Prostanoid receptor genes confer poor prognosis in head and neck squamous cell carcinoma via epigenetic inactivation.

BACKGROUND: Chronic inflammation is a risk factor for head and neck squamous cell carcinoma (HNSCC) and other diseases. Prostanoid receptors are clearly involved in the development of many types of cancer. However, their role is not simple and is poorly understood in HNSCC. METHODS: Methylation profiles of prostanoid receptor family genes were generated for tumour samples obtained from 274 patients with HNSCC, including 69 hypopharynx, 51 larynx, 79 oral cavity, and 75 oropharynx tumour samples, by quantitative methylation-specific PCR. Promoter methylation was then evaluated with respect to various clinical characteristics and patient survival. RESULTS: The mean number of methylated genes per sample was 2.05 ± 2.59 (range 0 to 9). Promoters of PTGDR1, PTGDR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGIR, and TBXA2R were methylated in 43.8%, 18.2%, 25.5%, 17.5%, 41.2%, 8.0%, 19.3%, 20.4%, and 11.3% of the samples, respectively. Methylation indices for prostanoid receptor family genes tended to be higher as the number of TET methylation events increased. Patients with 5-9 methylated genes had a significantly lower survival rate than that of patients with 0-4 methylated genes (log-rank test, P= 0.007). In multivariate analyses, PTGDR1 methylation was most highly correlated with recurrence in patients with hypopharyngeal cancer (P = 0.014). A similar correlation was observed for PTGER4 in patients with laryngeal cancer (P = 0.046). Methylation of the PTGIR and TBXA2R promoters was positively correlated with recurrence in oropharyngeal cancer (P = 0.028 and P = 0.006, respectively). Moreover, Patients with 5-9 methylated genes were extremely lower of 5hmC levels (P = 0.035) and was correlated with increasing expression of DNMT3A and DNMT3B (P < 0.05 and P < 0.05, respectively). CONCLUSION: We characterised the relationship between the methylation status of prostanoid receptor genes and recurrence in HNSCC. These results provide new perspectives for the development of molecular targeted treatment approaches.

Neuropeptide receptor genes GHSR and NMUR1 are candidate epigenetic biomarkers and predictors for surgically treated patients with oropharyngeal cancer.

Pathological staging and histological grading systems are useful, but imperfect, predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Aberrant promoter methylation is the main type of epigenetic modification that plays a role in the inactivation of tumor suppressor genes. To identify new potential prognostic markers, we investigated the promoter methylation status of five neuropeptide receptor genes. The methylation status of the target genes was compared with clinical characteristics in 278 cases; 72 hypopharyngeal cancers, 54 laryngeal cancers, 75 oropharyngeal cancers, and 77 oral cavity cancers were studied. We found that the NTSR1, NTSR2, GHSR, MLNR, and NMUR1 promoters were methylated in 47.8%, 46.8%, 54.3%, 39.2%, and 43.5% of the samples, respectively. GHSR and NMUR1 promoter methylation independently predicted recurrence in HNSCC. In patients with oropharyngeal cancer (n = 75), GHSR and NMUR1 promoter methylation significantly correlates with survival in surgically treated patients. We classified our patients as having a low, intermediate, or high-risk of death based on three factors: HPV status, and GHSR and NMUR1 promoter methylation. The disease-free survival (DFS) rates were 87.1%, 42.7%, and 17.0%, respectively. Combined data analysis of the methylation status of ten-eleven translocation (TET) family genes indicated a trend toward greater methylation indices as the number of TET methylation events increased. In the current study, we presented the relationship between the methylation status of the GHSR and NMUR1 genes and recurrence in HNSCC, specifically in risk classification of oropharyngeal carcinomas cases with HPV status.

Cyclic Neutropenia with ELANE Gene Mutation in 3 Generations of Kindred / 日本農村医学会雑誌

We report the case of a 3-year-old boy with a history of repeated neutropenia and infection along with a significant family medical history. The diagnosis was cyclic neutropenia based on genetic testing. He had experienced frequent repeated episodes of fever since age 8 months, and he was found to have neutropenia when hospitalized due to acute otitis media at age 13 months. We obtained serial data of complete blood cell counts for 6 weeks when he was 3 years and 4 months old, which confirmed a cyclic increase and decrease in the number of neutrophils. ELANE gene testing was performed after obtaining written informed consent from the parents. A missense mutation was identified. At the parents’ request, we ran further testing and identified the same mutation in the father and paternal grandmother. Thus, 3 generations of kindred had the ELANE gene mutation. Because of repeated infections, prophylactic sulfamethoxazole trimethoprim was started from age 3 years and 10 months, resulting in a considerable decrease in the frequency of infections. Since age 4 years and 11 months, cyclic neutrophil over about 3 weeks has persisted, but there have been no serious infections requiring hospitalization.

Maternal and fetal outcomes in pregnant Japanese women with inflammatory bowel disease: our experience with a series of 23 cases

BACKGROUND/AIMS: Our physicians work to expand the possibilities to treat female patients with inflammatory bowel disease (IBD) who wish to become pregnant. Although many drugs, including 5-aminosalicylate (5-ASA), corticosteroids, immunomodulators, and biologics, are used safely during pregnancy, few reports have described the therapeutic regimen throughout pregnancy and the management of patients who relapse during pregnancy precisely. The aim of this study was to assess the management of patients with IBD during pregnancy. METHODS: We identified 19 patients (five with Crohn's disease and 14 with ulcerative colitis [UC]) who became pregnant with a total of 23 pregnancies between May 2005 and May 2015 by reviewing the medical records of Kyoto University Hospital. The following data were collected: the maternal variables, the IBD treatment type, the disease activity, the pregnancy outcome, and the mode of delivery. RESULTS: Among the 19 patients, 18 had become pregnant after being diagnosed with IBD, while one had developed UC newly after pregnancy. Throughout the gestation, all patients were treated with probiotics, 5-ASA, prednisolone, cytapheresis, or infliximab. The relapse rate during pregnancy was 21.7% (5/23 cases). The five patients who experienced a relapse were able to pursue their pregnancy after intensification of their treatments. There were no adverse fetal or neonatal problems, except in one case that required an emergency Caesarean section because of placental dysfunction and in which a very low-birth-weight infant was born preterm. CONCLUSIONS: Our present data confirmed that even if the disease flares up during pregnancy, good pregnancy outcomes can be achieved with an optimal intensification of the patient's treatment.

Ischemic enteritis with intestinal stenosis

A 75-year-old man was admitted to our hospital with sudden onset of vomiting and abdominal distension. The patient was taking medication for arrhythmia. Computed tomography showed stenosis of the ileum and a small bowel dilatation on the oral side from the region of stenosis. A transnasal ileus tube was placed. Enteroclysis using contrast medium revealed an approximately 6-cm afferent tubular stenosis 10 cm from the terminal ileum and thumbprinting in the proximal bowel. Transanal double-balloon enteroscopy showed a circumferential shallow ulcer with a smooth margin and edema of the surrounding mucosa. The stenosis was so extensive that we could not perform endoscopic balloon dilation therapy. During hospitalization, the patient's nutritional status deteriorated. In response, we surgically resected the region of stenosis. Histologic examination revealed disappearance of the mucosal layer and transmural ulceration with marked fibrosis, especially in the submucosal layer. Hemosiderin staining revealed sideroferous cells in the submucosal layers. Based on the pathologic findings, the patient was diagnosed with ischemic enteritis. The patient's postoperative course was uneventful.

Efficacy and Safety of Long-Term Thiopurine Maintenance Treatment in Japanese Patients With Ulcerative Colitis

BACKGROUND/AIMS: The long-term clinical outcomes of patients with bio-naive ulcerative colitis (UC) who maintain remission with thiopurine are unclear. The aim of this study was to assess the long-term efficacy and safety of maintenance treatment with thiopurine in UC patients. METHODS: This was a retrospective observational cohort analysis conducted at a single center. Between December 1998 and August 2013, 59 of 87 patients with bio-naive UC who achieved remission after induction with treatments other than biologics were enrolled. Remission maintenance with thiopurine was defined as no concomitant treatment needed other than 5-aminosalicylate without relapse. We assessed the remission-maintenance rate, mucosal healing rate, colectomy-free rate, and treatment safety in UC patients who received thiopurine as maintenance treatment. RESULTS: The 84-month cumulative remission-maintenance and colectomy-free survival rates in the UC patients who were receiving maintenance treatment with thiopurine and 5-aminosalicylate were 43.9% and 88.0%, respectively. Of the 38 patients who underwent colonoscopy during thiopurine maintenance treatment, 23 (60.5%) achieved mucosal healing. Of the 59 patients who achieved clinical remission with thiopurine, 6 patients (10.2%) discontinued the thiopurine therapy because of adverse events. CONCLUSIONS: Our study demonstrates the long-term efficacy and safety of thiopurine treatment in patients with bio-naive UC.

Efficacy of Thiopurines in Biologic-Naive Japanese Patients With Crohn's Disease: A Single-Center Experience

BACKGROUND/AIMS: Early use of biologics in patients with Crohn's disease (CD) improves quality of life. However, the effects of the early use of immunomodulators on long-term outcomes remain unclear. This study aimed to evaluate the effects of immunomodulators in patients with CD. METHODS: Between January 2004 and December 2011, 47 biologic-naive CD patients treated with thiopurines alone for remission maintenance were analyzed. The patients were classified into 2 groups depending on the presence or absence of digestive complications. We evaluated the efficacy of and predictive factors for thiopurine use for remission maintenance. RESULTS: The cumulative relapse rates at 24 and 60 months were 13.7% and 35.4%, respectively. Regarding patient characteristics, there was a significant difference in patient history of surgery between the non-relapse and relapse groups (P=0.021). The cumulative relapse rate was lower in patients without a history of surgery than in those with such a history (27.2% and 52.9% at 60.0 months, respectively). Multivariate analysis suggested that the prevalence of stricturing and penetrating complications is an independent factor for relapse. The cumulative relapse rate in patients without a history of surgery was significantly lower in the non-stricturing and non-penetrating group than in the stricturing and penetrating group (11.8% at 85.0 months vs. 58.5% at 69.0 months; P=0.036). CONCLUSIONS: Thiopurine use might be beneficial for the long-term maintenance of remission in biologic-naive Crohn's disease patients without digestive complications and a history of surgery.

Conservative treatment for patients with osteoid osteoma: a case series.

BACKGROUND: Osteoid osteoma is one type of benign bone tumor that may respond to conservative treatment. PATIENTS AND METHODS: A retrospective study of 11 patients with osteoid osteoma was performed. Initially, patients were treated with non-steroidal anti-inflammatories (NSAIDs), unless they continued to have intolerable pain, or if the patient requested surgical resection and radiofrequency ablation (RFA). RESULTS: Conservative therapy was successful for five patients. Three patients were treated with NSAIDs and the mean duration of pain was 22 months. The other two patients went into remission without medication by 9 and 24 months, respectively. Four patients underwent surgery after an average of 12 months. Two patients were treated with RFA after 47 and 11 months, respectively. CONCLUSION: Osteoid osteoma can be treated conservatively. Surgical resection and radiofrequency ablation should also be taken into consideration as an option when the results of conservative treatment are poor.

Diagnosis and Treatment of Ulcerative Colitis with Cytomegalovirus Infection: Importance of Controlling Mucosal Inflammation to Prevent Cytomegalovirus Reactivation

Human cytomegalovirus (HCMV) is a member of the herpesvirus family. HCMV infection persists throughout the host lifespan in a latent state following primary infection. The ability of HCMV to escape control by the host immune system and its resulting reactivation suggests the importance of ongoing immune surveillance in the prevention of HCMV reactivation. HCMV is a common cause of opportunistic infection that causes severe and fatal disease in immune-compromised individuals. In inflammatory bowel disease patients, particularly those with ulcerative colitis (UC), HCMV is often reactivated because these patients are frequently treated with immunosuppressive agents. This reactivation exacerbates colitis. Additionally, HCMV infection can induce severe colitis, even in patients with UC who have never been treated with immunosuppressive agents. However, the role of HCMV in colonic inflammation in patients with UC remains unclear. Here, we present previous and current clinical data on the diagnosis and treatment of HCMV infection in UC. Additionally, our experimental data from a newly established mouse model mimicking UC with concomitant CMV infection clearly demonstrate that inflammation could result in the exacerbation of UC disease activity with induction of HCMV reactivation. In summary, optimal control of colonic inflammation should be achieved in UC patients who are refractory to conventional immunosuppressive therapies and are positive for HCMV.