Association of non-steroidal anti-inflammatory drug use with encephalopathy development: An analysis using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases.

Encephalopathy is the most severe complication of various common infections, including influenza and herpes, and it often results in death or severe neurological disability. The risk factors for viral encephalopathy include non-steroidal anti-inflammatory drug (NSAID) use; however, studies on NSAID-related encephalopathy are limited. In this study, we aimed to investigate the characteristics of NSAID-related encephalopathy. We investigated the incidence of NSAID-related encephalopathy using data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) databases containing reports on spontaneous adverse effects (AEs) published by the Pharmaceuticals and Medical Devices Agency. We used these databases to detect AEs based on reported odds ratios. By separating suspicious drugs, concomitant drugs, and drug interactions involving NSAIDs, we investigated the relationship between encephalopathy pathology and AEs of NSAIDs. Significant encephalopathy signals were detected for loxoprofen and etodolac in the FAERS database and loxoprofen in the JADER database. In the JADER database, significant encephalopathy signals in loxoprofen-treated patients were detected in 70-79-year-old, ≥80-year-old, influenza viral infection, and herpes virus infection groups. Significant encephalopathy signals in patients with herpes virus infection were detected in the ≥80-year-old and loxoprofen-treated groups. Regarding the involvement of loxoprofen in the development of encephalopathy, the JADER database listed loxoprofen as a suspect drug, without indicating any concomitant drug interactions. In conclusion, our findings suggest that loxoprofen and etodolac may be associated with viral encephalopathy. Accordingly, prudence is recommended when using loxoprofen in older individuals with viral infections.

Inguinal hernia repair in patients with artificial urinary sphincter after radical prostatectomy.

PURPOSE: Stress urinary incontinence (UI) often develops after radical prostatectomy for prostate cancer, and in those patients with moderate-to-severe stress UI an artificial urinary sphincter (AUS) is implanted. Inguinal hernias (IHs) often occur after radical prostatectomy. As the prevalence of AUS implantation increases, it is possible to encounter patients with IHs undergoing AUS implantation (IHA). This study investigated our treatment and discussed an appropriate approach for IHAs. METHODS: We retrospectively investigated patients who underwent IH repair with AUS implantation at our hospital from January 2018 to March 2023. We classified IHAs into Types A-D based on the positions of the IHs and AUS devices (the positions of the control pump, pressure-regulating balloon, and connecting tube). The hernia and control pump were ipsilateral in Types A and B, whereas the hernia and pressure-regulating balloon were ipsilateral in Types A and C. RESULTS: This study included 12 IHs of 11 patients. The median patient age was 77 years. We conducted open repair in nine patients with all types and laparoscopic repair in two patients with Type B. The median operation times for unilateral and bilateral repairs were 96 and 182 min, respectively. There were no complications with AUS or hernia surgeries. CONCLUSION: IHA has its own characteristics, and multidisciplinary knowledge thereof will help surgeons safely perform IH surgery.

Analysis of Urinary Retention Caused by Selective ß 3-adrenoceptor Agonists Using the Japanese Adverse Drug Event Report Database (JADER).

Overactive bladder (OAB) is a frequent chronic disorder which impairs quality of life by frequent, uncontrollable urination. Newly developed selectiveß 3-adrenoceptor agonists (sß 3-agonists) have the same efficacy in treating OAB but significantly fewer side effects than the traditionally used anti-muscarinics. However, safety data on these compounds are scarce. In this study, we analysed the occurrence of adverse effects in patients taking sß 3-agonists and their characteristics using the JADER database. The most frequently reported adverse effect associated with the use of sß 3-agonists was urinary retention [mirabegron; crude reporting odds ratios (ROR): 62.1, 95% confidence interval (CI): 52.0-73.6, P<0.001, vibegron; crude ROR: 250, 95% CI : 134-483, P<0.001]. Data from patients with urinary retention were stratified by sex. In both men and women, the rate of urinary retention was higher when using the mirabegron/anti-muscarinic drug when compared to mirabegron monotherapy; its occurrence was higher in men with a history of benign prostatic hypertrophy than in those without. Weibull analysis showed that approximately 50% of sß 3 agonist-induced urinary retention occurred within 15 days after initiation of treatment, and then gradually decreased. Although sß 3-agonists are useful against OAB, they may induce several side effects, especially urinary retention, which can further evolve into more severe conditions. Urinary retention occurs more frequently in patients concomitantly taking medication that either increases urethral resistance or has organic factors that block the urethra. When using sß 3-agonists, the concomitantly used medications and underlying diseases should be thoroughly reviewed, and safety monitoring should be instituted early during the treatment.

Prediction of surgical difficulty in minimally invasive surgery for rectal cancer by use of MRI pelvimetry.

BACKGROUND: Technical difficulties in rectal surgery are often related to dissection in a limited surgical field. This study investigated the clinical value of MRI pelvimetry in the prediction of surgical difficulty associated with minimally invasive rectal surgery. METHODS: Patients with rectal cancer who underwent laparoscopic or robotic total mesorectal excision between 2005 and 2017 were reviewed retrospectively and categorized according to surgical difficulty on the basis of duration of surgery, conversion to an open procedure, use of the transanal approach, postoperative hospital stay, blood loss and postoperative complications. Preoperative clinical and MRI-related parameters were examined to develop a prediction model to estimate the extent of surgical difficulty, and to compare anastomotic leakage rates in the low- and high-grade surgical difficulty groups. Prognosis was investigated by calculating overall and relapse-free survival, and cumulative local and distant recurrence rates. RESULTS: Of 121 patients analysed, 104 (86·0 per cent) were categorized into the low-grade group and 17 (14·0 per cent) into the high-grade group. Multivariable analysis indicated that high-grade surgical difficulty was associated with a BMI above 25 kg/m2 (odds ratio (OR) 4·45, P = 0·033), tumour size 45 mm or more (OR 5·42, P = 0·042), anorectal angle 123° or more (OR 5·98, P = 0·028) and pelvic outlet less than 82·7 mm (OR 6·62, P = 0·048). All of these features were used to devise a four-variable scoring model to predict surgical difficulty. In patients categorized as high grade for surgical difficulty, the anastomotic leakage rate was 53 per cent (9 of 17 patients), compared with 9·6 per cent (10 of 104) in the low-grade group (P < 0·001). The high-grade group had a significantly higher local recurrence rate than the low-grade group (P = 0·002). CONCLUSION: This study highlights the impact of clinical variables and MRI pelvimetry in the prediction of surgical difficulty in minimally invasive rectal surgery.

ANTECEDENTES: Las dificultades técnicas en la cirugía del recto a menudo están relacionadas con la disección en un campo quirúrgico limitado. Este estudio se propuso investigar la utilidad clínica de la pelvimetría con MRI para predecir la dificultad quirúrgica asociada con la cirugía mínimamente invasiva del recto. MÉTODOS: Pacientes con cáncer de recto sometidos a resección total del mesorrecto laparoscópica o robótica entre 2005 y 2017 fueron revisados retrospectivamente y categorizados de acuerdo con la dificultad técnica en base al tiempo operatorio, conversión, uso de abordaje transanal, estancia hospitalaria postoperatoria, pérdida sanguínea y complicaciones postoperatorias. Se examinaron parámetros clínicos preoperatorios y relacionados con la MRI para desarrollar un modelo de predicción que estimara el grado de dificultad técnica y pudiera comparar la tasa de dehiscencias anastomóticas en los grupos de bajo y alto riesgo. También se evaluó el pronóstico con el cálculo de la supervivencia global, supervivencia libre de recidiva y tasas acumuladas de recidiva local y a distancia. RESULTADOS: De un total de 121 pacientes analizados, 104 pacientes (85,9%) fueron categorizados en el grupo con bajo grado de dificultad técnica, mientras que 17 pacientes (14,1%) lo fueron en el grupo de alto grado. En el análisis multivariable, un alto grado de dificultad técnica se asociaba con un índice de masa corporal (body mass index, BMI) > 25 kg/m2 (razón de oportunidades, odds ratio (OR), 4,5; P = 0,033), tamaño tumoral ≥ 45 mm (OR, 5,4; P = 0,042), ángulo anorrectal ≥ 123 grados (OR, 6,0; P = 0,028), estrecho pélvico < 82,7 mm (OR, 6,6; P = 0,048); en consecuencia, todas estas características fueron utilizadas para establecer un modelo de puntuación con 4 variables que pudiera predecir la dificultad técnica. En los pacientes categorizados como de alto grado de dificultad técnica, la tasa de dehiscencia anastomótica fue del 52,9%, mientras que en el grupo de bajo grado fue del 9,6% (P < 0,001). Finalmente, el grupo con alto grado mostró una tasa significativamente más elevada de recidiva local en comparación con el grupo de bajo grado (P = 0,002). CONCLUSIÓN: Este estudio pone de relieve el impacto de variables clínicas y de la pelvimetría con MRI para predecir la dificultad técnica en la cirugía mínimamente invasiva del recto.

Revisiting the treatment strategy for rectal cancer through the pattern of local recurrence.

BACKGROUND: Local recurrence after rectal cancer surgery is categorized as lymphatic spread (pelvic sidewall node (PSN)) and other types. This study aimed to investigate the risk factors associated with different patterns of local recurrence and to optimize the treatment strategy after rectal cancer surgery. METHODS: Patients with cStage I-III rectal cancer who underwent surgery at our institute were included in this study. Local recurrence was categorized as follows: (1) PSN recurrence and (2) "other" types of local recurrence. The risk factors associated with each type of recurrence (metastasis) were investigated. RESULTS: A total of 212 patients with mid/low rectal cancer were included in this study (cStage I: 66; cStage II/III: 146). Additional treatment was employed in selected patients with high-risk features (n = 45; pelvic sidewall dissection: 18; preoperative chemo (radio)therapy: 37). Potential lateral node metastasis was significantly associated with PSN enlargement on imaging findings (no/yes, odds ratio (OR): 9.1; p = 0.007). The "other" local recurrence type was significantly associated with 3 different factors as follows: clinical circumferential resection margin (no/yes; OR: 18.0; p = 0.001), tumor histology (well and moderately/poorly differentiated, OR: 17.3; p = 0.008), and tumor diameter (p = 0.018). Among 146 cStage II/III patients, 66 (45.2%) who did not have any of the abovementioned 4 risk factors experienced no local recurrence even when no additional treatment was employed. CONCLUSIONS: Risk factors may differ for different types of postoperative local recurrence patterns in rectal cancer. Recognizing these risk factors based on pretreatment findings can allow the optimization of treatment strategies for rectal cancer.

Salvage chemoradiotherapy for locally advanced esophageal carcinomas.

'Salvage chemoradiotherapy (CRT)' was introduced in 2005 to treat thoracic esophageal carcinomas deemed unresectable based on the intraoperative findings. The therapeutic concept is as follows: the surgical plan is changed to an operation that aims to achieve curability by the subsequent definitive CRT. For this purpose, the invading tumor is resected as much as possible, and systematic lymph node dissection is performed except for in the area around the bilateral recurrent nerves. The definitive CRT should be started as soon as possible and should be performed as planned. We hypothesized that this treatment would be feasible and provide good clinical effects. We herein verified this hypothesis. Twenty-seven patients who received salvage CRT were enrolled in the study, and their clinical course, therapeutic response, and prognosis were evaluated. The patients who had poor oral intake because of esophageal stenosis were able to eat solid food soon after the operation. The radiation field could be narrowed after surgery, and this might have contributed to the high rate of finishing the definitive CRT as planned. As a result, the overall response rate was 74.1%, and 48.1% of the patients had a complete response. No patient experienced fistula formation. The 1-, 3-, and 5-year overall survival rates were 66.5%, 35.2%, and 35.2%, respectively. Salvage CRT had clinical benefits, such as the fact that patients became able to have oral intake, that fistula formation could be prevented, that the adverse events associated with the definitive CRT could be reduced, and that prognosis of the patients was satisfactory. Although the rate of recurrent nerve paralysis was relatively high even after the suspension of aggressive bilateral recurrent nerve lymph node dissection, and the rate of the progressive disease after the definitive CRT was high, salvage CRT appears to provide some advantages for the patients who would otherwise not have other treatment options following a non-curative and residual operation.

Endocytoscopic observation of various esophageal lesions at ×600: can nuclear abnormality be recognized?

Endocytoscopy (ECS) is a novel endoscopic technique that allows detailed diagnostic examination of the gastrointestinal tract at the cellular level. We previously reported that use of ECS at ×380 magnification (GIF-Y0002) allowed a pathologist to diagnose esophageal squamous cell carcinoma (ESCC) with high sensitivity (94.9%) but considerably low specificity (46.7%) because this low magnification did not reveal information about nuclear abnormality. In the present study, we used the same magnifying endoscope to observe various esophageal lesions, but employed digital 1.6-fold magnification to achieve an effective magnification of ×600, and evaluated whether this improved the diagnostic accuracy in distinguishing neoplastic from non-neoplastic lesions.We examined the morphology of surface cells using vital staining with toluidine blue and compared the histological features of 40 cases, including 19 case of ESCC and 21 non-neoplastic esophageal lesions (18 cases of esophagitis, 1 case of glycogenic acanthosis, 1 case of leiomyoma, and 1 case of normal squamous epithelium). One endoscopist classified the lesions using the type classification, and we consulted one pathologist for judgment of the ECS images as 'neoplastic', 'borderline', or 'non-neoplastic'. At ×600 magnification, the pathologist confirmed that nuclear abnormality became evident, in addition to the information about nuclear density provided by observation at ×380. The overall sensitivity and specificity with which the endoscopist was able to predict neoplastic lesions using the type classification was 100% (19/19) and 90.5% (19/21), respectively, in comparison with values of 94.7% (18/19 cases) and 76.2% (16/21), respectively, for the pathologist using a magnification of ×600. The pathologist diagnosed two non-neoplastic lesions and one case of ESCC showing an apparent increase of nuclear density with weak nuclear abnormality as 'borderline'. Among the 21 non-cancerous lesions, two cases of esophagitis that were misdiagnosed by the endoscopist were also misinterpreted as 'neoplastic' by the pathologist. We have shown, by consultation with a pathologist, that an ECS magnification of ×600 (on a 19-inch monitor) is adequate for recognition of nuclear abnormality. We consider that it is feasible to diagnose esophageal neoplasms on the basis of ECS images, and that biopsy histology can be omitted if a combination of increased nuclear density and nuclear abnormality is observed.

Male sexual function after laparoscopic total mesorectal excision.

AIM: The aim of this prospective study was to clarify the frequency of male sexual dysfunction after laparoscopic total mesorectal excision (LTME) and to examine the relationship between pelvic autonomic nerve (PAN) preservation status and functional outcomes. METHOD: Candidates for LTME were included in this study. PAN preservation status after LTME was examined in detail by video review. Patients completed a functional questionnaire (the International Index of Erectile Function) before and 3, 6 and 12 months after the operation. RESULTS: Twenty-six patients who underwent LTME were assessable. Detailed video reviews identified inadvertent PAN damage during surgery. PAN injury was observed in 11 cases (41%), including eight cases (32%) of inadvertent PAN damage (incomplete preservation group). There was a trend toward increasing inadvertent PAN injury rate in patients with high body mass index and large tumours. The results from all patients who underwent LTME showed no deterioration in total International Index of Erectile Function or its domain scores 12 months after surgery. In the incomplete preservation group, these scores temporarily decreased (3 and 6 months after surgery), but such deterioration was not observed in the complete preservation group. Most of the 12 patients with potentially active erectile function before the operation recovered this function, and only one patient (7%) with PAN injury was still judged as inactive 12 months after surgery. CONCLUSION: The proportion of patients with sexual dysfunction after LTME is low. With the enhanced visibility of the laparoscope, inadvertent PAN injury was detected in a significant number of cases and associated with transient deterioration of sexual function.

Chitinase 3-like 1 promotes macrophage recruitment and angiogenesis in colorectal cancer.

Chitinase 3-like 1 (CHI3L1), one of the mammalian members of the chitinase family, is expressed in several types of human cancer, and elevated serum level of CHI3L1 is suggested to be a biomarker of poor prognosis in advanced cancer patients. However, the overall biological function of CHI3L1 in human cancers still remains unknown. Studies were performed to characterize the role of CHI3L1 in cancer pathophysiology utilizing human colorectal cancer samples and human cell lines. Plasma protein and tissue mRNA expression levels of CHI3L1 in colorectal cancer were strongly upregulated. Immunohistochemical analysis showed that CHI3L1 was expressed in cancer cells, and CHI3L1 expression had a significant association with the number of infiltrated macrophages and microvessel density (MVD). By utilizing transwell migration and tube-formation assays, overexpression of CHI3L1 in SW480 cells (human colon cancer cells) enhanced the migration of THP-1 cells (human macrophage cells) and HUVECs (human endothelial cells), and the tube formation of HUVECs. The knockdown of CHI3L1 by RNA interference or the neutralization of CHI3L1 by anti-CHI3L1 antibody displayed strong suppression of CHI3L1-induced migration and tube formation. Cell proliferation assay showed that CHI3L1 overexpression significantly enhanced the proliferation of SW480 cells. Enzyme-linked immunosorbent assay (ELISA) analysis showed that CHI3L1 increased the secretion of inflammatory chemokines, IL-8 and monocyte chemoattractant protein-1 (MCP-1), from SW480 cells through mitogen-activated protein kinase (MAPK) signaling pathway. Both neutralization of IL-8 or MCP-1 and inhibition or knockdown of MAPK in SW480 cells significantly inhibited CHI3L1-induced migration and tube formation. In a xenograft mouse model, overexpression of CHI3L1 in HCT116 cells (human colon cancer cells) enhanced the tumor growth as well as macrophage infiltration and MVD. In conclusion, CHI3L1 expressed in colon cancer cells promotes cancer cell proliferation, macrophage recruitment and angiogenesis. Thus, the inhibition of CHI3L1 activity may be a novel therapeutic strategy for human colorectal cancer.