Objective: To identify candidate predictors for the prognosis of cervical intraepithelial neoplasia 2 (CIN2) lesions and evaluate the prognostic value of the local immune response. Methods: One hundred fifteen CIN2 patients were enrolled. The percentage of p16-, minichromosome maintenance complex component 2- or apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G)-positive cells was determined immunohistochemically. Tumor-infiltrating lymphocytes (TILs) in intertumoral lesions were scored using an automated system. CIN3 disease progression and regression rates were estimated by the Kaplan–Meier method. A case-control study was conducted to screen CIN2 prognostic factors in 10 regression and 10 progression patients. Selected factors were examined in a cohort study to determine their prognostic value for CIN2. Results: Among all participants, the cumulative progression and regression rates at 60 months were 0.477 and 0.510, respectively. In the case-control study, p16- and APOBEC3G-positive cells were higher in the progression group (p=0.043, p=0.023). Additionally, CD4+ cell infiltration was enhanced in the regression group (p=0.023). The cohort study revealed a significantly increased progression rate in patients with elevated p16-positive cells (p<0.001), and increased CD4+ TIL infiltration was associated with better regression (p=0.011). Kaplan–Meier analysis according to human papillomavirus (HPV) positivity revealed a greater CIN3 development risk in HPV16-positive patients than in HPV16-negative cases. Finally, multivariate analysis identified HPV16 infection and CD4+ TIL infiltration as independent prognostic factors in CIN2 regression. Conclusion CD4+ TIL infiltration in intertumoral lesions was related with CIN2 regression. Our findings suggest CD4+ TIL infiltration may be useful for the triage of CIN2 patients.

Objective: Human papillomavirus subtypes are predictive indicators of cervical intraepithelial neoplasia (CIN) progression. While colposcopy is also an essential part of cervical cancer prevention, its accuracy and reproducibility are limited because of subjective evaluation. This study aimed to develop an artificial intelligence (AI) algorithm that can accurately detect the optimal lesion associated with prognosis using colposcopic images of CIN2 patients by utilizing objective AI diagnosis. Methods: We identified colposcopic findings associated with the prognosis of patients with CIN2. We developed a convolutional neural network that can automatically detect the rate of high-grade lesions in the uterovaginal area in 12 segments. We finally evaluated the detection accuracy of our AI algorithm compared with the scores by multiple gynecologic oncologists. Results: High-grade lesion occupancy in the uterovaginal area detected by senior colposcopists was significantly correlated with the prognosis of patients with CIN2. The detection rate for high-grade lesions in 12 segments of the uterovaginal area by the AI system was 62.1% for recall, and the overall correct response rate was 89.7%. Moreover, the percentage of high-grade lesions detected by the AI system was significantly correlated with the rate detected by multiple gynecologic senior oncologists (r=0.61). Conclusion Our novel AI algorithm can accurately determine high-grade lesions associated with prognosis on colposcopic images, and these results provide an insight into the additional utility of colposcopy for the management of patients with CIN2.

Objective: To identify factors affecting adherence to medication, a subjective questionnaire survey was administered to schizophrenia patients regarding the prescribed antipsychotic formulations. Methods: We evaluated the patients’ satisfaction and dissatisfaction with prescribed antipsychotic formulations, and patients answered the Drug Attitude Inventory-10 Questionnaire (DAI-10). Inclusion criteria for patients are as follows:age between 20 and 75 years and taking antipsychotic agents containing the same ingredients and formulations, for at least 1 month. Results: In total, 301 patients answered the questionnaire survey. Tablets were found to be the most commonly used antipsychotic formulations among schizophrenia patients (n = 174, 57.8%), followed by long-acting injections (LAIs, n = 93, 30.9%). No significant differences in the formulation satisfaction level and DAI-10 scores were observed between all formulations. Formulations, except for LAI, were selected by physicians in more than half of the patients.Patients who answered “Decided by consultation with physicians” had significantly higher satisfaction levels and DAI-10 scores compared to those who answered “Decided by physicians” (4.11 ± 0.77 vs. 3.80 ± 1.00, p = 0.0073 and 6.20 ± 3.51 vs. 4.39 ± 4.56, p ＜ 0.001, respectively). Satisfaction levels moderately correlated with DAI-10 scores (r = 0.48, p ＜ 0.001). Conclusion No formulation had a high satisfaction level in all patients, and it is important to be reflect the patients’ individual preferences in pharmacotherapy. Shared decision-making in the selection of the formulations is seen to be useful for improving medication adherence.

Cough-variant asthma is the most common cause of chronic cough. It may progress to classic asthma and therefore requires adequate treatment intervention. We experienced two cases of cough-variant asthma that was refractory to standard drug therapy but improved after additional administration of kumibinroto. In Case 1, the patient was a 46-year-old woman receiving hormone therapy after breast cancer surgery. She developed cough-variant asthma 5 years ago, and though she has received drug therapy, the symptoms aggravated. Cough continued to appear at night without improvement of asthma symptoms. However, the symptoms improved with subsequent administration of kumibinroto. In Case 2, the patient was a 47-year-old woman who developed cough-variant asthma after childbirth, which repeatedly worsened and improved. The cough-variant asthma aggravated after change of workplace and did not improve with drug therapy. However, asthma symptoms improved with oral administration of kumibinroto and hangekobokuto, and subsequent administration of kumibinroto alone. In both patients, the asthma was seasonal. These cases suggest that kumibinroto administration may contribute to the improvement of cough-variant asthma.

Background/Aims: There are few published registry studies from Asia on pediatric inflammatory bowel disease (IBD). Registry network data enable comparisons among ethnic groups. This study examined the characteristics of IBD in Japanese children and compared them with those in European children. Methods: This was a cross-sectional multicenter registry study of newly diagnosed Japanese pediatric IBD patients. The Paris classification was used to categorize IBD features, and results were compared with published EUROKIDS data. Results: A total of 265 pediatric IBD patients were initially registered, with 22 later excluded for having incomplete demographic data. For the analysis, 91 Crohn’s disease (CD), 146 ulcerative colitis (UC), and 6 IBD-unclassified cases were eligible. For age at diagnosis, 20.9% of CD, 21.9% of UC, and 83.3% of IBD-unclassified cases were diagnosed before age 10 years. For CD location, 18.7%, 13.2%, 64.8%, 47.3%, and 20.9% were classified as involving L1 (ileocecum), L2 (colon), L3 (ileocolon), L4a (esophagus/stomach/duodenum), and L4b (jejunum/proximal ileum), respectively. For UC extent, 76% were classified as E4 (pancolitis). For CD behavior, B1 (non-stricturingon-penetrating), B2 (stricturing), B3 (penetrating), and B2B3 were seen in 83.5%, 11.0%, 3.3%, and 2.2%, respectively. A comparison between Japanese and European children showed less L2 involvement (13.2% vs. 27.3%, P< 0.01) but more L4a (47.3% vs. 29.6%, P< 0.01) and L3 (64.8% vs. 52.7%, P< 0.05) involvement in Japanese CD children. Pediatric perianal CD was more prevalent in Japanese children (34.1% vs. 9.7%, P< 0.01). Conclusions Upper gastrointestinal and perianal CD lesions are more common in Japanese children than in European children.

Intestinal spirochetosis is a rare gastrointestinal infection caused by Brachyspira. Clinical manifestations vary, ranging from asymptomatic infection to gastrointestinal bleeding, diarrhea, or abdominal pain. Antimicrobial medications such as metronidazole are routinely given, but their clinical efficacy has not determined with any precision. We report a case of intestinal spirochetosis treated with daikenchuto extract with literature reviews. Treatment of intestinal spirochetosis can be difficult, and use of daikenchuto extract may be an option especially for patients with symptoms such as chronic diarrhea, abdominal distention, or change in flatus.

Background: Gingyo-gedoku-san (GGGS) is an herbal medicine approved for upper respiratory infections in Japan. We conducted an open-label, multi-center, prospective trial, comparing GGGS with oseltamivir in patients with influenza and influenza-like illness (ILI) as a pilot study.
Methods: Subjects were healthy persons aged between 16 and 40, and were enrolled from January 12, 2010 to March 24, 2011. Fifteen patients were enrolled in this trial (8 and 7 for GGGS and oseltamivir, respectively). RT-PCR was positive for pandemic influenza A (H1N1) in 10 patients. The patients were provided with either GGGS or oseltamivir for 5 days. The primary outcome was mortality and/or hospitalization 7 days after the initial diagnosis. Body temperature and other clinical characteristics were also evaluated.
Results: All patients recovered from illness without complication or hospitalization. The mean time to resolve symptoms for the GGGS and oseltamivir groups was 3.9 days and 3.3 days, respectively (p=0.43). The GGGS group appeared to have a smaller symptom score AUC than the oseltamivir group, (p=0.26). Time to recover activity level appeared to be shorter in the GGGS group (p=0.10), with shorter time to recover health status (p=0.02). Sub-group analysis on patients with positive PCR showed similar results between the two groups.
Conclusion: GGGS was associated with symptom improvements resembling oseltamivir for both influenza and ILI. Randomized controlled trials involving larger sample sizes are needed to confirm these results.

The management of influenza has dramatically changed since the introduction of the rapid influenza diagnostic test, or RIDT, and neuraminidase inhibitors (NI). However, it is still far from optimal due to low RIDT sensitivity and problems involving NI such as side effects and the potential emergence of resistant virus.Therefore, we developed a decision-making model for the management of influenza, which includes Kampo medicines in its strategies. First, the severity of patients is evaluated. If a patient is judged at severe or high-risk, intravenous NI would be the main component of treatment. If a patient has neither a severe condition nor is at high-risk, the patient would be asked to choose either NI or Kampo medicine. In the former, RIDT would be used if pretest probability was less than 50%, but it would not be used if it was more than 50%, based on the lack of influence on the post-test probability. For the latter, RIDT would be not used in general as Kampo targets “phenomena”, not the virus per se. This model enables us to optimize the use of RIDT by appropriately selecting patients based on the characteristics of RIDT, and by avoiding unnecessary tests and their misinterpretation.

OBJECTIVE: In cervical intraepithelial neoplasia (CIN), p16INK4a immunohistochemistry has been reported to be a useful diagnostic biomarker. However, limited information is available about the association between the p16INK4a immunohistochemistry and the outcomes of CIN. Here, we report p16INK4a immunohistochemistry as an effective biomarker to predict the outcomes of CIN. METHODS: p16INK4a immunohistochemistry was performed in patients with CIN from January 2000 to August 2009. Among these patients, we have performed a retrospective analysis of the medical records to evaluate the outcome of CIN 1-2 and performed statistical analysis to determine the correlation between p16INK4a expression and the outcomes. We also performed HPV genotyping and analyzed the relation between the infecting human papillomavirus (HPV) genotype and the outcomes. RESULTS: A total of 244 patients, including 82 with CIN 1, 60 with CIN 2, and 102 with CIN 3, were examined. The rate of p16INK4a overexpression increased with increasing CIN grade, 20.7% for CIN 1, 80.0% for CIN 2, and 89.2% for CIN 3, with significant differences between CIN 1 and CIN 2-3 group. In the 131 CIN 1-2 patients, the progression rate was significantly higher for the patients showing p16INK4a overexpression than for those not showing p16INK4a overexpression (p=0.005); the regression rate was also found to be significantly lower for the patients showing p16INK4a overexpression (p=0.003). High-risk HPV genotypes were detected in 73 patients (73.7%). Both progression and regression rates were not significantly different between the high-risk HPV-positive and HPV-negative groups (p=0.401 and p=0.381, respectively). CONCLUSION: p16INK4a overexpression was correlated with the outcome of CIN 1-2, and p16INK4a is considered to be a superior biomarker for predicting the outcome of CIN 1-2 compared with HPV genotyping.
Cervical Intraepithelial Neoplasia ; Genotype ; Humans ; Immunohistochemistry ; Medical Records ; Retrospective Studies

Cancer stem cells (CSCs) play an important role in cancer development, its main functions are self-renewing capacity, chemoresistance and tumorigenic capacity. The aim of this study is to clarify the possible role of Shh signaling in regulation of CSCs. METHODS: Normal cancer cells (HCT-116) were cultured with serum medium and cancer stem-like cells (CSCs) were obtained from serum-free medium after incubation for 14 days. After cell culturing was done RNA extraction and cDNA transcription of NCs and CSCs (HCT-116). The expressions mRNA of surface markers (CD44, EpCAM), stemness genes (Oct-4, Nanog), Shh signaling (Ptch1, SMO), and shh pathway downstream gene (Gli1), EMT markers (E-Cadherin, Vimentin) and TJ genes (Claudin-4, Occludin) were determined by real time RT-PCR before and after administration of cyclopamine (2, 5 μM). RESULTS: The expressions of surface markers (CD44, EpCAM) and stemness genes (Oct-4, Nanog) were significantly highly expressed in CSCs. Shh signaling pathway Ptch1, SMO and downstream gene Gli1 were significantly higher in CSCs than in NCs. Epithelial marker E-Cadherin was reduced in CSCs, mesenchymal marker Vimentin was up-regulated in CSCs. The expressions of Claudin-4 and Occludin were significantly higher in CSCs compared with NCs. SMO, Gli1 and Vimnetin were significantly inhibited after administration of cyclopamine (2, 5μM), but E-Cadherin was up-regulated in CSCs. Tight junction proteins were significantly inhibited by cyclopamine (2, 5μM). Although CD-44, Oct-4 and Nanog were inhibited in CSCs after administration of cyclopamine, these alterations were statistically significant in different genes respectively, but EpCAM was not inhibited. CONCLUSION: EMT, TJ and CSCs markers were affected by Shh signaling pathway in CSCs. Shh signaling pathway may play in an important role of regulation of CSCs.