Search

Introduction: Vancomycin requires a population pharmacokinetic (popPK) model to estimate the area under the concentration-time curve (AUC), and an AUC-guided dosing strategy is necessary. This study aimed to develop a popPK model for vancomycin using a real-world database pooled from a nationwide web application (PAT)., Methods: In this retrospective study, the PAT database between December 14, 2022 and April 6, 2023 was used to develop a popPK model. The model was validated and compared with six existing models based on the predictive performance of datasets from another PAT database and the Kumamoto University Hospital. The developed model determined the dosing strategy for achieving the target AUC., Results: The modeling populations consisted of 7146 (13,372 concentrations from the PAT database), 3805 (7540 concentrations from the PAT database), and 783 (1775 concentrations from Kumamoto University Hospital) individuals. A two-compartment popPK model was developed that incorporated creatinine clearance as a covariate for clearance and body weight for central and peripheral volumes of distribution. The validation demonstrated that the popPK model exhibited the smallest mean absolute prediction error of 5.07, outperforming others (ranging from 5.10 to 5.83). The dosing strategies suggested a first dose of 30 mg/kg and maintenance doses adjusted for kidney function and age., Conclusions: This study demonstrated the updating of PAT through the validation and development of a popPK model using a vast amount of data collected from anonymous PAT users., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Introduction: During COVID-19 pandemic in Japan, nightclubs were identified as high-risk locations for COVID-19 outbreaks, but an outbreak investigation in this setting is challenging because of the anonymous and opportunistic nature of interactions., Methods: The joint rapid response team collected epidemiological data, conducted descriptive epidemiology to determine the characteristics of cases associated with the nightclub, and implemented countermeasures. Polymerase chain reaction (PCR) tests were performed by the Local Institute of Public Health, Kagoshima University, and several commercial laboratories., Results: Between June 15 and July 20, 2020, 121 individuals tested positive for SARS-CoV-2 (59 confirmed and 62 asymptomatic) of whom 8 were nightclub staff who had no travel history of outside Kagoshima, 66 were guests, and 47 were subsequent contacts. The median age was 32 years (interquartile range: 24-43 years). One individual showed severe symptoms but there were no fatal. The epidemic curve showed one peak on June 30 and July 1 with a limited number of cases subsequently. Of the 121 cases, 116 and 5 were in individuals living in and outside Kagoshima Prefecture, respectively. Haplotype network analysis showed 5 genome-wide single-nucleotide variants between the isolates before and during this outbreak., Conclusions: There is a possibility that unidentified guests from outside Kagoshima Prefecture could infect staff who could subsequently spread the virus to guests and other staff, who were mainly a younger population. The rapid outbreak response enabled onward transmission in the community to be minimized. This outbreak investigation could provide insights for effective responses to challenging situations in future pandemic., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Purpose: Surgical knot-tying requires careful selection of the appropriate technique for optimal outcomes; however, evidence is lacking about the common ligation techniques combining square and slip knots (combination knots). This study investigates the strength of a combination knot, compared with other techniques., Methods: In this observational cohort study, we assessed the strengths of square, slip-granny, slip-reef, and combination knots using absorbable monofilament sutures, and compared them using ANOVA and a multilevel linear regression analysis. We also assessed the correlation between the number of throws and knot strength using Spearman's correlation analysis., Results: Among 80 ligatures, ANOVA indicated significant differences in knot strength among the techniques (p < 0.01). Multilevel linear regression showed that a combination knot was stronger than a slip knot (p < 0.01) and comparable to a square knot (p = 0.0721). Secondary analysis indicated that for combination knots, five throws could achieve sufficient knot strength., Conclusion: Combination knots are as strong as square knots and stronger than slip knots, and thus present a reasonable option for surgical ligation., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Background: It is important to determine the prevalence and prognosis of community-acquired infection (CAI) and nosocomial infection (NI) to develop treatment strategies and appropriate medical policies in aging society., Methods: Patients hospitalized between January 2010 and December 2019, for whom culture tests were performed and antibiotics were administered, were selected using a national claims-based database. The annual trends in incidence and in-hospital mortality were calculated and evaluated by dividing the patients into four age groups., Results: Of the 73,962,409 inpatients registered in the database, 9.7% and 4.7% had CAI and NI, respectively. These incidences tended to increase across the years in both the groups. Among the patients hospitalized with infectious diseases, there was a significant increase in patients aged ≥ 85 years (CAI: + 1.04%/year and NI: + 0.94%/year, P < 0.001), while there was a significant decrease in hospitalization of patients aged ≤ 64 years (CAI: -1.63%/year and NI: -0.94%/year, P < 0.001). In-hospital mortality was significantly higher in the NI than in the CAI group (CAI: 8.3%; NI: 14.5%, adjusted mean difference 4.7%). The NI group had higher organ support, medical cost per patient, and longer duration of hospital stay. A decreasing trend in mortality was observed in both the groups (CAI: -0.53%/year and NI: -0.72%/year, P < 0.001)., Conclusion: The present analysis of a large Japanese claims database showed that NI is a significant burden on hospitalized patients in aging societies, emphasizing the need to address particularly on NI., (© 2024. The Author(s).)

We here present a rare case of development of a postoperative pancreatic fistula and breakdown of the pancreaticojejunal anastomosis 8 months after pancreaticoduodenectomy. A 70-year-old man underwent pancreaticoduodenectomy for distal cholangiocarcinoma and initially recovered well. However, 8 months later, he developed abdominal pain and distention and was admitted to our institution with suspected pancreatitis. On the 17th day of hospitalization, he suddenly bled from the jejunal loop and a fluid collection was detected near the pancreaticojejunal anastomosis site. The fluid collection was drained percutaneously. Subsequent fistulography confirmed breakdown of the pancreaticojejunal anastomosis. Considering the patient's overall condition and the presence of postoperative adhesions, we decided to manage him conservatively. An additional drain tube was placed percutaneously from the site of the anastomotic breakdown into the lumen of the jejunum, along with the tube draining the fluid collection, creating a completely new fistula. This facilitated the flow of pancreatic fluid into the jejunum and was removed 192 days after placement. During a 6-month follow-up, there were no recurrences of pancreatitis or a pancreatic fistula. This case highlights the efficacy of percutaneous drainage and creation of an internal fistula as a management strategy for delayed pancreatic fistula and anastomotic breakdown following pancreaticoduodenectomy., (© 2023. Japanese Society of Gastroenterology.)

Objectives: In recent years, Vancomycin (VCM) dosing design using area under the concentration-time curve (AUC) has been recommended as a measure of efficacy and safety, but there are fewer reports on pediatric patients than on adults. In this study, we evaluated the threshold of AUC for AKI occurrence in pediatric patients and investigated the factors that contribute to the occurrence of AKI., Methods: Pediatric patients aged 1-15 years on VCM treatment who underwent TDM at Kagoshima University Hospital from April 2016 to March 2022 were included in the computation of AUC using pediatric population pharmacokinetic parameters., Results: The ROC curve showed that the AUC threshold for the risk of developing AKI was 583.0 μg・h/mL, and the AUC-ROC curve was 0.873 (sensitivity 0.930, specificity 0.750). Univariate analysis showed that factors associated with AKI incidence were the duration of VCM administration, ICU admission, and AUC SS . Concomitant medications identified as risk factors for AKI incidence were tazobactam/piperacillin, liposomal amphotericin B, calcineurin inhibitors, contrast agents, and H 2 -receptor blockers. The multivariate analysis showed that AUC ≧ 583.0 μg・h/mL (odds ratio 20.14, 95% CI 3.52-115.22, p < 0.001) and H 2 -receptor blockers (odds ratio 8.70, 95% confidence interval = 1.38-54.87, p = 0.02) were independent factors for AKI incidence., Conclusions: We showed that in pediatric patients receiving VCM, the risk of AKI increases as AUC increases. The findings imply that concurrent use of VCM and H 2 -receptor blockers may increase the risk of AKI., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Kazuaki Matsumoto reports a relationship with Meiji Seika Pharma Co., Ltd that includes: funding grants. Kazuaki Matsumoto reports a relationship with Sumitomo Pharma Co., Ltd that includes: funding grants. Kazuaki Matsumoto reports a relationship with Meiji Seika Pharma Co., Ltd that includes: speaking and lecture fees. co-author is the editor of Journal of Infection and Chemotherapy – Kazuaki Matsumoto., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Introduction: In this study, we aimed to analyze the effectiveness of enhanced preventive measures against nosocomial COVID-19 Omicron outbreaks based on those encountered., Methods: We introduced PCR-based screening and syndromic surveillance, in addition to standard and transmission-based precautions, during a COVID-19 outbreak in three wards of Kagoshima University Hospital, a Japanese tertiary care hospital, in February 2022, amid the Omicron variant endemic. Furthermore, we analyzed the descriptive epidemiology and whole-genome sequencing (WGS) of positive SARS-CoV-2 PCR samples from this outbreak., Results: PCR-based screening tests were conducted following the identification of three cases through syndromic surveillance. As a result, 30 individuals tested positive for SARS-CoV-2, including 13 inpatients, five attendant family members, and 12 healthcare workers across the three wards. Notably, no new infections were observed within eight days following the implementation of preventive measures. Among the SARS-CoV-2 genomes analyzed (n = 16; 53.3%), all strains were identified as belonged to BA.1.1 variant. Detailed analysis of descriptive and molecular epidemiology, incorporating single-nucleotide polymorphism analysis of WGS and clarification of transmission links, considering two potential entry routes to the hospital., Conclusions: Introduction of additional preventive measures, including PCR-based screening and syndromic surveillance, in addition to WGS and descriptive epidemiology, is useful for the early intervention of nosocomial outbreaks and for revealing the transmission route of the COVID-19 Omicron variant., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Objective: Elizabethkingia anophelis causes meningitis, bloodstream infections, and respiratory infections in immunocompromised individuals. We examined two E. anophelis strains isolated from the first life-threatening cases caused by this species in Japan to determine the phylogenetic origin and genomic features of them., Methods: We performed whole genome-based analysis to clarify the genetic relationship for the two strains (EK0004 and EK0079) and Elizabethkingia sp. strains isolated from worldwide and to characterize the genomic features such as the prevalence of virulence- and antimicrobial resistance (AMR)-related genes., Patients: A 29-year-old man with hepatosplenic T-cell lymphoma and a 52-year-old man with systemic lupus erythematosus developed fatal bacteremia and meningitis due to E. anophelis, respectively., Results: Two strains, EK0004 and EK0079, were genetically different but most closely related to the strains isolated from the largest outbreak in Wisconsin, USA from 2015 to 2016, and the strain isolated from cerebrospinal fluid of a patient in Florida, USA in 1982, respectively. The two strains contained AMR-related genes such as those encoding for an extended-spectrum β-lactamase and multiple metallo-β-lactamases and several virulence-related genes such as capsular polysaccharide synthesis gene clusters., Conclusions: Although further functional analyses are required to understand the virulence of these clones, these finding suggests that enough caution of E. anophelis infection in immunocompromised patients is required since the number of infections by this species is increasing outside Japan., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Cervical cancer is one of the most common cancers in women. The development of new therapies with immune checkpoint inhibitors (ICIs) is being investigated for cervical cancer; however, their efficacy is not currently sufficient. Oncolytic virus therapy can increase tumor immunogenicity and enhance the antitumor effect of ICIs. In this report, the therapeutic potential of a triple-mutated oncolytic herpes virus (T-01) with an ICI for human papillomavirus (HPV)-related cervical cancer was evaluated using a bilateral syngeneic murine model. The efficacy of intratumoral (i.t.) administration with T-01 and subcutaneous (s.c.) administration of anti-programmed cell death ligand 1 (PD-L1) antibody (Ab) was equivalent to that of anti-PD-L1 Ab alone on the T-01-injected side. Moreover, combination therapy had no significant antitumor effect compared to monotherapy on the T-01-non-injected side. Combination therapy significantly increased the number of tumor specific T cells in the tumor. While T-01 could not be isolated from tumors receiving combination therapy, it could be isolated following T-01 monotherapy. Furthermore, T-01 had a cytotoxic effect on stimulated T cells. These results suggest that T-01 and anti-PD-L1 Ab partially counteract and therefore concomitant administration should be considered with caution.

The relationship between the chemical structure, physicochemical properties, and mucosal adjuvanticity of sugar-based surfactants (SBSs) has not been sufficiently elucidated. Thus, in the present study, we systematically analyzed 11 SBSs for mucosal adjuvanticity. Ovalbumin (OVA)-specific antibody titers were measured in mice immunized intranasally with OVA plus SBS. We found that four SBSs (trehalose monododecanoate, sucrose monododecanoate, n-dodecyl-α-d-maltopyranoside, and n-dodecyl-β-d-maltopyranoside) exhibited the most potent adjuvanticity. We identified the following associations between chemical structure and adjuvanticity: 1) OVA-specific antibody titer increased with an increasing number of carbon atoms in the alkyl chain; 2) the adjuvanticity was not affected by the type of sugar or bond between the sugar and alkyl chain; and 3) SBSs with rigid structures exhibited less adjuvanticity. The relationship between physicochemical properties and adjuvanticity was as follows: 1) SBSs exhibited adjuvanticity above the critical micelle concentration and 2) in the SBSs with potent adjuvanticity, the diameter of the SBS-OVA complex was 70-75 nm. Our study indicates evidence for the direct involvement of chemical structure and physicochemical properties in determining adjuvanticity in SBSs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Salmonella enterica subspecies enterica serovar Oranienburg (SO) is a foodborne pathogen but rarely causes systemic infections such as bacteremia. Between July and September 2018, bacteremia cases caused by SO were identified in 12 persons without any underlying medical conditions in the southern Kyushu area of Japan., Methods: Randomly amplified polymorphic DNA (RAPD) analysis was performed to investigate the genetic similarity of the 12 bacteremia-related strains and other Japanese isolates. Furthermore, a series of whole-genome sequence (WGS)-based phylogenetic analyses was performed with a global SO strain set (n = 1648)., Results: The resolution power of RAPD was insufficient to investigate the genetic similarity between the bacteremia-related strains and other strains. WGS-based phylogenetic analyses revealed that the bacteremia-related strains formed a tight cluster along with 2 strains isolated from asymptomatic carriers in 2018 in the same area, with a maximum within-cluster single-nucleotide polymorphism (SNP) distance of 11. While several strains isolated in the United States and the United Kingdom were found to be closely related to the bacteremia-related strains, 2 strains isolated in 2016 in the southern Kyushu area were most closely related, with SNP distances of 4-11 and 5-10, and had the same plasmids as the bacteremia-related strains., Conclusions: The 12 bacteremia cases identified were caused by a single SO clone. As none of the bacteremia patients had any underlying diseases, this clone may be prone to cause bacteremia. Although further analyses are required to understand its virulence, particular attention should be given to this clone and its close relatives in the surveillance of nontyphoidal salmonellae., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: The dissemination of difficult-to-treat carbapenem-resistant Enterobacterales (CRE) is of great concern. We clarified the risk factors underlying CRE infection mortality in Japan., Methods: We conducted a retrospective, multicentre, observational cohort study of patients with CRE infections at 28 university hospitals from September 2014 to December 2016, using the Japanese National Surveillance criteria. Clinical information, including patient background, type of infection, antibiotic treatment, and treatment outcome, was collected. The carbapenemase genotype was determined using PCR sequencing. Multivariate analysis was performed to identify the risk factors for 28-day mortality., Results: Among the 179 patients enrolled, 65 patients (36.3%) had bloodstream infections, with 37 (20.7%) infections occurring due to carbapenemase-producing Enterobacterales (CPE); all carbapenemases were of IMP-type (IMP-1: 32, IMP-6: 5). Two-thirds of CPE were identified as Enterobacter cloacae complex. Combination therapy was administered only in 46 patients (25.7%), and the 28-day mortality rate was 14.3%. Univariate analysis showed that solid metastatic cancer, Charlson Comorbidity Index ≥3, bloodstream infection, pneumonia, or empyema, central venous catheters, mechanical ventilation, and prior use of quinolones were significant risk factors for mortality. Multivariate analysis revealed that mechanical ventilation (OR: 6.71 [1.42-31.6], P = 0.016), solid metastatic cancers (OR: 5.63 [1.38-23.0], P = 0.016), and bloodstream infections (OR: 3.49 [1.02-12.0], P = 0.046) were independent risk factors for 28-day mortality., Conclusion: The significant risk factors for 28-day mortality in patients with CRE infections in Japan are mechanical ventilation, solid metastatic cancers, and bloodstream infections., Competing Interests: Declaration of competing interest There are no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Paraneoplastic neurological syndromes refer to a group of neurological disorders, which occur as distant effects of malignant tumors and are not caused by metastasis, nutritional disorders, or side effects of antitumor drugs., Case Presentation: A 70-year-old woman complained of a 1-month history of extremity numbness. Upon presentation to our hospital, she had worsening numbness, and experienced staggering and falling. Physical examination revealed diminished tendon reflexes in both lower limbs, stocking and glove-type abnormal sensation, and left-sided dominant high-steppage gait due to weakness of the bilateral tibialis anterior muscles. Blood tests indicated anemia, and upper gastrointestinal endoscopy revealed gastric cancer, leading to laparoscopic distal gastrectomy. A nerve conduction velocity test showed demyelinating peripheral neuropathy. Further blood tests and imaging studies ruled out nutritional disorders, such as vitamin deficiency, diabetes-related diseases, connective tissue diseases, and central nervous system metastasis, leading to the suspicion of paraneoplastic neurological syndrome. After laparoscopic distal gastrectomy, the progression of symptoms stopped, and with intravenous high-dose immunoglobulin and steroid therapy, the symptoms improved to only minor numbness in the peripheral limbs as of the 18-month follow-up. As of the 2-year follow-up, there has been no cancer recurrence or metastasis., Conclusions: When paraneoplastic neurological syndrome is suspected, early diagnosis and a multidisciplinary approach, including surgical treatment, are important before irreversible neurological damage occurs., (© 2022. The Author(s).)

Background: Protrusion of the lateral contour of the pancreatic head is a pancreatic morphological abnormality, which is known as rare shape atypia. We present a rare case of protrusion of the lateral contour of the pancreatic head, which was challenging to distinguish from an ectopic pancreas., Case Presentation: The patient was a 40-year-old man with a history of acute pancreatitis that occurred twice in the past. He complained of epigastric pain since the day before the visit; his blood workup showed high serum amylase level and a CT scan revealed a 25-mm-large mass with contrast effect from the anterior wall of the gastric pylorus to the duodenum and increased surrounding fatty tissue density. Endoscopic ultrasonography revealed a mass lesion in the gastric pylorus with continuity with the gastric wall and suspected partial continuity with the pancreatic head. Thus, the possibility of pancreatic morphological abnormality or an ectopic pancreas was considered. Following which, resection was attempted and intraoperative findings showed a wide extension of the pancreatic parenchyma from the pancreatic head to the anterior wall of the gastric pylorus to the duodenal bulb. Since the patient only had mild pancreatitis, the resection was judged to be too invasive and was completed by exploratory laparoscopy., Conclusions: Even if the findings on preoperative CT are suspicious for an ectopic pancreas or tumor, a pancreatic morphological abnormality, such as a protrusion of the lateral contour of the pancreatic head, should be included in the differential diagnosis., (© 2022. The Author(s).)

Introduction: This study investigated whether our urinary podocyte detection method using podocalyxin (PDX) and Wilms tumor 1 (WT1) immunoenzyme staining combined with liquid-based cytology can serve as a noninvasive routine laboratory test for glomerular disease., Methods: The presence of PDX- and WT1-positive cells was investigated in 79 patients with glomerular disease and 51 patients with nonglomerular disease., Results: The frequencies and numbers of PDX- and WT1-positive cells were significantly higher in the glomerular disease group than in the nonglomerular disease group. The best cutoffs for PDX- and WT1-positive cell counts for identifying patients with glomerular disease were 3.5 (sensitivity = 67.1% and specificity = 100%) and 1.2 cells/10 mL (sensitivity = 43.0% and specificity = 100%), respectively., Conclusion: Because our urinary podocyte detection method using PDX immunoenzyme staining can be standardized and it detected glomerular disease with high accuracy, it can likely serve as a noninvasive routine laboratory test for various glomerular diseases., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

We present a case of 63-year-old male patient who underwent subtotal stomach-preserving pancreaticoduodenectomy for pancreatic neuroendocrine tumor (NET) G2. He had been followed up for three years and had no signs of recurrence postoperatively. Five years after surgery, he had abdominal pain. Upper gastrointestinal endoscopy showed a gastric tumor. Laparoscopic distal gastrectomy was performed without postoperative complications. The histopathological findings of the resected specimen were consistent with mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). The immunohistochemical characteristics of the gastric MiNEN lesion were different from those of the pancreatic NET lesion resected five years ago, suggesting that those lesions were heterochronous.

Background: Several severity indexes have been reported for critically ill patients. The Pitt bacteremia score (PBS) is commonly used to predict the risk of mortality in patients with bacteraemia., Objectives: To develop a scoring system for predicting mortality in candidaemia patients., Methods: Medical records at five Japanese tertiary hospitals were reviewed. Factors associated with mortality were analysed using logistic regression modelling. The discriminatory power of scoring models was evaluated by assessing the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI) and integrated discrimination improvement (IDI)., Results: In total, 422 candidaemia patients were included. Higher PBS, dialysis and retainment of central venous catheter were independent risk factors for all-cause 30-day mortality. However, among the five PBS components, fever was not associated with mortality; therefore, we developed a modified version of the PBS (mPBS) by replacing fever with dialysis. AUC for PBS and mPBS were 0.74 (95% confidence interval [CI]: 0.68-0.80) and 0.76 (95% CI: 0.71-0.82), respectively. The increase in predictive ability of mPBS for 30-day mortality was statistically significant as assessed by NRI (0.24, 95% CI: 0.01-0.46, p = .04) and IRI (0.04, 95% CI: 0.02-0.06, p = .0008). When patients were stratified by mPBS into low (scores 0-3), moderate (4-7) and high risk (≥8), there were significant differences among the survival curves (p < .0001, log-rank test), and 30-day mortality rates were 13.8% (40/290), 36.8% (28/76) and 69.4% (34/49), respectively., Conclusions: mPBS can be a useful tool for predicting mortality in candidaemia patients., (© 2021 The Authors. Mycoses published by Wiley-VCH GmbH.)

Objectives: Compared with vancomycin trough concentration (C min )-guided dosing, area under the concentration-time curve (AUC)-guided dosing is associated with decreased acute kidney injury (AKI). However, whether C min -guided or AUC-guided dosing should be used in patients other than those with serious MRSA infections remains uncertain. The purposes of this multicentre study were to identify risk factors for early- and late-phase vancomycin-induced AKI and to identify candidates for AUC-guided dosing, rather than C min -guided dosing, who require a more accurate dose titration to reduce the AKI risk., Methods: A multivariate logistic regression analysis was applied to identify risk factors for AKI. Additionally, the cut‑off day for AKI onset, cut-off C min for AKI, safe C min for reduced AKI risk and probability of AKI were calculated., Results: In total, 8.4% (159/1882) of patients developed AKI. AKI occurred within the first 7 days of therapy (early phase) in the vast majority of patients. Significant risk factors for AKI during the early phase were identified as C min > 20 mg/L, ICU stay, concurrent diuretic or piperacillin/tazobactam use, and pre-existing renal dysfunction. A temporarily elevated C min (>15-20 mg/L) was not associated with a greater risk of AKI. In patients with risk factors, the cut-off C min for AKI and the estimated safe C min for reduced AKI risk were 18.8-21.0 mg/L and <11.7-13.5 mg/L, respectively., Conclusion: Patients with known AKI risk factors require a low target C min . The presence of several risk factors for AKI may indicate a need for more accurate dose titration using AUC-guided dosing., Competing Interests: Competing interests YT received grant support from Shionogi & Co., Ltd. and payment for lectures from Astellas Pharma Inc. and MSD Japan; KM received grant support from Meiji Seika Pharma Co., Ltd. All other authors declare no competing interests., (Copyright © 2021. Published by Elsevier Ltd.)

Background: In a previous retrospective observational study, a 3-day regimen of oseltamivir as post-exposure prophylaxis (PEP) for preventing transmission of influenza in wards was shown to be comparable to 7- to 10-day regimens provided index cases were immediately separated from close contacts. In order to confirm the efficacy of a 3-day regimen, we started to conduct a prospective, multi-center, single-arm trial., Methods: This study is a prospective, multi-center, single-arm study designed by the Sectional Meeting of Clinical Study, Japan Infection Prevention and Control Conference for National and Public University Hospitals. Index patients with influenza are prescribed a neuraminidase inhibitor and are discharged immediately or transferred to isolation rooms. The close contacts are given oseltamivir as 75 mg capsules once daily for adults or 2 mg/kg (maximum of 75 mg) once daily for children for 3 days as PEP. All close contacts are monitored for development of influenza for 7 days after starting PEP., Discussion: A 3-day regimen of oseltamivir as PEP has advantages over 7- to 10-day regimens in terms of costs, medication adherence and adverse effects. Trial registration The Institutional Review Board of Hokkaido University Hospital for Clinical Research, 015-0518, registered on November 11, 2016. UMIN Clinical Trials Registry, UMIN000024458, disclosed on October 31, 2016. https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000027881 . Japan Registry of Clinical Trials, jRCTs011180015, disclosed on March 14, 2019. https://jrct.niph.go.jp/latest-detail/jRCTs011180015., (© 2021. The Author(s).)

Inappropriate antimicrobial therapy for surgical site infections (SSIs) can lead to poor outcomes and an increased risk of antibiotic resistance. A nationwide survey was conducted in Japan from 2018 to 2019 to investigate the antimicrobial susceptibility of pathogens isolated from SSIs. The data were compared with those obtained in 2010 and 2014-2015 surveillance studies. Although the rate of detection of extended-spectrum β-lactamase producing strains of Escherichia coli was increased from 9.5% in 2010 to 23% in 2014-2015, the incidence decreased to 8.7% in 2018-2019. Although high susceptibility rates were detected to piperacillin/tazobactam (TAZ), the geometric mean MICs were substantially higher than to meropenem (2.67 vs 0.08 μg/mL). By contrast, relatively low geometric mean MICs (0.397 μg/mL) were demonstrated for ceftolozane/TAZ. Although the MRSA incidence rate decreased from 72% in the first surveillance to 53% in the second, no further decrease was detected in 2018-2019. For the Bacteroides fragilis group species, low levels of susceptibility were observed for moxifloxacin (65.3%), cefoxitin (65.3%), and clindamycin (CLDM) (38.9%). In particular, low susceptibility against cefoxitin was demonstrated in non-fragilis Bacteroides, especially B. thetaiotaomicron. By contrast, low susceptibility rates against CLDM were demonstrated in both B. fragilis and non-fragilis Bacteroides species, and a steady decrease in susceptibility throughout was observed (59.3% in 2010, 46.9% in 2014-2015, and 38.9% in 2018-2019). In conclusion, Japanese surveillance data revealed no significant lowering of antibiotic susceptibility over the past decade in organisms commonly associated from SSIs, with the exception of the B. fragilis group., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Purpose: Therapeutic drug monitoring guided by the area under the concentration-time curve (AUC-guided TDM) is recommended for vancomycin. However, validated efficient software remains elusive to popularize AUC-guided TDM in Japan. The aim of this study was to validate a newly developed web application, PAT, for AUC estimation., Methods: PAT was developed on the R ver. 3.6.2 platform for use with mobile phones and personal computers. AUC estimated by PAT (AUC PAT ) was evaluated against the reference AUC (AUC REF ) calculated with the log-linear trapezoidal rule using eight measured concentrations, or against AUC (AUC BM-P ) calculated using an evaluated available software with clinical data., Results: Investigating the best sampling points with limited sampling, PAT produced the least bias using two concentrations at 1 h and 11 h after the end of infusion (slope 1.18, intercept -15.57, median AUC PAT /AUC REF 0.93 [range 0.81-1.24]), where only one estimation (6%) was out of the predetermined acceptable range of 0.8-1.2. Employment of only a trough concentration was more biased (AUC PAT /AUC REF range 0.73-1.30 for 11 h, AUC PAT /AUC REF range 0.62-1.40 for 23 h). In comparison with the evaluated software, AUC PAT was not biased against the AUC BM-P (slope 1.04, intercept -15.80, median AUC PAT /AUC BM-P 1.00 [range 0.86-1.10])., Conclusions: The new application using two concentrations was appropriately validated and might be efficient in popularizing the AUC-guided TDM of vancomycin.

Purpose: Cervical cancer is the fourth most common cancer in women and the seventh most common of all human cancers. Development of new treatments is mandatory to improve the outcome of this disease. Replication-selective oncolytic herpes simplex viruses (HSVs) have emerged as a new platform for cancer therapy. The therapeutic potential of a triple-mutated oncolytic HSV (T-01) for human papillomavirus (HPV)-related cervical cancer was evaluated with immunodeficient and immune-complete models., Methods: (1) The in vitro efficacy of T-01 on human cervical cancer cell lines, TC-1, HeLa, CaSki, and SKG IIIa was evaluated. (2) The in vivo efficacy of T-01 was examined in human HeLa xenograft and TC-1 syngeneic models of human cervical cancer. After flank tumors reached 5 mm in diameter, the first intratumoral (i.t.) administration of T-01 was performed. Intratumoral administration of T-01 was performed with a 5 day interval a total of 6 times., Results: In the in vitro study, T-01 was highly cytotoxic for all cell lines (48 h after infection with T-01 at 1 × 10 5 PFU, T-01 killing HeLa: 67.5%, Caski: 62.8%, SKG IIIa: 43.2%). Furthermore, in the human HeLa xenograft and TC-1 syngeneic models, T-01 resulted in a significant reduction of tumor growth. In addition, tumor-bearing mice treated with T-01 showed significantly increased numbers of CD8 + T-cells precursors than the control mice (p = 0.03)., Conclusions: These results demonstrate that T-01 has cytotoxic efficacy and inhibited against HPV-related cervical cancer cells. These findings indicate that T-01 has therapeutic potential for HPV-related cervical cancer.

Background: Circulating tumor cells (CTCs) have been shown to be heterogeneous. Focusing on the epithelial-mesenchymal transition and perioperative kinetics, we evaluated CTCs with mesenchymal phenotypes as a potential prognostic biomarker for patients with gastric cancer., Methods: Peripheral blood was collected from 54 patients with gastric cancer before surgery and at 1 week and 1 month after surgery. CTCs were enriched using density-gradient centrifugation and magnetic-activated cell sorting (negative selection). Cell suspensions were characterized by multi-immunofluorescence staining against cytokeratin and N-cadherin, and by 4',6'-diamidino-2-phenyldole staining., Results: CTCs were detected in five patients (17%) with early cancer and 14 patients (56%) with advanced cancer (p < 0.05). In our system, N-cadherin, but not cytokeratin, was expressed in the CTCs of 90% (19/21) of patients. Postoperative recurrence was detected in 10 patients, all of whom had N-cadherin+/cytokeratin-/CD45- CTCs preoperatively. Regarding perioperative kinetics, we divided patients into three risk groups: a high-risk group, with one or more preoperative CTCs and increased CTCs postoperatively; an intermediate-risk group, with one or more preoperative CTCs and decreased CTCs postoperatively; and a low-risk group, with no preoperative CTCs. Recurrence rates were 57% (4/7), 33% (4/12), and 6% (2/35), respectively. The relapse-free survival rate was lower in patients at high risk versus those at intermediate or low risk, for all patients (p = 0.00024) and in patients with advanced cancer (p = 0.00103)., Conclusions: N-cadherin is a highly useful marker to detect CTCs lacking cytokeratin, and the perioperative kinetics of CTC numbers is beneficial in risk stratification for survival in patients with gastric cancer.

Introduction and Objective: In the case of non-palpable testes, we often find a small nodule which is called "testicular nubbin (TN)" in scrotum or inguinal canal. There is no agreement about the treatment for TN. This time we investigated whether or not ultrasound examination (US) can be a useful modality for detecting TN., Materials and Methods: We recruited 66 boys who were diagnosed with non-palpable testes and who had undergone US studies. We examined age, affected side, size of the unaffected side, presence of testicular hypertrophy, and findings from US studies. Radiologists or sonographers familiar with examination of testicular nubbin carried out the ultrasound studies. When TN is detected in a patient, preservation or excision of the TN was chosen by their families., Results: Sixty-six boys and 76 testes were examined. Thirty-four testes (44.7%) were diagnosed as having TN, 39 (51.3%) were undescended testes, and 3 (3.9%) were retractile testes. The median age of all participants was 13 months (range: 2-118 months). The mean ages of patients with TN, undescended testes, and retractile testes were 7.6 months, 14.5 months and 55 months, respectively. The size ratio between the affected and unaffected sides in cases of TN was 0.144 (range; 0.03-0.48) and in cases of undescended testes was 0.99 (0.46-1.2). Thirty cases of TN (88.2%) had testicular hypertrophy on the unaffected side. Only one case of TN underwent excision; viable cells were not seen. A high US region was observed in 31 (91.1%) cases with TN., Conclusion: US was a useful modality for detecting TN. From this study, TN can be detected if the size ratio between the affected and unaffected sides is < 0.4 and a high US region is seen. If TN can be detected using US, preservation can recommended, preventing unnecessary surgeries. However, there is no evidence on the required duration and interval of follow-up for these cases and examination will be needed over a period of time., Competing Interests: Conflict of interest The authors have no conflicts of interest to declare., (Copyright © 2020 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background: Hepatotoxicity and visual symptoms are common adverse effects (AEs) of voriconazole therapy., Objective: To retrospectively evaluate the effects of treatment modification based on therapeutic drug monitoring on AEs in patients undergoing voriconazole therapy., Methods: The target voriconazole trough concentration (C min ) was 1-5 µg/mL. Receiver operating characteristic curves were used to determine C min cut-offs for AEs., Results: A total of 401 patients were included. Among 108 patients with high initial C min , voriconazole was discontinued in 32 and the dose was reduced in 71. Among 44 patients with low initial C min , voriconazole was discontinued in 4 and the dose was increased in 19. Hepatotoxicity occurred in 6.0% of patients, after a median of 10 days. Visual symptoms were evident in 9.5% of patients after a median of 4 days. Initial C min was significantly associated with visual symptoms but not hepatotoxicity, which suggested the effect of treatment modification on hepatotoxicity. However, both hepatotoxicity and visual symptoms were significantly correlated with C min at the onset of AEs, and the C min cut-offs were 3.5 μg/mL for hepatotoxicity and 4.2 μg/mL for visual symptoms. Voriconazole was discontinued after the occurrence of AEs in 62.5% of patients with hepatotoxicity but only 26.3% of patients with visual symptoms. With dose adjustment, treatment was completed in 8/9 patients with hepatotoxicity and 27/28 patients with visual symptoms., Conclusions: A significant preventive effect was demonstrated on hepatotoxicity, but not on visual symptoms because of earlier occurrence. With treatment modification after the occurrence of AEs, most patients completed therapy., (© 2020 The Authors. Mycoses published by Blackwell Verlag GmbH.)

The actual proficiency levels of surgeons after their qualification by the Endoscopic Surgical Skill Qualification System have not been established. This study aimed to investigate whether technically qualified surgeons could safely perform laparoscopic low anterior resection and to evaluate the proficiency level at the time of certification acquisition. A total of 46 patients (mean age, 63.3 y; male to female ratio, 29:17) who underwent low anterior resection were included. Outcomes of 46 low anterior resections for rectal cancer performed by 3 novice surgeons certified by the Endoscopic Surgical Skill Qualification System from 2013 to 2018 at 2 hospitals were retrospectively assessed. The mean operative time and blood loss were 201 minutes and 12.9 mL, respectively. One patient (2.2%) required conversion to open surgery, and major postoperative complications occurred in 4 patients (8.6%), including anastomotic leakage in 2 patients (4.3%). Histologic R0 resection was achieved in all cases. The operative time moving average for the 3 surgeons gradually decreased from 233 to 158 minutes. In cumulative sum charts, the operative time values continuously decreased after the 12th case compared with the target operative time (180 min). In conclusion, surgeons can safely perform laparoscopic low anterior resection just after their qualification but have the potential to further attain proficiency.

It is unknown as to how liver metastases are correlated with host immune status in colorectal cancer. In this study, we found that IL6, a proinflammatory cytokine produced in tumor-bearing states, promoted the metastatic colonization of colon cancer cells in association with dysfunctional antitumor immunity. In IL6-deficient mice, metastatic colonization of CT26 cells in the liver was reduced, and the antitumor effector function of CD8 + T cells, as well as IL12 production by CD11c + dendritic cells, were augmented in vivo IL6-deficient mice exhibited enhanced IFN-AR1-mediated type I interferon signaling, which upregulated PD-L1 and MHC class I expression on CT26 cells. In vivo injection of anti-PD-L1 effectively suppressed the metastatic colonization of CT26 cells in Il6 -/- but not in Il6 +/+ mice. Finally, we confirmed that colorectal cancer patients with low IL6 expression in their primary tumors showed prolonged disease-free survival. These findings suggest that IL6 may be a promising target for the treatment of metastasis in colorectal cancers by improving host immunity., (©2019 American Association for Cancer Research.)

Introduction: To investigate the oncological feasibility and technical safety of laparoscopic gastrectomy with D2 lymphadenectomy for advanced gastric cancer., Methods: A total of 186 advanced gastric cancer patients treated by gastrectomy with D2 lymphadenectomy were eligible for inclusion including those with invasion into the muscularis propria, subserosa, and serosa without involvement of other organs, and stages N0-2 and M0. We retrospectively compared the short-term and long-term outcomes between laparoscopic gastrectomy and open gastrectomy., Results: We analyzed short-term outcomes by comparing distal with total gastrectomy results. We found no significant difference for distal gastrectomy for postoperative morbidity [laparoscopic vs. open: n=4 (4.6%) vs. n=1 (3.6%); P=1.00]. We also found no significant difference in postoperative morbidity for total gastrectomy [laparoscopic vs. open: n=2 (4.0%) vs. n=1 (4.0%); P=1.00]. No deaths occurred in any group.The entire cohort analysis revealed no statistically significant differences in overall-free or recurrence-free survival between the laparoscopic and open groups. For overall survival, there were no significant differences between open and laparoscopic groups for clinical stage II or III (P=0.29 and 0.27, respectively), and for pathologic stage II or III (P=0.88 and 0.86, respectively). For recurrence-free survival, there were no significant differences between open and laparoscopic groups for clinical stage II or III (P=0.63 and 0.60, respectively), and for pathologic stage II or III (P=0.98 and 0.72, respectively)., Conclusion: Laparscopic gastrectomy for advanced gastric cancer compared favorably with open gastrectomy regarding short-term and long-term outcomes.

Background: The incidence of ocular candidiasis (OC) in patients with candidemia varies across different reports, and the issue of whether routine ophthalmoscopy improves outcomes has been raised. This study investigated the incidence of OC and evaluate whether the extent of OC impacts the clinical outcomes., Methods: This retrospective study included non-neutropenic patients with candidemia who underwent treatment at one of 15 medical centers between 2010 and 2016. Chorioretinitis without other possible causes for the ocular lesions and endophthalmitis was classified as a probable OC. If signs of chorioretinitis were observed in patients with a systemic disease that causes similar ocular lesions, they were classified as a possible OC., Results: In total, 781 of 1089 patients with candidemia underwent an ophthalmic examination. The prevalence of OC was 19.5%. The time from the collection of a positive blood culture to the initial ophthalmic examination was 5.0 ± 3.9 days in patients with OC. The leading isolate was Candida albicans (77.9%). Possible OC was associated with unsuccessful treatments (resolution of ocular findings) (odds ratio: 0.354, 95% confidence interval: 0.141-0.887), indicating an overdiagnosis in patients with a possible OC. If these patients were excluded, the incidence fell to 12.8%. Endophthalmitis and/or macular involvement, both of which require aggressive therapy, were detected in 43.1% of patients; a significantly higher incidence of visual symptoms was observed in these patients., Conclusion: Even when early routine ophthalmic examinations were performed, a high incidence of advanced ocular lesions was observed. These results suggest that routine ophthalmic examinations are still warranted in patients with candidemia., Competing Interests: Y. Takesue has received grant support from Sumitomo Dainippon Pharma Co., Ltd., and Shionogi & Co., Ltd., and payment for lectures from Astellas Pharma Inc., and MSD Japan. T Miyazaki has received research grants from Astellas Pharma Inc., Pfizer Japan Inc., MSD Japan, and Asahi Kasei Pharma Co. H. Mikamo has received grant support from Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma Inc., Pfizer Japan Inc., MSD Japan, and payment for lectures from MSD Japan, Astellas Pharma Inc., and Sumitomo Dainippon Pharma Co., Ltd. Y. Yamagishi has received grant support from Pfizer Japan Inc., MSD Japan, Astellas Pharma Inc., and Sumitomo Dainippon Pharma Co., Ltd., and payment for lectures from Sumitomo Dainippon Pharma Co., Ltd., and MSD Japan. K. Yoshida has received payment for lectures from MSD Japan, Pfizer Japan Inc., and Sumitomo Dainippon Pharma Co., Ltd. H. Kakeya has received grant support from Pfizer Japan Inc., MSD Japan, Astellas Pharma Inc., and Sumitomo Dainippon Pharma Co., Ltd. Other authors have no conflict of interest to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral infectious disease with high mortality. It causes multiple organ dysfunction; however, myocarditis has never been reported as a complication with SFTS., Case Presentation: A 62-year-old previously healthy woman developed fever, fatigue, diarrhea, and a mild consciousness disorder. She visited a local clinic, and laboratory data showed leukocytopenia, thrombocytopenia, and elevation of the aspartate aminotransferase level. She was transferred to Kagoshima University Hospital and diagnosed as having SFTS by real-time reverse transcription polymerase chain reaction. Subsequently, her blood pressure gradually decreased despite fluid resuscitation and vasopressor administration. Based on elevated toroponin I levels in serum, a transient diffuse left ventricular hypokinesis and wall thickening in echocardiography, diffuse ST elevation in electrocardiography, and exclusion of other heart diseases, she was diagnosed as having fulminant myocarditis. After hemodynamic support with inotropic agents, she recovered near normal cardiac function. She was discharged to home on day 28., Conclusions: We report the first case of fulminant myocarditis associated with SFTS.

The development of colorectal cancer in long-standing Crohn's disease (CD) patients has become a major complication. Therapeutic guidelines for CD-associated cancer (CDAC) have already been established in Western countries; however, specific guidelines are not currently available in Japan. Surveillance of the residual intestine for cancer screening is important for long-standing CD patients. The present case report describes the occurrence of rectal carcinoma in a patient with a 25-year history of CD. A 37-year-old male with a 17-year history of CD underwent semi-emergent subtotal colectomy and ileostomy for bowel obstruction secondary to the transverse colon stenosis, and multiple severe stenosis and inflammation. Postoperatively, the patient resumed pharmacological treatment and underwent follow-up colonoscopies at ~1-2-year intervals. Despite continued pharmacological treatment, inflammation continued in the residual rectum. A total of 8 years following the primary operation, colonoscopy revealed inflammatory polyposis at the remnant rectum, which was diagnosed as adenocarcinoma. The interval between the last colonoscopy was 16 months. The patient then underwent laparoscopic abdominoperineal resection, and remained without recurrence for 12 months following resection. Thus, in long-standing CD patients, annual colonoscopy of the residual intestine may be considered for cancer screening, and specific surveillance guidelines for CDAC should be established.

Tumor budding is thought to represent a manifestation of epithelial-to-mesenchymal transition (EMT) and it has been correlated with poor patient outcomes in colorectal cancer (CRC). Our group recently demonstrated that human chorionic gonadotropin-β (hCGβ) modulates EMT in CRC. In the current study, based on the likely relationships between tumor budding and hCGβ expression, we examined their clinicopathologic significance in CRC. Twenty-eight of 80 (35.0%) CRC showed tumor budding. Tumor budding significantly correlated with lymph node metastasis (P < 0.01), pathologic stage (P < 0.01), lymphatic invasion (P = 0.044), and vascular invasion (P = 0.013). Thirteen of 80 (16.3%) CRC were hCGβ positive on immunohistochemistry. More tumor buds were present in the hCGβ-positive cases (P < 0.01), and tumor budding was significantly correlated with hCGβ positivity (P < 0.01). Cases with both tumor budding and hCGβ expression had the poorest prognosis compared with all other groups (P < 0.01). In conclusion, tumor budding and hCGβ expression are closely associated with EMT, and they are independent prognostic factors in CRC. They identify patients with an "EMT phenotype" who may respond to targeted molecular therapies.

Background: Here we report a rare case of lumbar spine epidural abscess and facet joint septic arthritis caused by Streptococcus agalactiae, which had spread to the iliopsoas muscles, leading to urine retention., Case Presentation: A 68-year-old woman with low back pain experienced a sudden onset of bilateral lower limb weakness, it was followed 14 days later by urine retention. At consultation, magnetic resonance imaging and identification of serum β-hemolytic streptococci provided a diagnosis of Streptococcus agalactiae infection. She was started on antibiotics. Despite diminishing signs of inflammation, preoperative MRI showed an epidural mass at T12-L4 compressing the cord and involving the paravertebral muscles as well. Group B beta-hemolytic streptococci were detected in both urine and blood. Because of bilateral lower limb weakness and urine retention, T12-L4 hemilaminectomy was performed. The L3/L4 intertransverse ligament resected and abscess drained. Histopathology revealed that inflammatory cells had invaded the facet joint. Group B beta-hemolytic streptococci were identified, confirming the diagnosis. The patient continued with the antibiotics postoperatively, and her health rapidly improved., Conclusion: Lumbar spine epidural abscess and facet joint septic arthritis caused by Streptococcus agalactiae is a clinical emergency, with significant morbidity and mortality especially with delayed diagnosis. A delay in both diagnosis and aggressive treatment can lead to not only severe neurological deficit but also to septicaemia, multiorgan failure, and even death.

Situs inversus totalis (SIT) is a rare congenital anomaly. Generally, laparoscopic surgery is difficult to perform in patients with SIT because of both the potential challenges associated with unexpected vascular anomalies and the lack of standardized strategy for handling such cases. This is the first report of laparoscopic total gastrectomy with lymph node dissection for advanced gastric cancer in a patient with SIT. A 79-year-old man with SIT was diagnosed with advanced gastric cancer. We performed laparoscopic total gastrectomy with modified D2 lymph node dissection (D2 without splenectomy) and esophagojejunal anastomosis using an overlap method involving retrocolic Roux-en-Y reconstruction. The total operating time was 232 min, and blood loss was 110 mL. There were no postoperative complications. In summary, laparoscopic total gastrectomy for gastric cancer can be performed safely, even in a patient with SIT., (© 2017 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd.)

Background: The use of laparoscopic colectomy is becoming widespread and acquisition of its technique is challenging. In this study, we investigated whether supervision by a technically qualified surgeon affects the proficiency and safety of laparoscopic colectomy performed by novice surgeons., Methods: The outcomes of 23 right colectomies and 19 high anterior resections for colon cancers performed by five novice surgeons (experience level of <10 cases) between 2014 and 2016 were assessed. A laparoscopic surgeon qualified by the Endoscopic Surgical Skill Qualification System (Japan Society for Endoscopic Surgery) participated in surgeries as the teaching assistant., Results: In the right colectomy group, one patient (4.3%) required conversion to open surgery and postoperative morbidities occurred in two cases (8.6%). The operative time moving average gradually decreased from 216 to 150 min, and the blood loss decreased from 128 to 28 mL. In the CUSUM charts, the values for operative time decreased continuously after the 18th case, as compared to the Japanese standard. The values for blood loss also plateaued after the 18th case. In the high anterior resection group, one patient (5.2%) required conversion to open surgery and no postoperative complication occurred in any patient. The operative time moving average gradually decreased from 258 to 228 min, and the blood loss decreased from 33 to 18 mL. The CUSUM charts showed that the values of operative time plateaued after the 18th case, as compared to the Japanese standard. In the CUSUM chart for blood loss, no distinguishing peak or trend was noted., Conclusions: Supervision by a technically qualified surgeon affects the proficiency and safety of laparoscopic colectomy performed by novice surgeons. The trainee's learning curve in this study represents successful mentoring by the laparoscopic surgeon qualified by the Endoscopic Surgical Skill Qualification System.

Ectopic production of free β human chorionic gonadotropin (hCGβ) has been associated with aggressive behavior in non-trophoblastic tumors. hCGβ shares common evolutionary sequences with transforming growth factor-β (TGF-β), which represents a major driving force of epithelial-to-mesenchymal transition (EMT). In this study, we examined the biological roles of hCGβ during EMT and its clinical significance in colorectal cancer (CRC) progression. Eighty CRC specimens and 54 preoperative serum samples were analyzed. hCGβ-overexpressing human CRC cell lines were examined for invasiveness and tumorigenicity, and the expression of EMT-associated genes was investigated. In human CRC, histologic hCGβ positivity [13/80 (16.3%)] was lower than serologic hCGβ positivity [13/54 (24.1%)]. However, it was significantly correlated with several clinicopathological features and unfavorable outcome (P < 0.05). hCGβ-overexpressing cell lines had increased invasiveness, migratory ability, and metastatic potential in mice (P < 0.01). Western blot, PCR, and microarray analyses showed hCGβ altered expression of EMT-related genes, including E-cadherin, phosphorylated SMAD2, SNAIL, and TWIST. hCGβ-induced SNAIL and TWIST overexpression levels were reversible by type I and type II TGF-β receptor inhibitors (P < 0.05). hCGβ thus induces EMT via the TGF-β signaling pathway, and it may represent a molecular target in CRC treatment., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: We retrospectively assessed the efficacy of our mentor tutoring system for teaching laparoscopic colorectal surgical skills in a general hospital., Materials and Methods: A series of 55 laparoscopic colectomies performed by 1 trainee were evaluated. Next, the learning curves for high anterior resection performed by the trainee (n=20) were compared with those of a self-trained surgeon (n=19)., Results: Cumulative sum analysis and multivariate regression analyses showed that 38 completed cases were needed to reduce the operative time. In high anterior resection, the mean operative times were significantly shorter after the seventh average for the tutored surgeon compared with that for the self-trained surgeon. In cumulative sum charting, the curve reached a plateau by the seventh case for the tutored surgeon, but continued to increase for the self-trained surgeon., Conclusions: Mentor tutoring effectively teaches laparoscopic colorectal surgical skills in a general hospital setting.

Background: Esophagojejunostomy after laparoscopic total gastrectomy (LTG) is the most technically difficult type of anastomosis; thus, anastomotic complications such as leakage and stenosis sometimes occur. Identification of the safest anastomotic procedure is important for successful LTG. We have performed LTG since 2004 either with a circular stapler using an OrVil ™ anvil or via the overlap Orringer method with a linear stapler. This retrospective study aimed to determine which method results in a lower incidence of anastomotic complications in patients undergoing LTG., Methods: Data on 188 consecutive patients who underwent LTG between April 2004 and August 2016 were retrospectively reviewed. Patients were divided into those who underwent esophagojejunostomy performed via a circular stapler using an OrVil ™ anvil (group C, n = 49) or via the overlap method (group L, n = 139)., Results: Anastomotic complications occurred in five of 188 esophagojejunostomies (2.7%). They comprised three cases of leakage (1.6%), and two of stenosis (1.1%). There was no significant difference in patient characteristics or hematological variables between groups C and L. There was no significant difference between groups in operation time, blood loss, lymph node dissection, and intraoperative anastomotic problems. The rate of anastomotic complications was significantly lower in group L (0.7%, 1/139) than in group C (8.2%, 4/49; p = 0.005). In particular, anastomotic leakage in group L tended to be lower (0.7% 1/139) than in group C (4.1% 2/49), although this difference was not significant. The rate of anastomotic stenosis in group L was significantly lower (0%, 0/139) than in group C (4.1%, 2/49; p = 0.017). Furthermore multivariate analysis showed anastomotic procedure was an independent factor for anastomotic complication., Conclusions: There were fewer anastomotic complications after overlap esophagojejunostomy than after esophagojejunostomy via the OrVil ™ procedure, especially regarding anastomotic stenosis. We therefore recommend the overlap technique when performing esophagojejunostomy.

Background: Muir-Torre syndrome (MTS) is a rare autosomal dominant genodermatosis caused by mutations in mismatch repair genes. It is characterized by the presence of at least one sebaceous skin tumor associated with internal malignancies. Whether positron emission tomography/computed tomography (PET/CT) is useful for the detection of malignancies in patients with MTS has not been determined. We herein report two cases in which PET/CT was useful for the diagnosis and follow-up of internal malignancies in patients with MTS., Case Presentation: In case 1, a 57-year-old woman underwent excision of a sebaceous carcinoma on the left upper eyelid. She underwent follow-up PET/CT once yearly thereafter. Forty-two months after the eyelid surgery, PET/CT showed intense tracer uptake in the right lower abdomen. An ascending colon tumor was identified, and examination of a biopsy specimen showed adenocarcinoma. In case 2, a 77-year-old man presented for evaluation of three continuous papules with telangiectasia on his right cheek. Examination of a skin biopsy specimen of the cheek papule revealed a sebaceous carcinoma. He underwent PET/CT to detect other malignancies. PET/CT showed intense tracer uptake in the sigmoid colon. A sigmoid colon tumor was identified, and examination of a biopsy specimen showed adenocarcinoma. Both patients underwent resection of their tumors, and both were still free of recurrence of the sebaceous and colon carcinomas at the time of this writing., Conclusion: PET/CT is a reliable imaging modality for the detection of internal malignancies and is useful for the diagnosis and follow-up of MTS.

Background: Although several types of staplers have been developed, staple-line leaks have been a great problem in gastrointestinal surgery. Powered linear staplers were recently developed to further reduce the risk of tissue trauma during laparoscopic surgery. The aim of this study was to identify the factors that predict staple malformation and determine the effect of precompression and slow firing on the staple formation of this novel powered stapling method., Methods: Porcine stomachs were divided using an endoscopic powered linear stapler with gold reloads. We divided the specimens into 9 groups according to the precompression time (0/60/180 seconds) and firing time (0/60/180 seconds). The occurrence and length of laceration and the shape of the staples were evaluated. We examined the factors influencing successful stapling and investigated the key factors for staple malformation., Results: Precompression significantly decreased the occurrence and length of serosal laceration. Precompression and slow firing significantly improved the optimal stapling formation rate. Univariate analysis showed that the precompression time (0 seconds), firing time (0 seconds), and presence of serosal laceration were significantly associated with a low optimal formation rate. Multivariate analysis showed that these three factors were associated independently with low optimal formation rate and that the presence of serosal laceration was the only factor that could be detected during the stapling procedure., Conclusions: We have shown that serosal laceration is a predictor of staple malformation and demonstrated the importance of precompression and slow stapling when using the powered stapling method.

Objective: This study aims to clarify the incidence of Aurora kinase A (Aurora-A) protein expression and its correlation with clinical parameters in ovarian clear cell carcinoma (OCCC) tumor tissues. In addition, we assessed the efficacy of ENMD-2076, a novel selective Aurora-A inhibitor, in combination with chemotherapeutic agents for the treatment of OCCC., Methods/materials: Aurora-A protein expression was determined by immunohistochemical staining of OCCC specimens from 56 patients to evaluate its correlation with clinical outcomes in OCCC. In the in vitro study, 6 OCCC cell lines were exposed to ENMD-2076 in combination with cisplatin, SN38, doxorubicin, or paclitaxel, and cell proliferation, cell cycle distribution, and apoptosis were assessed., Results: The 5-year survival rates of International Federation of Gynecology and Obstetrics stages IC3 to IV patients with intermediate or strong Aurora-A expression were significantly lower than those of patients with negative or weak Aurora-A expression. Increased Aurora-A expression was associated with significantly worse overall survival of International Federation of Gynecology and Obstetrics stages IC3 to IV patients (21% vs 77%). Multivariate analysis revealed that Aurora-A expression was an independent prognostic factor for stages IC3 to IV OCCC patients. Furthermore, synergistic effects were observed with ENMD-2076 in combination with cisplatin or SN-38 in 4 of the 6 tested cell lines. ENMD-2076 dramatically enhanced apoptosis and cell cycle arrest at the G2/M phase induced by cisplatin., Conclusions: Aurora-A is a promising biomarker that is predictive of patient outcomes and a potential target for OCCC. The results suggested that chemotherapy, including ENMD-2076 in combination with cisplatin, is a potential treatment modality for patients with OCCC.

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)-6, a pleiotropic cytokine, is highly produced in the tumor-bearing host. Previous studies have indicated that IL-6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL-6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor-infiltrating CD11b + CD11c + cells isolated from colorectal cancer tissues showed strong induction of the IL-6 gene, downregulated surface expression of human leukocyte antigen (HLA)-DR, and an attenuated T cell-stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL-6-mediated STAT3 activation reduced surface expression of HLA-DR on CD14 + monocyte-derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL-6-mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL-6-mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL-6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Conquering immunosuppression in tumor microenvironments is crucial for effective cancer immunotherapy. It is well known that interleukin (IL)-6, a pleiotropic cytokine, is produced in the tumor-bearing state. In the present study, we investigated the precise effects of IL-6 on antitumor immunity and the subsequent tumorigenesis in tumor-bearing hosts. CT26 cells, a murine colon cancer cell line, were intradermally injected into wild-type and IL-6-deficient mice. As a result, we found that tumor growth was decreased significantly in IL-6-deficient mice compared with wild-type mice and the reduction was abrogated by depletion of CD8 + T cells. We further evaluated the immune status of tumor microenvironments and confirmed that mature dendritic cells, helper T cells and cytotoxic T cells were highly accumulated in tumor sites under the IL-6-deficient condition. In addition, higher numbers of interferon (IFN)-γ-producing T cells were present in the tumor tissues of IL-6-deficient mice compared with wild-type mice. Surface expression levels of programmed death-ligand 1 (PD-L1) and MHC class I on CT26 cells were enhanced under the IL-6-deficient condition in vivo and by IFN-γ stimulation in vitro. Finally, we confirmed that in vivo injection of an anti-PD-L1 antibody or a Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid, effectively inhibited tumorigenesis under the IL-6-deficient condition. Based on these findings, we speculate that a lack of IL-6 produced in tumor-bearing host augments induction of antitumor effector T cells and inhibits tumorigenesis in vivo, suggesting that IL-6 signaling may be a promising target for the development of effective cancer immunotherapies., (© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Objective: This study aimed to evaluate the feasibility and effectiveness of a comprehensive theoretical and hands-on training program in performing laparoscopic colonic resections under supervision of an expert surgeon., Materials and Methods: Laparoscopic right colectomy was performed in 78 patients (10 with benign disease, 68 with carcinoma). Demographic, intraoperative, pathologic examination, and short-term outcome data were retrospectively compared between 25 patients operated by surgical residents (R group) and 53 patients operated by senior surgeons (S group). The residents who performed surgeries in the R group had between 1 and 6 years after graduation; no experience with open or laparoscopic colorectal surgery was necessary. The residents completed a training program under supervision of a single expert laparoscopic colorectal surgeon, which included 6 steps, from basic skills to certification., Results: There were no differences in patient age, sex, and body mass index between the R and S groups. Significantly more patients in the R group had early cancer and benign lesions (P<0.05). Thirteen of the 16 residents (81.2 %) had not had prior experience with colonic resection. The time of suturing and knot tying in the dry box did not differ between residents and senior surgeons (68 and 69 s, respectively). All the residents performed laparoscopic right colectomy without intraoperative complications. There were no significant differences in operating time (R group: 173±34 min, S group: 172±52 min), mean estimated blood loss (50±111 vs. 49±100 mL), number of lymph nodes dissected (20.8±12.8 vs. 17.1±9.0), and mean postoperative hospital stay (9.1±3.3 vs. 10.7±4.1 d). On the basis of the year of their residency period, all 3 residents at 6 years after graduation had far greater experience than the other residents and therefore performed the surgery with minor verbal support from the expert. However, residents with 1 or 2 years after graduation had to receive guidance provision by the expert during surgery., Conclusions: When supervised and led by an expert laparoscopic surgeon, surgical residents are capable of performing laparoscopic surgery without negative effects on outcomes.

We report two cases of melanomas in patients who developed intestinal metastasis despite other metastatic sites responding to nivolumab and despite the patients having favorable findings such as vitiligo and normal lactate dehydrogenase. The first case is an 85-year-old man who had been administrated nivolumab for lung/cutaneous metastases. After 22 courses of nivolumab therapy, fever and anorexia had appeared and his bodyweight had decreased. An intussusception on the ileocecal valve was revealed by computed tomography, and emergency surgery revealed metastatic lesions on the colon. The second case is an 87-year-old woman treated with nivolumab for lymph node metastases. After 10 courses, laboratory tests had revealed anemia and positive fecal occult blood. Her bodyweight had decreased. Capsule endoscopy showed scattered tumors and clots, indicating metastases of melanoma. The frequency of symptomatic intestinal metastasis of melanoma is very low. Further, intestinal metastasis of melanoma is difficult to detect through routine examinations. Our cases suggest that fecal occult blood test and decreased bodyweight are indications of intestinal metastases., (© 2017 Japanese Dermatological Association.)

Purpose: Effective postoperative analgesia is essential to a patient's recovery after laparoscopic colon resection (LCR). We introduce a new analgesic protocol using fentanyl plus celecoxib following LCR., Methods: The subjects of this retrospective comparative study were 137 patients who underwent LCR, 63 of whom were treated with 72 h of epidural anesthesia (group E), and 74 of whom were treated with 24 h of fentanyl intravenous injection followed by 7 days of oral celecoxib (group FC). We evaluated the safety and efficacy of this new protocol., Results: The combination of fentanyl and celecoxib maintained a low postoperative pain score (<1.5, evaluated by the FACES Pain Scale) and reduced the need for rescue analgesic drugs for 7 days (groups E vs. FC: 5.39 ± 3.77 vs. 2.79 ± 2.92, p < 0.001). The postoperative hospital stay was almost equal for the two groups (E vs. FC: 11.1 ± 4.5 vs. 10.3 ± 4.8 days, p = 0.315). The operating room stay other than for surgery was significantly shorter for group FC (E vs. FC: 128.7 ± 30.5 vs. 107.2 ± 17.0 min, p < 0.001). Neither group experienced complications, apart from one group FC patient, who suffered transient nausea and vertigo., Conclusions: The new analgesic protocol using fentanyl plus celecoxib is an effective and time-saving strategy for LCR.

In gastric cancer, primary systemic chemotherapy is the standard approach for the management of patients with initially unresectable metastasis, and it occasionally leads to a reduction in the size of the lesion, which facilitates surgical resection. The aim of this study was to examine the prognosis of patients who were able to undergo complete resection following chemotherapy. A total of 10 patients who underwent radical surgery for stage IV primary gastric cancer after chemotherapy between 2009 and 2015 at the Department of Surgery of Hokkaido Social Work Association Obihiro Hospital (Obihiro, Japan) were retrospectively investigated. Three regimens were used (S-1, n=1; S-1 + cisplatin, n=8; and S-1 + docetaxel, n=1). The mean time from chemotherapy to surgery was 210 days. One total gastrectomy + splenectomy + colectomy, one total gastrectomy + splenectomy, four total gastrectomies and three distal gastrectomies were performed. There were two cases of pancreatic fistula formation postoperatively. All the patients survived for >1 year. Of the 10 patients, 5 survived without recurrence. The median survival time was 871.1 days after diagnosis. Therefore, curative resection after chemotherapy is associated with a better prognosis in stage IV gastric cancer patients.

Background: The incidence of rectovaginal fistula in women with Crohn's disease has been reported to be 3-10 %. Although rectovaginal fistulas can be managed medically and surgically, they have high rates of recurrence and complications. Rectal stenosis is another condition that occurs due to perianal Crohn's disease. A novel, minimally invasive procedure, dual-port laparoscopic abdominoperineal resection using a multichannel port, has been shown effective in patients with lower rectal cancer and patients with medically uncontrolled ulcerative colitis. This report describes the use of the same method for two patients with Crohn's disease-related rectovaginal fistula and rectal stenosis., Case Presentation: The first patient, a 22-year-old woman, was diagnosed with rectovaginal fistula and rectal stenosis due to perianal Crohn's disease 2 years earlier. Induction therapy with infliximab and endoscopic balloon dilatation did not improve her symptoms. The second patient, a 33-year-old woman, was also diagnosed with rectovaginal fistula and rectal stenosis due to perianal Crohn's disease, and medical treatment was also unsuccessful. Both patients underwent dual-port laparoscopic abdominoperineal resection using a multichannel port, with no perioperative and postoperative complications., Conclusion: These findings show that this reduced port method can be used to successfully treat patients with Crohn's disease-associated rectovaginal fistula and rectal stenosis.