Dendritic cells pulsed with multifunctional Wilms' tumor 1 (WT1) peptides combined with multiagent chemotherapy modulate the tumor microenvironment and enable conversion surgery in pancreatic cancer.

BACKGROUND: We aimed to develop a chemoimmunotherapy regimen consisting of a novel Wilms' tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy and to investigate the safety, clinical outcomes, and WT1-specific immune responses of patients with unresectable advanced pancreatic ductal adenocarcinoma (UR-PDAC) who received this treatment. METHODS: Patients with UR-PDAC with stage III disease (locally advanced (LA-PDAC; n=6)), stage IV disease (metastatic (M-PDAC; n=3)), or recurrent disease after surgery (n=1) were enrolled in this phase I study. The patients received one cycle of nab-paclitaxel plus gemcitabine alone followed by 15 doses of the WT1-DC vaccine independent of chemotherapy. The novel WT1 peptide cocktail was composed of a multifunctional helper peptide specific for major histocompatibility complex class II, human leukocyte antigen (HLA)-A*02:01, or HLA-A*02:06 and a killer peptide specific for HLA-A*24:02. RESULTS: The chemoimmunotherapy regimen was well tolerated. In the nine patients for whom a prognostic analysis was feasible, the clinical outcomes of long-term WT1 peptide-specific delayed-type hypersensitivity (WT1-DTH)-positive patients (n=4) were significantly superior to those of short-term WT1-DTH-positive patients (n=5). During chemoimmunotherapy, eight patients were deemed eligible for conversion surgery and underwent R0 resection (four patients with LA-PDAC, one patient with M-PDAC, and one recurrence) or R1 resection (one patient with M-PDAC), and one patient with LA-PDAC was determined to be unresectable. Long-term WT1-DTH positivity was observed in three of the four patients with R0-resected LA-PDAC. These three patients exhibited notable infiltration of T cells and programmed cell death protein-1+ cells within the pancreatic tumor microenvironment (TME). All patients with long-term WT1-DTH positivity were alive for at least 4.5 years after starting therapy. In patients with long-term WT1-DTH positivity, the percentage of WT1-specific circulating CD4+ or CD8+ T cells that produced IFN-γ or TNF-α was significantly greater than that in patients with short-term WT1-DTH positivity after two vaccinations. Moreover, after 12 vaccinations, the percentages of both circulating regulatory T cells and myeloid-derived suppressor cells were significantly lower in patients with long-term WT1-DTH-positive PDAC than in short-term WT1-DTH-positive patients. CONCLUSIONS: Potent activation of WT1-specific immune responses through a combination chemoimmunotherapy regimen including the WT1-DC vaccine in patients with UR-PDAC may modulate the TME and enable conversion surgery, resulting in clinical benefits (Online supplemental file 1). TRIAL REGISTRATION NUMBER: jRCTc030190195.

Endoscopic and clinicopathological features of segmental colitis associated with diverticulosis.

Objectives: Segmental colitis associated with diverticulosis (SCAD) has close endoscopic and pathological similarities to ulcerative colitis (UC) and Crohn's disease. Clinical data on SCAD are limited in Japan. We examined the endoscopic and clinicopathological features of patients with SCAD. Methods: This single-center retrospective study included 13 patients with SCAD between 2012 and 2022. Endoscopic findings were categorized as follows: type A (swollen red patches 5-10 mm at the top of mucosal folds), mild and moderate type B (mild-to-moderate UC-like findings), type C (aphthous ulcers resembling Crohn's disease), and type D (severe UC-like findings). Results: Overall, six, five, and two patients were diagnosed with type A, mild type B, and moderate type B disease, respectively. Among the type A cases, two spontaneously progressed to moderate type B and one escalated to type D, necessitating an emergency sigmoidectomy owing to perforation peritonitis, despite repeated antibiotic treatments. Histopathologically, diffuse neutrophil and lymphocyte infiltration with cryptitis were noted in all type A cases, whereas UC-like alterations were observed in type B and D cases. Seven type B cases were treated with oral 5-aminosalicylic acid and/or salazosulfapyridine. Clinical remission was achieved in three mild type B cases and one moderate type B case, while clinical relapse and remission were noted in three moderate type B cases. No anti-inflammatory treatment was required in three type A and two mild type B cases. Conclusions: Aggressive anti-inflammatory treatment should be considered for SCAD with UC-like findings due to the potential risk of severe ulceration, stenosis, and/or perforation.

Analysis of the NUDT15 gene and metabolites of azathioprine in Japanese patients with inflammatory bowel disease.

BACKGROUND: Thiopurines continue to play an important role in the treatment of inflammatory bowel disease (IBD). It is well known that thiopurines can cause several adverse reactions. Especially, hematopoietic toxicity may lead to severe agranulocytosis. In a previous prospective study, we investigated the relationship between inosine triphosphate pyrophosphatase (ITPA) c.94c > a polymorphism, 6-thioguanine nucleotide (6-TGN) concentration and toxicity. METHODS: To clarify the cause of thiopurine toxicity, we analysed nucleoside disphosphate-linked moiety X-type motif 15 (NUDT15) gene polymorphisms, i.e., R139C, V18I, and V19_V19insGV, and measured 6-mercaptopurines and 6-methylmercaptopurines (6-MMP) using the archived blood samples collected from 49 IBD patients for our previous study. RESULTS: The ITPA c.94c > a polymorphism was detected in 19 patients (38.7%, all heterozygous). The R139C polymorphism was found in 10 patients (20.4%, 1 homozygous, 9 heterozygous), V18_V19insGV in 7 patients (14.3%, all heterozygous), and V18I in 2 patients (4.08%, all heterozygous). Although R139C was more strongly associated with leukopenia than c.94c > a, there were no significant correlations with 6-TGN and 6-MMP levels, as for c.94c > a. The leukopenia incidence rates for each gene polymorphism were 0% in those with all wild-type genes, 21.4% for c.94c > a only, 42.9% for NUDT15 polymorphism (s) only, and 80.0% for both polymorphisms. CONCLUSIONS: All cases of leukopenia were associated with ITPA c.94c > a and/or polymorphism of NUDT15 and the risk of developing leukopenia was synergistically increased by ITPA and NUDT15 gene polymorphism. However, there was no association between the level of azathioprine metabolites and these polymorphisms.

The insoluble excretion of multi-matrix system mesalazine preparations in patients with ulcerative colitis.

BACKGROUND: Multi-matrix mesalazine (MMX) is an important treatment for ulcerative colitis (UC); however, it is often excreted intact, which increases the risk of relapse. This study aimed to clarify the risk factors for insoluble MMX excretion. METHODS: The subjects were 102 UC patients who were newly prescribed MMX alone to induce remission. Their stools were evaluated on the Bristol Stool Form Scale (BSFS), the presence/absence of insoluble MMX excretion was investigated in interviews, and defecation frequency at the start of treatment and disease type were retrospectively investigated by examining their medical records. RESULTS: The insoluble excretion rate (IER) was 14.7%. It tended to be higher in the patients with left-sided colitis or extensive colitis, although the differences among the disease types were not significant (p = 0.053). The mean defecation frequency of the patients that reported insoluble MMX excretion was significantly higher than that of the patients that did not report it (6.27 ± 5.28 vs. 3.69 ± 3.17, p < 0.05). The IER tended to be higher among the patients with soft stools (4.5%, 21.9%, and 23.1% in those with BSFS scores of ≤ 4, 5, and ≥ 6, respectively). In ROC analysis of defecation frequency, ≥ 3.5 defecations was found to exhibit sensitivity and specificity of 66.7% and 65.5%, respectively, for predicting insoluble MMX excretion. CONCLUSIONS: The likelihood of insoluble MMX excretion is influenced by defecation frequency and the extent of inflammation. It is important to keep the possibility of insoluble excretion in mind when prescribing MMX.

The stimulatory effect of fusobacteria on dendritic cells under aerobic or anaerobic conditions.

Fusobacteria have been suspected to be pathobionts of colon cancer and inflammatory bowel disease. However, the immunomodulatory properties that affect these inflammatory reactions in dendritic cells (DCs) under anaerobic and aerobic conditions have not yet been characterized. We directly assessed the stimulatory effects of anaerobic commensal bacteria, including fusobacteria, on a human DC line through coculture under aerobic or anaerobic conditions. Under aerobic or anaerobic conditions, stimulation of the DC line with all live commensal bacteria examined, except the probiotic Lactobacillus delbrueckii subsp. bulgaricus (L. bulgaricus), significantly increased the geometric mean fluorescent intensity (MFI) of marker proteins (HLA-ABC, HLA-DR, CD80, CD86, CD83, or CCR7) on the DC surface. In particular, both Fusobacterium nucleatum (F. nucleatum) and Escherichia coli (E. coli) significantly increased the expression of DC-associated molecules, except for CD83 under both aerobic and anaerobic conditions. The DC line stimulated with Fusobacterium varium (F. varium) significantly increased only CD80, HLA-ABC, and HLA-DR expression under anaerobic conditions. Moreover, differences in the levels of proinflammatory cytokines, such as IL-6, IL-8, and TNF-α, were detected in the DC line stimulated by all live commensal bacteria under either aerobic or anaerobic conditions. Under aerobic conditions, the DC line stimulated with E. coli produced significantly more IL-6, IL-8, and TNF-α than did the cells stimulated with any of the bacteria examined. When E. coli were used to stimulate the DC line under anaerobic conditions, TNF-α was predominantly produced compared to stimulation with any other bacteria. Compared to the DC line stimulated with any other bacteria, the cells stimulated with F. nucleatum showed significantly increased production of IL-6, IL-8 and TNF-α only under anaerobic conditions. In particular, E. coli, F. nucleatum, and F. varium strongly stimulated the DC line, resulting in significantly increased expression of surface molecules associated with DCs and production of inflammatory cytokines.

Prognostic value of immune factors in the tumor microenvironment of patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Both activated tumor-infiltrating lymphocytes (TILs) and immune-suppressive cells, such as regulatory T cells (Tregs), in the tumor microenvironment (TME) play an important role in the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: The densities of TILs, programmed death receptor 1 (PD-1) + T cells, and forkhead box P3 (Foxp3) + T cells were analyzed by immunohistochemical staining. The associations of the immunological status of the PDAC microenvironment with overall survival (OS) time and disease-free survival (DFS) time were evaluated. RESULTS: PDAC patients with a high density of TILs in the TME or PD-1-positive T cells in tertiary lymphoid aggregates (TLAs) demonstrated a significantly better prognosis than those with a low density of TILs or PD-1-negativity, respectively. Moreover, PDAC patients with high levels of Foxp3-expressing T cells showed a worse prognosis than those with low levels of Foxp3-expressing T cells. Importantly, even with a high density of the TILs in TME or PD-1-positive T cells in TLAs, PDAC patients with high levels of Foxp3-expressing T cells showed a worse prognosis than patients with low levels of Foxp3-expressing T cells. A PDAC TME with a high density of TILs/high PD-1 positivity/low Foxp3 expression was an independent predictive marker associated with superior prognosis. CONCLUSION: Combined assessment of TILs, PD-1+ cells, and Foxp3+ T cells in the TME may predict the prognosis of PDAC patients following surgical resection.

Long-term outcomes of antibiotic combination therapy for ulcerative colitis.

AIMS: An antibiotic combination of amoxicillin, tetracycline and metronidazole (ATM) is effective for ulcerative colitis (UC), but this regimen is discontinued in some cases due to adverse events. This study aimed to assess a revised combination, namely, amoxicillin, fosfomycin and metronidazole (AFM), in UC patients with the goal of reducing side effects while maintaining therapeutic efficacy. METHODS: A prospective open-label trial was undertaken in 104 adult UC patients. A combination of oral amoxicillin (1500 mg), fosfomycin (3000 mg) and metronidazole (750 mg) was administered to patients daily for 2-4 weeks in addition to their conventional medication. Clinical assessment was performed using the Lichtiger index before treatment and at 0, 3, 6, 9 and 12 months and 2 and 3 years. Endoscopic evaluation was performed using the Mayo score before treatment and at 3 and 12 months. RESULTS: The compliance rate was 99.2%. Response and remission rates were 80.8% and 63.5% at completion, 73.1% and 64.4% at 3 months, and 39.4% for both at 12 months, respectively. Of the 41 patients who were in remission at 12 months, 63.4% maintained that status until the 2-year follow-up. Similarly, 69.2% of those in remission at 2 years remained relapse free at the 3-year follow-up. Side effects were observed in 44.2% of the participants. Fever occurred in one patient (1.0%), which was lower than the rate observed with ATM therapy. CONCLUSION: These results indicate that AFM therapy induces remission and is appropriate for long-term maintenance of UC while producing fewer and milder adverse events than ATM therapy. CLINICAL TRIALS: This study was registered in the University Hospital Medical Information Network (No. R000046546).

Efficacy and safety of short-term therapy with indigo naturalis for ulcerative colitis: An investigator-initiated multicenter double-blind clinical trial.

INTRODUCTION: Indigo naturalis (IN) is a blue pigment extracted from Assam indigo and other plants and has been confirmed to be highly effective for ulcerative colitis (UC) treatment in several clinical studies. OBJECTIVE: We conducted a multicenter double-blind study to confirm the efficacy and safety of short-term IN administration. METHODS: A multicenter, randomized controlled trial was conducted between December 2015 and October 2018 in our facilities. Forty-six patients with mild to moderate active UC (Lichtiger index: 5-10) were randomly assigned to the IN group or the placebo group and received 5 capsules (500 mg) twice a day for 2 weeks. We investigated the efficacy according to blood tests and the Lichtiger index before and after administration, and we also examined adverse events. RESULTS: The analysis included 42 patients (20 males, 22 females) with an average age of 45 years. Nineteen patients were assigned to the placebo group, and 23 were assigned to the IN group. After treatment administration, in the placebo group, no change in the Lichtiger index was observed (7.47 to 6.95, p = 0.359), and hemoglobin was significantly reduced (12.7 to 12.4, p = 0.031), while in the IN group, the Lichtiger index (9.04 to 4.48, p = 0.001) and albumin (4.0 to 4.12, p = 0.022) improved significantly. Mild headaches were observed in 5 patients and 1 patient in the IN and placebo groups, respectively. CONCLUSIONS: Short-term administration of IN is highly effective without serious adverse events such as pulmonary hypertension or intussusception and may prevent the occurrence of serious adverse events.

Association between Passive Smoking from the Mother and Pediatric Crohn's Disease: A Japanese Multicenter Study.

Smoking is a risk factor for adult-onset Crohn's disease (CD). Although passive smoking from family members is a major concern, especially in pediatric CD, the number of existing epidemiological studies is limited. This multicenter case-control study aimed to assess the effects of familial smoking on pediatric CD. We examined 22 pediatric CD cases and 135 controls. The subjects' mothers were given a self-administered questionnaire about family smoking before disease onset in the CD group or the corresponding period in the control group. Univariable logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), whereas dose-response relationship analyses were performed for more in-depth evaluations. Univariable analyses indicated that passive smoking from the mother (OR, 2.09; 95% CI, 0.61-7.10) was not a significant, but a candidate risk factor for developing pediatric CD. In contrast, the dose-response relationship analyses revealed that passive smoking from the mother (OR, 1.17; 95% CI, 1.04-1.31) was significantly associated with pediatric CD. Therefore, passive smoking from the mother may be predominantly associated with the development of pediatric CD. Further follow-up studies comprising environmental measurements of passive smoking exposure doses and genetic factors interaction analysis are necessary.

Metagenomic analyses of the gut microbiota associated with colorectal adenoma.

Recent studies have suggested an association between certain members of the Fusobacterium genus, especially F. nucleatum, and the progression of advanced colorectal carcinoma (CRC). We assessed such an association of the gut microbiota in Japanese patients with colorectal adenoma (CRA) or intramucosal CRC using colonoscopy aspirates. We analyzed samples from 81 Japanese patients, including 47 CRA and 24 intramucosal CRC patients, and 10 healthy subjects. Metagenomic analysis of the V3-V4 region of the 16S ribosomal RNA gene was performed. The linear discriminant analysis (LDA) effect size (LEfSe) method was used to examine microbial dysbiosis, revealing significant differences in bacterial abundances between the healthy controls and CRA or intramucosal CRC patients. In particular, F. varium was statistically more abundant in patients with CRA and intramucosal CRC than in healthy subjects. Here, we present the metagenomic profile of CRA and intramucosal CRC and demonstrate that F. varium is at least partially involved in the pathogenesis of CRA and intramucosal CRC.

Randomized Trial of Vitamin D Supplementation to Prevent Seasonal Influenza and Upper Respiratory Infection in Patients With Inflammatory Bowel Disease.

BACKGROUND: We evaluated whether oral vitamin D supplementation during the winter and early spring reduces the incidence of influenza and upper respiratory infections in patients with inflammatory bowel disease (IBD). METHODS: A randomized, double-blind, controlled trial was conducted to compare the effects of vitamin D supplementation (500 IU/day) and a placebo. The primary outcome was the incidence of influenza; the secondary outcome was the incidence of upper respiratory infection. Prespecified subgroup analyses were performed according to 25-hydroxyvitamin D (25-OHD) levels (low <20 ng/mL or high ≥20 ng/mL) and whether ulcerative colitis (UC) or Crohn's disease (CD) was present. We also used the Lichtiger clinical activity index for patients with UC and the Crohn's Disease Activity Index (CDAI) for patients with CD before and after interventions. RESULTS: We included 223 patients with IBD and randomized them into 2 groups: vitamin D supplementation (n = 108) and placebo (n = 115). The incidence of influenza did not differ between the groups. However, the incidence of upper respiratory infection was significantly lower in the vitamin D group (relative risk [RR], 0.59; 95% confidence interval (CI), 0.35-0.98; P = 0.042). This effect was enhanced in the low 25-OHD level subgroup (RR, 0.36; 95% CI, 0.14-0.90; P = 0.02). With respect to adverse events, the Lichtiger clinical activity index score was significantly worse in the vitamin D group (P = 0.002) and remained significant only in the high 25-OHD level subgroup. CONCLUSIONS: Vitamin D supplementation may have a preventative effect against upper respiratory infection in patients with IBD but may worsen the symptoms of UC.

FADS2 and ELOVL6 mutation frequencies in Japanese Crohn's disease patients.

Crohn's disease (CD) development is thought to involve genetic factors related to immune response as well as environmental factors, such as intestinal bacteria and diet, though no clear cause has yet been identified. In our previous study, we found that the concentrations of linoleic acid, stearic acid, and metabolites in erythrocytes differed between CD patients and healthy subjects. These factors related to lipid metabolism are controlled by Δ6 desaturase (fatty acid desaturase 2, FADS2) and elongase 6 (ELOVL6), respectively. In the present study, we analyzed the gene sequences of FADS2 and ELOVL6 in 52 Japanese CD patients, and then compared mutation frequencies with findings in healthy individuals. Nineteen FADS2 mutations and 33 ELOVL6 mutations were found. Furthermore, a new variant in the promoter region was shown in both genes, though no mutation in the coding region was found in either. For the FADS2 intron, the allele frequency of rs227784 (0.3365; 95% CI = 0.0337-0.01460) was higher than that in healthy subjects (0.0190). Furthermore, allele rs227784 had a greater association with CD (odds ratio = 4.4; 95% CI = 2.1-9.3). As compared with healthy Japanese healthy individuals, no mutations were found with a largely deviated allele frequency in the present CD group. However, the number of patients examined was small, thus the reliability of our results is limited. The present findings regarding genetic effects on CD onset and lipid metabolism may be weak.

Fatty Acids as Useful Serological Markers for Crohn's Disease.

BACKGROUND: We have previously reported that patients with Crohn's disease (CD) have a very specific erythrocyte membrane phospholipid fatty acid profile. The findings of this study suggest that the activities of enzymes involved in the metabolism of linoleic acid (LA), that is, delta-6 desaturase, are higher in CD patients than in healthy individuals. METHODS: We evaluated the utilities of various fatty acid compositions of the plasma (p-) as new serological markers for CD compared to those of erythrocyte membranes (e-). RESULTS: Fifty CD patients and 50 healthy individuals were enrolled. In both plasma and erythrocyte membranes, the weight percentages of palmitic acid (PA) were significantly higher, while those of LA were significantly lower in CD patients than in controls. Fatty acids with high sensitivity and specificity were p-PA (0.86 and 0.74) and e-PA (0.80 and 0.74). With PA and LA as a CD fatty acid index (CDFAi), that is, CDFAi = (PA/LA), the sensitivity and specificity of plasma CDFAi (p-CDFAi) and e-CDFAi were 0.80 and 0.80; and 0.82 and 0.88 respectively. CONCLUSION: In CD patients, various fatty acids were specifically altered in both plasma and erythrocytes, and p-PA and p-CDFAi are potentially useful as new serological markers for CD.

Prognostic significance of plasma interleukin-6/-8 in pancreatic cancer patients receiving chemoimmunotherapy.

AIM: To investigate the association of plasma levels of interleukin (IL)-6 and -8 with Wilms' tumor 1 (WT1)-specific immune responses and clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDA) treated with dendritic cells (DCs) pulsed with three types of major histocompatibility complex class I and II-restricted WT1 peptides combined with chemotherapy. METHODS: During the entire treatment period, plasma levels of IL-6 and -8 were analyzed by ELISA. The induction of WT1-specific immune responses was assessed using the WT1 peptide-specific delayed-type hypersensitivity (DTH) test. RESULTS: Three of 7 patients displayed strong WT1-DTH reactions throughout long-term vaccination with significantly decreased levels of IL-6/-8 after vaccinations compared with the levels prior to treatment. Moreover, overall survival (OS) was significantly longer in PDA patients with low plasma IL-6 levels (< 2 pg/mL) after 5 vaccinations than in patients with high plasma IL-6 levels (≥ 2 pg/mL) (P = 0.025). After disease progression, WT1-DTH reactions decreased severely and were ultimately negative at the terminal stage of cancer. The decreased levels of IL-6/-8 observed throughout long-term vaccination were associated with WT1-specific DTH reactions and long-term OS. CONCLUSION: Prolonged low levels of plasma IL-6/-8 in PDA patients may be a prognostic marker for the clinical outcomes of chemoimmunotherapy.

A Prospective Study Evaluating Metabolic Capacity of Thiopurine and Associated Adverse Reactions in Japanese Patients with Inflammatory Bowel Disease (IBD).

Azathioprine (AZA) is frequently used in patients with inflammatory bowel disease (IBD). However, toxic adverse reactions frequently develop and limit the clinical benefits. Currently, the precise mechanisms underlying thiopurine-related toxicity are not well understood. To investigate the relationship between the extent of thiopurine metabolism and adverse reactions in Japanese IBD patients, we prospectively observed 48 IBD patients who received AZA. We analyzed the thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) gene mutations and measured the concentrations of 6-thioguanine nucleotide (6-TGN) continuously for 52 weeks. All patients possessed wild-type TPMT gene sequences. The ITPA 94C>A mutation was detected in 19 patients (39.6%). Adverse reactions developed in 14 of the 48 patients (29.2%), including leukopenia in 10 patients (20.8%). In the leukopenia group, the percentages of patients with 94C>A were higher than those in the without-leukopenia group (70.0% vs. 31.6%, P < 0.05). The average concentrations of 6-TGN in the patients with 94C>A were generally higher than those in the patients without 94C>A, however, there were no significant differences. Only 3 out of 10 patients with leukopenia exhibited high 6-TGN levels (30.0%). No negative correlations between white blood cell (WBC) counts and 6-TGN concentrations were observed. The cumulative incidence of leukopenia were higher for patients with 94C>A. Seven out of 19 patients (36.8%) with the ITPA 94C>A mutation developed leukopenia; however, this mutation may not unequivocally increase the risk of developing leukopenia. In addition, there are factors other than increased 6-TGN levels that are involved in the onset of leukopenia.

[Corrigendum] Induction of antigen-specific cytotoxic T lymphocytes by fusion cells generated from allogeneic plasmacytoid dendritic and tumor cells.

Some errors in Fig. 3B and Fig. 6C have been identified. The errors do not change the conclusion of the paper. The conclusion is supported by other figures in the paper, as well as results described in the text. The corrected Fig. 3B and Fig. 6C are shown below. [the original article was published in the International Journal of Oncology 45: 470-478, 2014 DOI: 10.3892/ijo.2014.2433]

Potential utility of a new ulcerative colitis segmental endoscopic index combining disease severity and the extent of inflammation.

GOAL: To investigate the potential utility of a new scoring system, the Ulcerative Colitis Segmental Endoscopic Index (UCSEI), which combines measures of disease severity and extent of inflammation. BACKGROUND: Intestinal mucosal healing (MH) is a new therapeutic goal for ulcerative colitis (UC). Discontinuous lesions are common in UC and endoscopic observation of the entire colon is important. STUDY: Patients with active mild-to-moderate UC received daily treatment with oral mesalazine (4 g/d) and mesalazine enemas (1 g/d) for 8 weeks. Endoscopic evaluations, using the UCSEI and Mayo Endoscopic Score (MES), were performed in 5 colonic segments at baseline and week 8. The UCSEI criteria included erythema, vascular pattern, friability, and erosion/ulcer. The sum of 5 subscores, determined for each segment, was calculated as the UCSEI. Disease activity was also assessed using the UC Disease Activity Index (UCDAI). MH was defined as MES=0 to 1. RESULTS: Of 58 patients, 51 completed the scheduled endoscopic evaluations. At week 8, the UCDAI score had significantly decreased from 6.63 (baseline) to 2.73 (P<0.001). The remission and MH rates were 35.3% and 55.3%, respectively. Segmental endoscopic evaluation, using UCSEI, showed that baseline inflammation tended to be more severe in the distal colon. The baseline UCSEI increased with the extent of disease, which was not seen in MES. Improvements in UCSEI were observed, even in the patients without decreases in the MES. CONCLUSIONS: UCSEI, reflecting disease severity and extent of inflammation, provides useful information for UC management that is not available with MES.

Production of corticotropin-releasing factor and urocortin from human monocyte-derived dendritic cells is stimulated by commensal bacteria in intestine.

AIM: To examine whether commensal bacteria are a contributing cause of stress-related mucosal inflammation. METHODS: Human peripheral blood monocyte-derived dendritic cells (MoDCs) were stimulated by commensal bacterial strains, including Escherichia coli, Clostridium clostridioforme, Bacteroides vulgatus (B. vulgatus), Fusobacterium varium (F. varium), and Lactobacillus delbrueckii subsp. bulgaricus. After incubation, corticotropin-releasing factor (CRF) and urocortin 1 (UCN1) mRNA in the cells was examined by real-time reverse transcription polymerase chain reaction. Supernatants from the cells were tested for CRF and UCN1 using an enzyme-linked immunosorbent assay. RESULTS: Both CRF and UCN1 were significantly augmented by B. vulgatus and F. varium at both the mRNA and protein levels. In particular, B. vulgatus stimulated human MoDCs, resulting in extremely high levels of CRF and UCN1. CONCLUSION: Stimulation of MoDCs by B. vulgatus and F. varium may be associated with CRF/UCN1-related intestinal disorders, such as irritable bowel syndrome and inflammatory bowel disease.

Treatment with chemotherapy and dendritic cells pulsed with multiple Wilms' tumor 1 (WT1)-specific MHC class I/II-restricted epitopes for pancreatic cancer.

PURPOSE: We performed a phase I trial to investigate the safety, clinical responses, and Wilms' tumor 1 (WT1)-specific immune responses following treatment with dendritic cells (DC) pulsed with a mixture of three types of WT1 peptides, including both MHC class I and II-restricted epitopes, in combination with chemotherapy. EXPERIMENTAL DESIGN: Ten stage IV patients with pancreatic ductal adenocarcinoma (PDA) and 1 patient with intrahepatic cholangiocarcinoma (ICC) who were HLA-positive for A*02:01, A*02:06, A*24:02, DRB1*04:05, DRB1*08:03, DRB1*15:01, DRB1*15:02, DPB1*05:01, or DPB1*09:01 were enrolled. The patients received one course of gemcitabine followed by biweekly intradermal vaccinations with mature DCs pulsed with MHC class I (DC/WT1-I; 2 PDA and 1 ICC), II (DC/WT1-II; 1 PDA), or I/II-restricted WT1 peptides (DC/WT1-I/II; 7 PDA), and gemcitabine. RESULTS: The combination therapy was well tolerated. WT1-specific IFNγ-producing CD4(+) T cells were significantly increased following treatment with DC/WT1-I/II. WT1 peptide-specific delayed-type hypersensitivity (DTH) was detected in 4 of the 7 patients with PDA vaccinated with DC/WT1-I/II and in 0 of the 3 patients with PDA vaccinated with DC/WT1-I or DC/WT1-II. The WT1-specific DTH-positive patients showed significantly improved overall survival (OS) and progression-free survival (PFS) compared with the negative control patients. In particular, all 3 patients with PDA with strong DTH reactions had a median OS of 717 days. CONCLUSIONS: The activation of WT1-specific immune responses by DC/WT1-I/II combined with chemotherapy may be associated with disease stability in advanced pancreatic cancer.