Increasing Effects of Selective 5-Hydroxytryptamine Type 2C Receptor Stimulation on Evoked Momentary Urethral Closure in Female Rats and Humans.

Under healthy conditions, more than one urethra-closing reflex, including both bladder afferent-independent and -dependent actions, function during momentary elevation of intravesical (bladder) pressure to prevent urinary incontinence. In the current study, the effects of a novel selective 5-hydroxytryptamine type 2C (5-HT2C) receptor agonist, TAK-233, on evoked momentary urethra-closing functions were investigated in female rats and humans to elucidate 5-HT2C receptor functions. In anesthetized female rats, TAK-233 dose-dependently and significantly increased urethral resistance during sneezing in rats with distended vaginas and bilaterally transected pelvic nerves. The drug also dose-dependently and significantly increased urethral resistance during momentary intravesical pressure elevation by electrical stimulation of abdominal muscles in rats with a transected spinal cord at the T8-T9 level and intact pelvic nerves. The increased effects observed during electrical stimulation were abolished by either an intravenously administered selective 5-HT2C receptor antagonist, SB 242084, or bilateral transection of the pelvic nerves or somatic nerves innervating the external urethral sphincter and pelvic floor muscles. In the spinal cord-transected and pelvic nerve-intact rats, TAK-233 enlarged the urethra-closing responses induced by both passive and abrupt intravesical pressure elevation, measured by a microtip transducer located in the middle urethra. Additionally, the effects of TAK-233 on the stimulus threshold of urethral contractile responses induced by transcranial magnetic stimulation were investigated in healthy female volunteers. The drug dose-dependently and significantly lowered this stimulus threshold, indicating an increased sensitivity of the response. These results demonstrate that 5-HT2C receptor stimulation enhances the evoked momentary urethra-closing functions in both female rats and humans. SIGNIFICANCE STATEMENT: 5-hydroxytryptamine (serotonin) type 2C (5-HT2C) receptor stimulation by TAK-233 enhanced urethral resistance in rats during an evoked momentary event in which the bladder afferent-independent or -dependent reflex functions via striated muscle-mediated mechanisms. The increases in sensitivity of transcranial magnetic stimulation-evoked urethral contractile responses in healthy female subjects indicates that this mechanism also functions in humans. The evoked momentary conditions activating these reflexes provide a suitable model to demonstrate the effects of 5-HT2C receptor stimulation.

Efficacy of intraperitoneally administered paclitaxel for colorectal cancer with peritoneal metastases.

PURPOSE: Prognosis after peritoneal metastases in colorectal cancer is worse than that after lung or liver metastases. Previously, we demonstrated the safety of intraperitoneal (ip) administration of paclitaxel (PTX) combined with mFOLFOX6/CapeOX plus bevacizumab for colorectal cancer with peritoneal metastasis in a phase-I trial. Here, we evaluated the efficacy of this chemotherapy. METHODS: We enrolled six patients with histologically confirmed peritoneal metastases secondary to colorectal cancer. PTX was administered through a peritoneal access port, in combination with oxaliplatin-based systematic chemotherapy. Response rate, progression-free survival, 1-year survival rate, frequency of improvement in peritoneal cancer index (PCI), and cytology in peritoneal lavage were evaluated. This study was registered in the University Hospital Medical Information Network Clinical Trial Registry on July 1, 2016 (UNIN000022924). RESULTS: Three patients received the mFOLFOX6-bevacizumab regimen, whereas the other three received the CapeOX-bevacizumab regimen. The response rate was 25%. PCI score improved in 50% of the cases. Peritoneal lavage cytology that was positive in five patients before initiating the chemotherapy turned negative during chemotherapy in all patients. One-year survival rate was 100%, progression-free survival was 8.8 months (range, 6.8-12 months), and median survival time was 29.3 months. CONCLUSION: The ip administration of PTX with systemic chemotherapy can potentially control peritoneal metastases in colorectal cancer.

LGR5 expression predicts peritoneal recurrence after curative resection of primary colon cancer.

BACKGROUND: The aim of this study was to clarify whether a cancer stem cell marker could be an indicator of post-operative peritoneal recurrence of colon cancer. METHODS: Expression of four putative markers (CD133, CD44 variant 6, aldehyde dehydrogenase-1 and leucine-rich repeating G-protein-coupled receptor-5 (LGR5)) was evaluated immunohistochemically in primary tumour samples from 292 patients who underwent curative resection for non-metastasised pT4 colon cancer at the University of Tokyo Hospital between 1997 and 2015. RESULTS: Peritoneal recurrence was significantly higher in LGR5-negative cases (5-year cumulative incidence: 27.5% vs. 14.4%, p = 0.037). Multivariable analysis confirmed that negative LGR5 expression was an independent risk factor for peritoneal recurrence (hazard ratio (HR) 2.79, p = 0.005) in addition to poor differentiation, positive lymph node metastasis, preoperative carcinoembryonic antigen > 5 ng/mL and anastomotic leakage. The addition of LGR5 significantly improved the predictive value of the multivariable model (net reclassification improvement: 0.186, p = 0.028: integrated discrimination improvement: 0.047, p = 0.008). CONCLUSIONS: Negative LGR5 expression was a significant predictor of peritoneal recurrence in patients with pT4 colon cancer. Therefore, LGR5 might be a promising biomarker to identify patients at high risk of post-operative peritoneal metastasis.

A MicroRNA Signature Associated With Metastasis of T1 Colorectal Cancers to Lymph Nodes.

Most T1 colorectal cancers treated by radical surgery can now be cured by endoscopic submucosal dissection. Although 70%-80% of T1 colorectal cancers are classified as high risk, <16% of these patients actually have lymph node metastases. Biomarkers are needed to identify patients with T1 cancers with the highest risk of metastasis, to prevent unnecessary radical surgery. We collected data from The Cancer Genome Atlas and identified 5 microRNAs (MIR32, MIR181B, MIR193B, MIR195, and MIR411) with significant changes in expression in T1 and T2 colorectal cancers with vs without lymph node metastases. Levels of the 5 microRNAs identified patients with lymph node invasion by T1 or T2 cancers with an area under the receiver operating characteristic curve (AUROC) value of 0.84. We validated these findings in 2 cohorts of patients with T1 cancers, using findings from histology as the reference. The 5-microRNA signature identified T1 cancers with lymph node invasion in cohort 1 with an AUROC value of 0.83, and in cohort 2 with an AUROC value of 0.74. When we analyzed biopsy samples from untreated patients, the 5-microRNA signature identified cancers with lymph node metastases with an AUROC value of 0.77. The 5-microRNA therefore identifies high-risk T1 colorectal cancers with a greater degree of accuracy than currently used pathologic features.

Development and Validation of a Prediction Model for Organ-Specific Recurrences After Curative Resection of Colon Cancer.

BACKGROUND: Early detection of postoperative recurrence is beneficial for patients with cancer; however, optimal surveillance remains an issue. To optimize the follow-up plan, the estimation of an individual patient's risk of recurrence is indispensable. OBJECTIVE: This study aimed to establish a statistical model for predicting the risk of organ-specific recurrence after curative resection of colon cancer. DESIGN: This was a retrospective cohort study at a tertiary referral hospital. SETTINGS: This study included 1720 patients with colon cancer treated at the University of Tokyo Hospital between 1997 and 2015. Data were retrospectively retrieved from patient medical charts. The risk score was developed using a competing risk model in a derivation cohort (973 patients treated in 1997-2009) and then validated in a validation cohort (747 patients treated in 2010-2015). PATIENTS: Patients who underwent curative resection for stage I to III colon cancer were included. MAIN OUTCOME MEASURES: The prediction of the incidence of postoperative liver and lung metastasis of colon cancer was measured. RESULTS: The factors selected for the prediction model for liver metastasis included differentiation, T category, venous invasion, N category, and preoperative CEA level. The model for lung metastasis included sex, lymphatic invasion, venous invasion, N category, preoperative CEA level, and malignant bowel obstruction. During external validation, the area under the curve at 60 months was 0.78 (95% CI, 0.71-0.84) for liver metastasis and 0.72 (95% CI, 0.64-0.81) for lung metastasis. LIMITATIONS: The generalizability of the model to different healthcare settings remains to be elucidated. CONCLUSIONS: We developed a prediction model to estimate the risk of recurrence in the liver and lung after curative resection of colon cancer, which demonstrated good discrimination ability in the external validation cohort. Our model can aid clinicians and patients in customizing postoperative surveillance according to an individual patient's risk of organ-specific recurrence. See Video Abstract at http://links.lww.com/DCR/A977. DESARROLLO Y VALIDACIÓN DE UN MODELO DE PREDICCIÓN PARA RECURRENCIAS ESPECÍFICAS DESPUÉS DE RESECCIÓN CURATIVA DE UN CÁNCER DE COLON: La detección temprana de una recidiva postoperatoria es beneficiosa para los pacientes afectados de cáncer. Sin embargo, la mejor vigilancia sigue siendo un problema. Para optimizar el plan de seguimiento, la estimación del riesgo individual de recurrencia de un paciente es indispensable. OBJETIVO: Establecer un modelo estadístico para predecir el riesgo de recurrencia en un organo específico luego de la resección curativa de un cáncer de colon. DISEÑO:: Estudio retrospectivo de cohortes en un hospital de referencia terciaria. AJUSTES: Este estudio incluyó 1720 pacientes con cáncer de colon tratados en el Hospital de la Universidad de Tokio entre 1997 y 2015. Los datos se recuperaron retrospectivamente de las historias clinicas de los pacientes. La puntuación de riesgo fué desarrollada utilizando un modelo de riesgo competitivo en cohortes de derivación (973 pacientes tratados en 1997-2009) y luego se lo validó en cohortes de validación (747 pacientes tratados en 2010-2015). PACIENTES: Todos aquellos casos que se sometieron a una resección curativa de cáncer de colon en estadio I-III RESULTADOS PRINCIPLES:: La predicción de la incidencia de metástasis hepáticas y pulmonares postoperatorias del cáncer de colon. RESULTADOS: Los factores seleccionados para el modelo de predicción de metástasis hepáticas incluyeron diferenciación tumoral, categoría T, invasión venosa, categoría N y nivel de antígeno carcinoembrionario preoperatorio. El modelo de predicción de metástasis pulmonar incluyó el sexo del paciente, la invasión linfática, la invasión venosa, la categoría N, el nivel de antígeno carcinoembrionario preoperatorio y la obstrucción intestinal maligna. Durante la validación externa, el área inferior de la curva a 60 meses fue de 0,78 (intervalo de confianza del 95%: 0,71 a 0,84) para las metástasis hepáticas y de 0,72 (intervalo de confianza del 95%: 0,64 a 0,81) para las metástasis pulmonares. LIMITACIONES: La generalización del presente modelo a diferentes entornos de atención en salud aún no ha podido ser dilucidado. CONCLUSIONES: Desarrollamos un modelo de predicción para estimar el riesgo de recurrencia en el hígado y el pulmón después de resección curativa de cáncer de colon, éste modelo demostró una buena capacidad de discriminación en las cohortes de validación externa. El modelo puede ayudar a médicos y pacientes a personalizar la vigilancia postoperatoria de acuerdo con el riesgo individual de recurrencia específica en un órgano específico. Vea el Resumen del Video en http://links.lww.com/DCR/A977.

Prognostic significance of doubling time in patients undergoing radical surgery for metachronous peritoneal metastases of colorectal cancer.

PURPOSE: The doubling times of tumor volume and tumor markers are associated with the prognosis of liver or lung metastases from colorectal cancer (CRC). However, no studies have assessed peritoneal metastases. Therefore, we aimed to elucidate the association between doubling time and the prognosis of patients who underwent radical surgery for metachronous peritoneal metastases of CRC. METHODS: We calculated the tumor doubling times (TDT) of peritoneal metastases and serum carcinoembryonic antigen-doubling times (CEA-DT) in 33 consecutive patients who underwent radical surgery for metachronous peritoneal metastases between January 2006 and April 2017. The impact of short TDT and CEA-DT on overall survival (OS) and relapse-free survival (RFS) was retrospectively reviewed. RESULTS: In long TDT (> 137 days) group, the 5-year OS rate was 74.1% and median OS time was 6.6 years. In long CEA-DT (> 102 days) group, the 5-year OS rate was 50.0% and median OS time was 5.6 years. Conversely, in short TDT (≤ 137 days) and CEA-DT (≤ 102 days) group, the 5-year OS rates and median OS times were both 0.0% and 3.2 years, respectively. In the multivariate analysis, short TDT was an independent risk factor for poor RFS (P = 0.006) and OS (P = 0.010). Similarly, short CEA-DT was also a poor risk factor for RFS (P < 0.001) and OS (P = 0.012). CONCLUSIONS: Short TDT and CEA-DT are independent risk factors for poor OS and RFS after surgery for metachronous peritoneal metastases of CRC. TDT and CEA-DT should be considered when selecting candidates for surgical resection.

Development and Validation of a Prediction Model for Postoperative Peritoneal Metastasis After Curative Resection of Colon Cancer.

BACKGROUND: Detection of peritoneal metastasis remains challenging due to the limited sensitivity of current examination methods. This study aimed to establish a prediction model for estimating the individual risk of postoperative peritoneal metastasis from colon cancer to facilitate early interventions for high-risk patients. METHODS: This study investigated 1720 patients with stages 1-3 colon cancer who underwent curative resection at the University of Tokyo Hospital between 1997 and 2015. The data for the patients were retrospectively retrieved from their medical records. The risk score was developed using the elastic net techniques in a derivation cohort (973 patients treated in 1997-2009) and validated in a validation cohort (747 patients treated in 2010-2015). RESULTS: The factors selected using the elastic net approaches included the T stage, N stage, number of examined lymph nodes, preoperative carcinoembryonic antigen level, large bowel obstruction, and anastomotic leakage. The model had good discrimination (c-index, 0.85) and was well-calibrated after application of the bootstrap resampling method. Discrimination and calibration were favorable in external validation (c-index, 0.83). The model presented a clear stratification of patients' risk for postoperative peritoneal recurrence, and decision curve analysis showed its net benefit across a wide range of threshold probabilities. CONCLUSIONS: This study established and validated a prediction model that can aid clinicians in optimizing postoperative surveillance and therapeutic strategies according to the individual patient risk of peritoneal recurrence.

High-Pressure Synthesis, Crystal Chemistry, and Ionic Conductivity of a Structural Polymorph of Li3BP2O8.

A new structural polymorph of Li3BP2O8 has been successfully synthesized via a solid-state reaction between Li3PO4 and BPO4 at 4 GPa and 600 °C. The high-pressure phase of Li3BP2O8 (HP-Li3BP2O8) was found to crystallize in monoclinic symmetry with the cell parameters of a = 8.57010(4) Å, b = 11.11812(5) Å, c = 5.55380(3) Å, and ß = 97.7269(3)° [space group P21/ a (No. 14)]. HP-Li3BP2O8 has a new crystal structure that has not been reported so far. The total ionic conductivities measured for the polycrystalline sample by alternating-currrent impedance were 3.4 × 10-7 and 2.1 × 10-6 S/cm at 399 and 456 K, respectively. The lithium ionic conductivity of HP-Li3BP2O8 was higher than that of the low-pressure phase Li3BP2O8 in the temperature range of 375-456 K. This is caused by the difference in the dimensions of the lithium arrangements between LP- and HP-Li3BP2O8.

Survival and Prognostic Factors for Metachronous Peritoneal Metastasis in Patients with Colon Cancer.

BACKGROUND: The clinical course of metachronous peritoneal metastasis of colorectal origin is poorly understood. In this retrospective study, we aimed to elucidate survival and prognostic factors for metachronous peritoneal metastasis. METHODS: Patients with metachronous peritoneal metastasis after curative resection for stage I-III colon cancer were retrospectively reviewed, and the incidence and prognosis of metachronous peritoneal metastasis were investigated. Prognostic factors were identified by univariate and multivariate analyses. RESULTS: Among 1582 surgically resected stage I-III colon cancer patients, 65 developed metachronous peritoneal metastasis. The 5-year cumulative incidence rate was 4.5%, and the median survival after diagnosis of peritoneal metastasis was 29.6 months. None of the patients underwent peritonectomy or intraperitoneal chemotherapy. Independent prognostic factors included right colon cancer [hazard ratio (HR) 2.69, 95% confidence interval (CI) 1.26-5.64; p = 0.011], time to metachronous peritoneal metastasis of <1 year (HR 2.02, 95% CI 1.04-3.87; p = 0.040), Peritoneal Cancer Index (PCI) >10 (HR 3.68, 95% CI 1.37-8.99; p = 0.012), concurrent metastases (HR 4.09, 95% CI 2.02-8.23; p < 0.001), and peritoneal nodule resection (HR 0.31, 95% CI 0.13-0.65; p = 0.002). CONCLUSIONS: A proportion of colon cancer patients with metachronous peritoneal metastasis may benefit from combined peritoneal nodule resection and systemic chemotherapy. Right colon cancer, early peritoneal metastasis, a high PCI, and concurrent metastases negatively affected prognosis in patients with metachronous peritoneal metastasis.

Association of baseline plasma des-acyl ghrelin level with the response to rikkunshito in patients with functional dyspepsia.

BACKGROUND AND AIM: We recently conducted a randomized placebo-controlled trial on the efficacy and safety of rikkunshito, a standardized Japanese herbal medicine, for the treatment of functional dyspepsia (FD). The present post-hoc study aimed to evaluate the differences in clinical characteristics between responders and non-responders among FD patients who received rikkunshito for 8 weeks. METHODS: Rikkunshito responders were defined by using a global patient assessment. Candidate predictors included age, gender, smoking, alcohol consumption, body mass index, comorbidity, Helicobacter pylori infection, plasma levels of acyl ghrelin and des-acyl ghrelin, severity of dyspeptic symptoms, FD subgroup, previous medication, and the type of recruiting institution (clinic or hospital). We calculated hazard ratios (HRs) by using Cox regression analysis with the factors that were indicated to be associated with responders. RESULTS: We assigned 83 and 42 patients to responder and non-responder categories, respectively. Lack of alcohol consumption (HR, 2.04; 95% confidence interval, 1.08-3.88) and low plasma des-acyl ghrelin levels (< 177 fmol/mL; HR, 2.42; 95% confidence interval, 1.24-4.73) were significantly associated with the efficacy of rikkunshito. Lack of alcohol consumption was associated with the efficacy of rikkunshito especially among H. pylori-infected participants. On the other hand, the low plasma des-acyl ghrelin was associated with the efficacy of rikkunshito especially among H. pylori-negative participants. CONCLUSIONS: A low baseline level of plasma des-acyl ghrelin was associated with an increased treatment efficacy of rikkunshito against FD. Lack of alcohol consumption was also clinically useful for predicting the response to rikkunshito.

Long-Term Clinical Course after Conservative and Endoscopic Treatment of Colonic Diverticular Bleeding.

BACKGROUND/AIM: What naturally happens to patients after they undergo conservative and endoscopic treatment of colonic diverticular bleeding (CDB) is largely unknown. We retrospectively track the long-term outcome of the recurrence of CDB between patients with endoscopic and conservative treatment. METHODS: The group was divided into 2 groups: patients treated with injection and/or clipping (endoscopic group) and patients in whom such treatment could not be performed (conservative group). CDB recurrence was assessed via a questionnaire, and recurrence rates were investigated between groups using the Kaplan-Meier's method. The Cox proportional hazards model was performed to identify potential risk factors for recurrence. RESULTS: Eighty-eight patients answered the questionnaires. The median (interquartile range) follow-up period was 42.7 (61.8) months. Twenty-four (38.7%) of 62 conservatively treated patients and 16 (61.5%) of 26 endoscopically treated patients experienced recurrence of CDB during the follow-up period. Kaplan-Meier's analysis showed that the rate of recurrence was significantly higher (p < 0.05) in cases with endoscopic treatment than in those with conservative treatment (mean time to recurrence = 55.3 months (95% CI 30.8-79.9) vs. 99.9 months (95%CI 80.7-119.1)). The Cox proportional hazards model did not identify any significant variables. CONCLUSION: We should carefully follow-up patients to check for the recurrence of CDB, even when it could be successfully treated endoscopically. Can endoscopic treatment of CDB prevent CDB recurrence? Also, what happens to the patient's well-being after they undergo conservative and endoscopic treatment (cases diagnosed by Jensen's criteria) is largely unknown. We examined a population of patients undergoing conservative or endoscopic treatment to clarify the clinical course, particularly with regard to CDB recurrence.

Surgeons have knowledge gaps in the safe use of energy devices: a multicenter cross-sectional study.

BACKGROUND: Despite the widespread use of surgical energy devices and the potential for rare but serious complications, pilot data from North America suggest that surgeons and surgical trainees have knowledge gaps in their safe use. The purpose of this study was to determine baseline knowledge of general surgeons and surgical trainees regarding the safe use of electrosurgery (ES) across varying levels of experience in Japan. METHODS: Participants completed a 35-item multiple-choice question examination, testing critical knowledge of ES. The examination was developed according to the objectives and blueprints of SAGES' Fundamental Use of Surgical Energy™ curriculum. Sections of the examination included: "principles of ES," "ES-related adverse events," "monopolar and bipolar devices," and "pediatric considerations and interference with implantable devices." Scores were compared between PGY > 5 and PGY 1-5 participants. RESULTS: A total of 145 general surgeons and surgical trainees of all years after medical school (PGY 1-5: 57, PGY > 5: 88) from ten academic and five community hospitals completed the assessment (mean age 35; 91% male). The mean score in the entire cohort was 58 ± 12% (range 23-83%), with significantly higher scores in the PGY > 5 group compared to the PGY 1-5 group (60 ± 11 vs. 53 ± 12%, p < 0.01). Among all participants, 92% were not familiar with best practices when using ES on patients with a pacemaker; 44% believe that ES uses thermal energy from cautery; 19% did not know how to manage an operating room fire; 16% thought that a dispersive electrode should be cut to fit a child; and 27% believe that insulation failure in minimally invasive surgical instruments is mostly visible under careful inspection. CONCLUSIONS: General surgeons and trainees at all levels have knowledge gaps in the safe and effective use of energy devices, regardless of years of experience. There is a need for educational curricula to help address these gaps and contribute to safer surgery.

Comparative Study of Direct Immunofluorescence in Discoid Lupus Erythematosus and Bullous Pemphigoid.

Immunoreactants are found in the epidermal basement membrane in both lupus erythematosus and bullous pemphigoid (BP). To our knowledge, there are no comparative studies on direct immunofluorescence (DIF) of discoid lupus erythematosus (DLE) and BP. The authors studied DIF of lesional skins in 9 patients (2 males and 7 females) with DLE and 29 patients (11 males and 18 females) with BP to disclose the difference between these 2 diseases. IgG deposition was significantly more frequent at the epidermal basement membrane zone (BMZ) in the BP group than in the DLE group; however, IgA and IgM depositions were significantly more frequent at both the epidermal and follicular BMZs in the DLE group than in the BP group. In addition, the mean number of positive immunoreactants at both the epidermal and follicular BMZs was significantly larger in the DLE group than in the BP group. On an average, ≥3 immunoreactants were seen at the epidermal and follicular BMZs in DLE, whereas ≤2.5 immunoreactants were seen in BP. DIF may contribute to the differentiation between these 2 diseases.

Recurrence of pancreatic cancer presented as cervical lymphadenopathy.

BACKGROUND: We report a case of recurrent pancreatic cancer that presented as cervical lymphadenopathy. CASE PRESENTATION: A 69-year-old woman with stage IIb pancreatic cancer underwent a curative Whipple's procedure after neoadjuvant chemoradiation therapy. Despite adjuvant chemotherapy with S-1, postoperative recurrence was diagnosed as left cervical lymphadenopathy 11 months postoperatively. After she underwent chemoradiation therapy to the cervical area followed by systemic chemotherapy with S-1, the lymphadenopathy became unremarkable 17 months postoperatively. S-1 treatment was discontinued 23 months postoperatively at the patient's request. She has remained free of disease since that time and has achieved an overall duration of survival of 48 months. CONCLUSIONS: To the best of our knowledge, this is the first reported case of middle cervical lymph node metastasis of pancreatic cancer. Although rare, it should be considered as a site of recurrence. This case suggests concurrent radiation therapy can be a good option for patients who cannot tolerate an aggressive regimen.

A giant mucinous cystadenocarcinoma of the appendix: a case report and review of the literature.

BACKGROUND: Mucinous cystadenocarcinoma is the second most common etiology of appendiceal mucocele. We report a relatively rare case of a giant appendiceal mucocele caused by mucinous cystadenocarcinoma, which occupied the entire abdomen of an adult woman. CASE PRESENTATION: A 63-year-old woman presented with a chief complaint of abdominal distention. Imaging studies showed a giant cystic mass occupying her entire abdomen. Laparotomy confirmed a giant appendiceal mucocele, and the patient underwent ileocecal resection. A mucinous deposit was not found in her abdominal cavity, and the ovaries were grossly normal bilaterally. The pathological diagnosis was mucinous adenocarcinoma with a low-grade mucinous neoplasm that invaded the subserosa. Regional lymph node metastasis was not found. She has had recurrence-free survival for 5 years. CONCLUSIONS: The present case is the largest appendiceal cystadenocarcinoma ever reported. The optimal treatment of an appendiceal neoplasm requires further research based on consensus terminology of an appendiceal mucocele.

A Multicenter, Randomized, Open-Label Trial: Efficacy of Once-Daily Versus Twice-Daily Double-Dose Rabeprazole on Refractory Gastroesophageal Reflux Disease-Related Symptoms and Quality of Life.

BACKGROUND: Approximately 20% to 40% of patients with gastroesophageal reflux disease (GERD) are refractory to standard-dose proton-pump inhibitor (PPI) treatment. OBJECTIVE: We compared the efficacy and quality-of-life effects of 20 mg once daily (QD) versus 10 mg twice daily (BID) rabeprazole (RPZ) in patients with refractory GERD-related symptoms and sleep disturbances. METHODS: This multicenter, prospective, randomized, open-label study included patients in whom PPI treatment >4 weeks was ineffective. According to the Global Overall Symptom (GOS) scale, PPI-refractory GERD was defined as ≥1 category with >3 points among 10 specific upper gastrointestinal symptoms. Seventy-eight patients were randomly assigned to 20 mg QD and 10 mg BID RPZ groups for 8 weeks. Efficacy was evaluated using self-reported questionnaires, including the GOS scale and Pittsburg Sleep Quality Index (PSQI), whereas quality of life was assessed using the Short-Form 8 Health Survey (SF-8), at 4 and 8 weeks. Patients showing improvement at 8 weeks received follow-up every 4 to 8 weeks. RESULTS: GOS scale scores were significantly improved at 8 weeks in both groups, with no significant intergroup differences. Although SF-8 scores showed an increasing trend over 8 weeks in both groups, the physical component summaries in the 10 mg BID group significantly improved. The mental component summaries clearly improved in the 10 mg BID group. Of the 74 cases (4 missing), 51 (68.9%) had PSQI scores ≥5.5. PSQI scores remained unchanged during follow-up in both groups. The recurrence rate was not significantly different (46.1% vs 47.1% in the 20 mg QD and 10 mg BID groups, respectively) during the follow-up period at median (interquartile range) 24.0 (30.5) months. CONCLUSIONS: In patients with refractory GERD, there was no significant difference in GOS scale score, PSQI, or recurrence rate between the groups. With regard to subscores of the SF-8, the 10 mg BID group might be potentially effective.

Poly I:C enhances production of nitric oxide in response to interferon-γ via upregulation of interferon regulatory factor 7 in vascular endothelial cells.

The effect of poly I:C on interferon (IFN)-γ-induced nitric oxide (NO) production in vascular endothelial cells was examined using murine aortic endothelial END-D cells. Poly I:C augmented IFN-γ-induced NO production although it alone did not induce the NO production. Poly I:C augmented the NO production via enhanced expression of an inducible NO synthase protein. Poly I:C did not affect the activation of Janus kinase (JAK) 1/2, and signal transducer and activator of transcription (STAT) 1 in IFN-γ signaling. Moreover, there was no significant difference in the IFN-γ-induced interferon regulatory factor (IRF) 1 expression between the presence and absence of poly I:C. Poly I:C led to the activation of IRF7 in END-D cells. Inhibition of poly I:C signaling by amlexanox, an inhibitor of TANK-binding kinase (TBK) 1 and IκB kinase (IKK) ε, abolished the augmentation of IFN-γ-induced NO production. Therefore, poly I:C was suggested to augment IFN-γ-induced NO production at the transcriptional level via enhanced IRF7 activation.

Novel quinuclidinyl heteroarylcarbamate derivatives as muscarinic receptor antagonists.

Herein, we describe the synthesis and pharmacological profiles of novel quinuclidinyl heteroarylcarbamate derivatives. Among them, the quinuclidin-4-yl thiazolylcarbamate derivative ASP9133 was identified as a promising long-acting muscarinic antagonist (LAMA) showing more selective inhibition of bronchoconstriction against salivation and more rapid onset of action in a rat model than tiotropium bromide.

Differentiating a large abdominal cystic lymphangioma from multicystic mesothelioma: report of a case.

We report a case of retroperitoneal cystic lymphangioma in a 30-year-old woman who presented with abdominal distention and pain. Imaging studies revealed a large, thin-walled multicystic mass occupying the whole abdomen. Based on a preoperative diagnosis of multicystic mesothelioma, we performed laparotomy, which revealed a tumor arising from the gastropancreatic ligament in the posterior wall of the omental bursa. We resected the tumor completely, without the adjacent viscera. The final pathological diagnosis was cystic lymphangioma, based on the immunohistochemical findings of positive CD31 and CD34 expression, the presence of smooth muscle confirmed by smooth muscle antigen and desmin, and negative calretinin, WT-1 and cytokeratins 5/6 expression. Multicystic mesotheliomas and cystic lymphangiomas are so similar in morphology that immunohistochemical staining should be fully utilized to differentiate them.

[A case of colorectal cancer with pelvic recurrence treated by systemic chemotherapy and radiotherapy].

A 63-year-old man who had a history of rectal cancer and was treated with low anterior resection in February 2006, presented with liver metastases in September 2007 and underwent right anterior sectionectomy of the liver. He developed a pelvic wall recurrence with buttock pain in September 2009. This was treated with conventional radiation therapy and Cyber- Knife. The buttock pain was relieved after CyberKnife treatment and the patient received systemic chemotherapy in the outpatient clinic. Subsequently, he developed a left sacral recurrence with buttock pain and gait disturbance in August 2013. Since the tumor was located close to the field previously subjected to radiotherapy, we opted for CyberKnife treatment again. Although the pain subsided, our patient died of lymphangitic carcinomatosis in April 2014, 7 years and 2 months after the surgery. In this case, CyberKnife was effective in treating pelvic recurrence with pain, and thus, may have a significant role to play in the multidisciplinary treatment of metastatic colorectal cancer.