Pegfilgrastim for the management of neutropenia during neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil in esophageal cancer patients.

BACKGROUND: Neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (DCF) therapy is a new standard for locally advanced esophageal squamous cell carcinoma. The optimal timing of pegfilgrastim with the DCF regimen to prevent febrile neutropenia (FN) remains controversial. The effectiveness of concomitant pegfilgrastim administration with continuous 5-fluorouracil (5-FU) infusion in the DCF regimen was therefore assessed. METHODS: All patients who received neoadjuvant DCF for esophageal cancer were retrospectively assessed. Patients who had been scheduled to receive pegfilgrastim on days 3-5 (early group) or days 7-9 (regular group) of the DCF regimen were included. Uni- and multivariate analyses were used to assess risk factors for FN. RESULTS: Eighty-eight patients were included in the analysis. The 26 patients in the early group received pegfilgrastim as scheduled. In the 62 patients of the regular group, 51 received pegfilgrastim at a median of 7 days after starting DCF chemotherapy. However, 11 patients in the regular group could not receive pegfilgrastim. Twenty-two patients of the regular group and 2 patients of the early group developed FN after the first session of DCF. Early administration of pegfilgrastim and grade 4 neutropenia were significantly associated with onset of FN, with multivariate analysis identifying early administration of pegfilgrastim as an independent preventive factor and grade 4 neutropenia as a risk factor, after adjusting for sex and age. CONCLUSION: Early pegfilgrastim administration is a safe approach that reduces the incidence of FN in DCF therapy. Using pegfilgrastim with continuous 5-FU infusion in the DCF regimen represents a reasonable option to prevent FN.

Bioactivity-boosting strategy based on combination of anti-allergic O-methylated catechin with a Citrus flavanone, hesperetin.

Many patients with allergies have anxiety about taking anti-allergic medicines due to their side effects and increased medical expenses. Thus, developing functional foods/agricultural products for allergy prevention is strongly desired. In this study, we revealed that a Citrus flavanone, hesperetin, amplified IgE/antigen-mediated degranulation-inhibitory potency of anti-allergic catechin, (-)-epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3''Me), in the rat basophilic/mast cell line RBL-2H3. Hesperetin also significantly elevated the activation of acid sphingomyelinase (ASM), essential for eliciting anti-allergic effect of EGCG3''Me through the cell surficial protein, 67-kDa laminin receptor (67LR). Furthermore, oral administration of the highly absorbent hesperidin, α-glucosyl hesperidin, also enhanced the inhibitory potency of EGCG3''Me-rich 'Benifuuki' green tea (Camellia sinensis L.) on passive cutaneous anaphylaxis (PCA) reaction evoked by IgE/antigen in BALB/c mice. These observations indicate that hesperetin amplifies the ability of EGCG3''Me to inhibit the IgE/antigen-mediated degranulation through activating ASM signaling.

Duodenal cholinergic tuft cell number is increased in functional dyspepsia.

BACKGROUND: Low-grade duodenal inflammation has recently been identified in patients with functional dyspepsia (FD). Chemosensory tuft cells were reported to be associated with gastrointestinal diseases. We therefore assessed duodenal tuft cell density and microinflammation in patients with FD to determine whether these measures could serve as useful biomarkers, and also correlated tuft cell density and microinflammation in FD patients. METHODS: Duodenal biopsy specimens were obtained from patients with FD and from controls. Tuft cells, eosinophils, and mast cells were immunochemically stained with specific antibodies. Tuft cells were identified by immunostaining for doublecortin-like kinase 1 (DCLK1); cholinergic tuft cells were assessed by double staining for choline acetyltransferase (ChAT) and DCLK1. Immune-type tuft cells were assessed by IL-25 mRNA expression using real-time PCR. KEY RESULTS: The density of intramucosal eosinophils and mast cells was significantly higher in the duodenum of FD patients than in controls. The density of tuft cells was significantly higher in the duodenum of FD patients compared with controls, and significantly correlated with eosinophil density in the duodenum of FD patients and controls. Moreover, a fraction of ChAT-positive cells was DCLK1 positive; all duodenal DCLK1+ tuft cells were ChAT-immunoreactive in FD and in control subjects. CONCLUSIONS AND INFERENCES: Cholinergic tuft cell density was higher in the duodenum of patients with FD and significantly correlated with eosinophil density. Further studies are needed to investigate the pathophysiological significance of tuft cells in FD and may provide valuable clues to the pathophysiology of FD.

Microinflammation in the intestinal mucosa and symptoms of irritable bowel syndrome.

BACKGROUND: Potential etiological mechanisms of irritable bowel syndrome (IBS) have been reported, and emerging data suggest that immune activation is present in a major subset of IBS, especially in those with diarrhea. Intestinal mucosal mast cell and intraepithelial lymphocyte (IEL) infiltration and related factors were examined in patients with IBS. In addition, the correlations of symptoms and micro-inflammation were assessed. METHODS: Intestinal biopsy specimens were obtained from patients with IBS and controls. Mast cells and IELs were stained with specific antibodies. The mRNA levels of cytokines and chemokines were assessed by quantitative reverse transcription polymerase chain reaction. RESULTS: Infiltration of mast cells in the duodenum was significantly higher in IBS patients than in control subjects. The infiltration of IELs was higher in the duodenum and terminal ileum of IBS patients compared to the control subjects. The numbers of duodenal and ileal IELs were significantly correlated. The number of IELs but not mast cells in the duodenum and terminal ileum was significantly correlated with diarrhea frequency in control subjects and IBS patients. The expression level of the chemotactic chemokine CXCL11 was significantly higher in the duodenum of IBS patients. CONCLUSION: Duodenal mast cells and IELs were increased in IBS patients. In addition, a positive correlation was found between the number of duodenal and ileal IELs and the frequency of diarrhea. Given that the present study was strictly observational, further studies are needed to clarify the pathophysiological functions associated with micro-inflammation in IBS.

Eriodictyol-Amplified 67-kDa Laminin Receptor Signaling Potentiates the Antiallergic Effect of O-Methylated Catechin.

(-)-Epigallocatechin-3-O-(3-O-methyl) gallate (1, EGCG3″Me), an antiallergic O-methylated catechin, is present in high quantities in the green tea cultivar "Benifuuki" (Camellia sinensis L.). Previous studies have shown that EGCG3″Me inhibited basophil degranulation mediated through the cell-surface 67-kDa laminin receptor (67LR), but the mechanisms are not fully elucidated. This study aimed to investigate the mechanisms underlying the inhibitory effect of EGCG3″Me on IgE/antigen (Ag)-mediated degranulation and the combined effect of EGCG3″Me with eriodictyol (2), a bioactive flavanone. EGCG3″Me inhibited ß-hexosaminidase release from the rat basophilic/mast cell line RBL-2H3 stimulated by IgE/Ag and induced acid sphingomyelinase (ASM) activity. This induction was inhibited by anti-67LR antibody treatment. The ASM-specific inhibitor desipramine inhibited EGCG3″Me-induced suppression of degranulation. The soluble guanylate cyclase (sGC) inhibitor NS2028 weakened the potency of EGCG3″Me, and the sGC activator BAY41-2272 suppressed degranulation. The ability of EGCG3″Me to induce ASM activity and inhibit degranulation was amplified by eriodictyol. Furthermore, oral administration of the lemon-peel-derived eriodyctiol-7-O-glucoside (3) potentiated the suppressive effect of EGCG3″Me-rich "Benifuuki" green tea on the IgE/Ag-induced passive cutaneous anaphylaxis (PCA) reaction in BALB/c mice. These results suggest that EGCG3″Me inhibits IgE/Ag-mediated degranulation by inducing the 67LR/sGC/ASM signaling pathway, and eriodictyol amplifies this signaling.

Impacts of the COVID-19 pandemic on functional dyspepsia and irritable bowel syndrome: A population-based survey.

BACKGROUND AND AIM: Functional gastrointestinal disorders are a group of stress-sensitive gut-brain disorders. The COVID-19 outbreak has caused immense stress and anxiety among the general public. Strict measures to counter COVID-19 emergency, including physical distancing, have also taken a toll on physical and mental health. We investigated the impact of the COVID-19 pandemic on the gastrointestinal and psychological symptoms of functional dyspepsia (FD) and irritable bowel syndrome (IBS). METHODS: An online survey was conducted in Japan for a group of randomly assigned panelists from May 26 to 27, 2020. Each respondent answered a questionnaire on stress, physical distancing, and worries about COVID-19. Gastrointestinal symptoms were assessed to diagnose FD and IBS (Rome III), and psychological symptoms were assessed using the Hospital Anxiety and Depression Scale. RESULTS: A total of 5157 subjects were finally enrolled, with FD in 8.5%, IBS in 16.6%, and FD-IBS overlap in 4.0%. For both gastrointestinal and psychological symptoms, respondents with FD-IBS overlap showed the worst scores, followed by IBS-alone, then FD-alone respondents. During the COVID-19 pandemic, 11.9% of respondents reported deterioration and 2.8% reported improvement of gastrointestinal symptoms. FD-IBS overlap, psychological disease comorbidity, and stress at work/school were significantly associated with symptom deterioration. Younger age, commuting by public transport, and work/study from home were associated with symptom improvement. CONCLUSIONS: The COVID-19 pandemic negatively affected FD/IBS subjects, with respondents showing FD-IBS overlap syndrome as the most important independent factor associated with deterioration in gastrointestinal symptoms. Physicians need to take extra care of FD/IBS patients in the post-COVID period.