinical features of cystatin A expression in patients with pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy known, with an extremely poor prognosis due to the lack of an efficient diagnostic scheme and no radical treatment option, except surgery. Therefore, understanding the pathophysiology of, and finding a novel biomarker to detect, PDAC should be prioritized. We observed an increase in mRNA expression of the cysteine protease inhibitor cystatin A (CSTA) in CD4+ T cells in peripheral blood cells of nine patients with PDAC, compared with the expression in seven healthy volunteers. Moreover, we confirmed significantly higher CSTA mRNA expression in a larger cohort of 41 patients with PDAC compared with that in 20 healthy volunteers. Correspondingly, the serum CSTA concentrations in 36 patients with PDAC were higher than those in 37 healthy volunteers, and this increase was correlated with PDAC clinical stage. Furthermore, the expression of CSTA and cathepsin B, which is a lysosomal cysteine protease inhibited by CSTA, was observed in tumor tissues and tumor-infiltrating immune cells in 20 surgically resected PDAC tissues by immunohistochemical staining. Expression of CSTA was detected in some tumor tissues and many tumor-infiltrating immune cells. Cathepsin B expression was also observed in most tumor tissues and tumor-infiltrating immune cells. In conclusion, CSTA and its substrate cathepsin B are involved in PDAC-related inflammation. The increment of CSTA expression in peripheral blood of patients with PDAC may have a potential role as a PDAC immunopathologic biomarker.

Lidocaine spray alone is similar to spray plus viscous solution for pharyngeal observation during transoral endoscopy: a clinical randomized trial.

Background and study aims It is important to examine the pharynx during upper gastrointestinal endoscopy. Pharyngeal anesthesia using topical lidocaine is generally used as pretreatment. In Japan, lidocaine viscous solution is the anesthetic of choice, but lidocaine spray is applied when the former is considered insufficient. However, the relationship between the extent of pharyngeal anesthesia and accuracy of observation is unclear. We compared the performance of lidocaine spray alone versus lidocaine spray combined with lidocaine viscous solution for pharyngeal observation during transoral endoscopy. Patients and methods In this prospective, double-blinded, randomized clinical trial conducted between January and March 2015, 327 patients were randomly assigned to lidocaine spray alone (spray group, n = 157) or a combination of spray and viscous solution (combination group, n = 170). We compared the number of pharyngeal observable sites (non-inferiority test), pain by visual analogue scale, observation time, and the number of gag reflexes between the two groups. Results The mean number of images of suitable quality taken at the observable pharyngeal sites in the spray group was 8.33 (95 % confidence interval [CI]: 7.94 - 8.72) per patient, and 8.77 (95 % CI: 8.49 - 9.05) per patient in the combination group. The difference in the number of observable pharyngeal sites was - 0.44 (95 % CI: - 0.84 to - 0.03, P = 0.01). There were no differences in pain, observation time, or number of gag reflexes between the 2 groups. Subgroup analysis of the presence of sedation revealed no differences between the two groups for the number of pharyngeal observation sites and the number of gag reflexes. However, the number of gag reflexes was higher in the spray group compared to the combination group in a subgroup analysis that looked at the absence of sedation. Conclusions Lidocaine spray for pharyngeal anesthesia was not inferior to lidocaine spray and viscous solution in terms of pharyngeal observation. It was considered that lidocaine viscous solution was unnecessary for pharyngeal observation. UMIN000016073.

Inflammatory features of pancreatic cancer highlighted by monocytes/macrophages and CD4+ T cells with clinical impact.

Pancreatic ductal adenocarcinoma (PDAC) is among the most fatal of malignancies with an extremely poor prognosis. The objectives of this study were to provide a detailed understanding of PDAC pathophysiology in view of the host immune response. We examined the PDAC tissues, sera, and peripheral blood cells of PDAC patients using immunohistochemical staining, the measurement of cytokine/chemokine concentrations, gene expression analysis, and flow cytometry. The PDAC tissues were infiltrated by macrophages, especially CD33+CD163+ M2 macrophages and CD4+ T cells that concomitantly express programmed cell death-1 (PD-1). Concentrations of interleukin (IL)-6, IL-7, IL-15, monocyte chemotactic protein-1, and interferon-γ-inducible protein-1 in the sera of PDAC patients were significantly elevated. The gene expression profile of CD14+ monocytes and CD4+ T cells was discernible between PDAC patients and healthy volunteers, and the differentially expressed genes were related to activated inflammation. Intriguingly, PD-1 was significantly upregulated in the peripheral blood CD4+ T cells of PDAC patients. Correspondingly, the frequency of CD4+PD-1+ T cells was increased in the peripheral blood cells of PDAC patients, and this increase correlated to chemotherapy resistance. In conclusion, inflammatory conditions in both PDAC tissue and peripheral blood cells in PDAC patients were prominent, highlighting monocytes/macrophages as well as CD4+ T cells with influence of the clinical prognosis.