Tokyo Medical University Hospital

Abstract The Tokyo Guidelines 2013 (TG13) for acute cholangitis and cholecystitis were globally disseminated and various clinical studies about the management of acute cholecystitis were reported by many researchers and clinicians from all over the world. The 1 st edition of the Tokyo Guidelines 2007 ( TG 07) was revised in 2013. According to that revision, the TG 13 diagnostic criteria of acute cholecystitis provided better specificity and higher diagnostic accuracy. Thorough our literature search about diagnostic criteria for acute cholecystitis, new and strong evidence that had been released from 2013 to 2017 was not found with serious and important issues about using TG 13 diagnostic criteria of acute cholecystitis. On the other hand, the TG 13 severity grading for acute cholecystitis has been validated in numerous studies. As a result of these reviews, the TG 13 severity grading for acute cholecystitis was significantly associated with parameters including 30‐day overall mortality, length of hospital stay, conversion rates to open surgery, and medical costs. In terms of severity assessment, breakthrough and intensive literature for revising severity grading was not reported. Consequently, TG 13 diagnostic criteria and severity grading were judged from numerous validation studies as useful indicators in clinical practice and adopted as TG 18/ TG 13 diagnostic criteria and severity grading of acute cholecystitis without any modification. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47 . Related clinical questions and references are also included.

The use of laparoscopy for liver surgery is increasing rapidly. The Second International Consensus Conference on Laparoscopic Liver Resections (LLR) was held in Morioka, Japan, from October 4 to 6, 2014 to evaluate the current status of laparoscopic liver surgery and to provide recommendations to aid its future development. Seventeen questions were addressed. The first 7 questions focused on outcomes that reflect the benefits and risks of LLR. These questions were addressed using the Zurich-Danish consensus conference model in which the literature and expert opinion were weighed by a 9-member jury, who evaluated LLR outcomes using GRADE and a list of comparators. The jury also graded LLRs by the Balliol Classification of IDEAL. The jury concluded that MINOR LLRs had become standard practice (IDEAL 3) and that MAJOR liver resections were still innovative procedures in the exploration phase (IDEAL 2b). Continued cautious introduction of MAJOR LLRs was recommended. All of the evidence available for scrutiny was of LOW quality by GRADE, which prompted the recommendation for higher quality evaluative studies. The last 10 questions focused on technical questions and the recommendations were based on literature review and expert panel opinion. Recommendations were made regarding preoperative evaluation, bleeding controls, transection methods, anatomic approaches, and equipment. Both experts and jury recognized the need for a formal structure of education for those interested in performing major laparoscopic LLR because of the steep learning curve.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

We propose a new flowchart for the treatment of acute cholecystitis (AC) in the Tokyo Guidelines 2018 (TG18). Grade III AC was not indicated for straightforward laparoscopic cholecystectomy (Lap-C). Following analysis of subsequent clinical investigations and drawing on Big Data in particular, TG18 proposes that some Grade III AC can be treated by Lap-C when performed at advanced centers with specialized surgeons experienced in this procedure and for patients that satisfy certain strict criteria. For Grade I, TG18 recommends early Lap-C if the patients meet the criteria of Charlson comorbidity index (CCI) ≤5 and American Society of Anesthesiologists physical status classification (ASA-PS) ≤2. For Grade II AC, if patients meet the criteria of CCI ≤5 and ASA-PS ≤2, TG18 recommends early Lap-C performed by experienced surgeons; and if not, after medical treatment and/or gallbladder drainage, Lap-C would be indicated. TG18 proposes that Lap-C is indicated in Grade III patients with strict criteria. These are that the patients have favorable organ system failure, and negative predictive factors, who meet the criteria of CCI ≤3 and ASA-PS ≤2 and who are being treated at an advanced center (where experienced surgeons practice). If the patient is not considered suitable for early surgery, TG18 recommends early/urgent biliary drainage followed by delayed Lap-C once the patient's overall condition has improved. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

Although the diagnostic and severity grading criteria on the 2013 Tokyo Guidelines (TG13) are used worldwide as the primary standard for management of acute cholangitis (AC), they need to be validated through implementation and assessment in actual clinical practice. Here, we conduct a systematic review of the literature to validate the TG13 diagnostic and severity grading criteria for AC and propose TG18 criteria. While there is little evidence evaluating the TG13 criteria, they were validated through a large-scale case series study in Japan and Taiwan. Analyzing big data from this study confirmed that the diagnostic rate of AC based on the TG13 diagnostic criteria was higher than that based on the TG07 criteria, and that 30-day mortality in patients with a higher severity based on the TG13 severity grading criteria was significantly higher. Furthermore, a comparison of patients treated with early or urgent biliary drainage versus patients not treated this way showed no difference in 30-day mortality among patients with Grade I or Grade III AC, but significantly lower 30-day mortality in patients with Grade II AC who were treated with early or urgent biliary drainage. This suggests that the TG13 severity grading criteria can be used to identify Grade II patients whose prognoses may be improved through biliary drainage. The TG13 severity grading criteria may therefore be useful as an indicator for biliary drainage as well as a predictive factor when assessing the patient's prognosis. The TG13 diagnostic and severity grading criteria for AC can provide results quickly, are minimally invasive for the patients, and are inexpensive. We recommend that the TG13 criteria be adopted in the TG18 guidelines and used as standard practice in the clinical setting. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients > 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals <70 years, 2.3% between 70 and 80 years, and 6.3% >80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.

A Phase III study was started in Japan to evaluate the non-inferiority in overall survival of segmentectomy compared with lobectomy in patients with small-sized (diameter </=2 cm) peripheral non-small cell lung cancer, excluding radiologically determined non-invasive cancer. This study began in August 2009, and a total of 1100 patients will be accrued from 71 institutions within 3 years. The primary endpoint is overall survival. The secondary endpoints are post-operative respiratory function, relapse-free survival, proportion of local recurrence, adverse events, proportion of patients who complete segmentectomy, duration of hospitalization, duration of chest tube placement, operation time, blood loss and number of auto-sutures used. This study is one of the first intergroup studies in Japan between the Japan Clinical Oncology Group and the West Japan Oncology Group.

OBJECTIVE: To report the clinical, radiological, and immunological association of demyelinating disorders with anti–Nmethyl- D-aspartate receptor (NMDAR) encephalitis. METHODS: Clinical and radiological analysis was done of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. RESULTS: Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent magnetic resonance imaging (MRI) and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of neuromyelitis optica (NMO) spectrum disorder (5 cases, 4 anti-AQP4 positive) or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4 positive, 2 MOG positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis; NMDAR antibodies were detected only in the 50 anti-NMDAR patients, MOG antibodies in 3 of 50 anti-NMDAR and 1 of 56 NMO patients, and AQP4 antibodies in 48 of 56 NMO and 1 of 50 anti-NMDAR patients (p<0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1 of 23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18 of 50 anti-NMDAR controls (p50.011). INTERPRETATION: Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (eg, dyskinesias, psychosis) may have anti-NMDAR encephalitis.

RATIONALE: Interstitial lung disease (ILD) occurs in Japanese patients with non-small cell lung cancer (NSCLC) receiving gefitinib. OBJECTIVES: To elucidate risk factors for ILD in Japanese patients with NSCLC during treatment with gefitinib or chemotherapy. METHODS: In a prospective epidemiologic cohort, 3,166 Japanese patients with advanced/recurrent NSCLC were followed for 12 weeks on 250 mg gefitinib (n = 1,872 treatment periods) or chemotherapy (n = 2,551). Patients who developed acute ILD (n = 122) and randomly selected control subjects (n = 574) entered a case-control study. Adjusted incidence rate ratios were estimated from case-control data by odds ratios (ORs) with 95% confidence intervals (CIs) using logistic regression. Crude (observed) incidence rates and risks were calculated from cohort data. MEASUREMENTS AND MAIN RESULTS: The observed (unadjusted) incidence rate over 12 weeks was 2.8 (95% CI, 2.3-3.3) per 1,000 person-weeks, 4.5 (3.5-5.4) for gefitinib versus 1.7 (1.2-2.2) for chemotherapy; the corresponding observed naive cumulative incidence rates at the end of 12-week follow-up were 4.0% (3.0-5.1%) and 2.1% (1.5-2.9%), respectively. Adjusted for imbalances in risk factors between treatments, the overall OR for gefitinib versus chemotherapy was 3.2 (1.9-5.4), elevated chiefly during the first 4 weeks (3.8 [1.9-7.7]). Other ILD risk factors in both groups included the following: older age, poor World Health Organization performance status, smoking, recent NSCLC diagnosis, reduced normal lung on computed tomography scan, preexisting chronic ILD, concurrent cardiac disease. ILD-related deaths in patients with ILD were 31.6% (gefitinib) versus 27.9% (chemotherapy); adjusted OR, 1.05 (95% CI, 0.3-3.2). CONCLUSIONS: ILD was relatively common in these Japanese patients with NSCLC during therapy with gefitinib or chemotherapy, being higher in the older, smoking patient with preexisting ILD or poor performance status. The risk of developing ILD was higher with gefitinib than chemotherapy, mainly in the first 4 weeks.

PURPOSE: A novel therapeutic approach is urgently needed for BCR-ABL-positive acute lymphoblastic leukemia (ALL). In this study, we assessed the efficacy and feasibility of chemotherapy combined with imatinib. PATIENTS AND METHODS: A phase II study of imatinib-combined chemotherapy was conducted for newly diagnosed BCR-ABL-positive ALL in adults. Eighty patients were entered into the trial between September 2002 and January 2005. RESULTS: Remission induction therapy resulted in complete remission (CR) in 77 patients (96.2%), resistant disease in one patient, and early death in two patients, as well as polymerase chain reaction negativity of bone marrow in 71.3%. The profile and incidence of severe toxicity were not different from those associated with our historic chemotherapy-alone regimen. Relapse occurred in 20 patients after median CR duration of 5.2 months. Allogeneic hematopoietic stem-cell transplantation (HSCT) was performed for 49 patients, 39 of whom underwent transplantation during their first CR. The 1-year event-free and overall survival (OS) rates were estimated to be 60.0%, and 76.1%, respectively, which were significantly better than those for our historic controls treated with chemotherapy alone (P < .0001 for both). Among the current trial patients, the probability for OS at 1 year was 73.3% for those who underwent allogeneic HSCT, and 84.8% for those who did not. CONCLUSION: Our results demonstrated that imatinib-combined regimen is effective and feasible for newly diagnosed BCR-ABL-positive ALL. Despite a relatively short period of observation, a major potential of this treatment is recognized. Longer follow-up is required to determine its overall effect on survival.

The initial management of patients with suspected acute biliary infection starts with the measurement of vital signs to assess whether or not the situation is urgent. If the case is judged to be urgent, initial medical treatment should be started immediately including respiratory/circulatory management if required, without waiting for a definitive diagnosis. The patient's medical history is then taken; an abdominal examination is performed; blood tests, urinalysis, and diagnostic imaging are carried out; and a diagnosis is made using the diagnostic criteria for cholangitis/cholecystitis. Once the diagnosis has been confirmed, initial medical treatment should be started immediately, severity should be assessed according to the severity grading criteria for acute cholangitis/cholecystitis, and the patient's general status should be evaluated. For mild acute cholangitis, in most cases initial treatment including antibiotics is sufficient, and most patients do not require biliary drainage. However, biliary drainage should be considered if a patient does not respond to initial treatment. For moderate acute cholangitis, early endoscopic or percutaneous transhepatic biliary drainage is indicated. If the underlying etiology requires treatment, this should be provided after the patient's general condition has improved; endoscopic sphincterotomy and subsequent choledocholithotomy may be performed together with biliary drainage. For severe acute cholangitis, appropriate respiratory/circulatory management is required. Biliary drainage should be performed as soon as possible after the patient's general condition has been improved by initial treatment and respiratory/circulatory management. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

OBJECTIVE: The aim of the study was to confirm the noninferiority of mesorectal excision (ME) alone to ME with lateral lymph node dissection (LLND) in terms of efficacy. BACKGROUND: Lateral pelvic lymph node metastasis is occasionally found in clinical stage II or III lower rectal cancer, and ME with LLND is the standard procedure in Japan. ME alone, however, is the international standard surgical procedure for rectal cancer. METHODS: Eligibility criteria included histologically proven rectal cancer at clinical stage II/III; main lesion located in the rectum, with the lower margin below the peritoneal reflection; no lateral pelvic lymph node enlargement; Peformance Status of 0 or 1; and age 20 to 75 years. Patients were intraoperatively allocated to undergo ME with LLND or ME alone in a randomized manner. The primary endpoint was relapse-free survival, with a noninferiority margin for the hazard ratio of 1.34. Secondary endpoints included overall survival and local-recurrence-free survival. Analysis was by intention to treat. RESULTS: In total, 701 patients were randomized to the ME with LLND (n = 351) and ME alone (n = 350) groups. The 5-year relapse-free survival in the ME with LLND and ME alone groups were 73.4% and 73.3%, respectively (hazard ratio: 1.07, 90.9% confidence interval 0.84-1.36), with a 1-sided P value for noninferiority of 0.0547. The 5-year overall survival, and 5-year local-recurrence-free survival in the ME with LLND and ME alone groups were 92.6% and 90.2%, and 87.7% and 82.4%, respectively. The numbers of patients with local recurrence were 26 (7.4%) and 44 (12.6%) in the ME with LLND and ME alone groups, respectively (P = 0.024). CONCLUSIONS: The noninferiority of ME alone to ME with LLND was not confirmed in the intent-to-treat analysis. ME with LLND had a lower local recurrence, especially in the lateral pelvis, compared to ME alone.

Antimicrobial therapy is a mainstay of the management for patients with acute cholangitis and/or cholecystitis. The Tokyo Guidelines 2018 (TG18) provides recommendations for the appropriate use of antimicrobials for community-acquired and healthcare-associated infections. The listed agents are for empirical therapy provided before the infecting isolates are identified. Antimicrobial agents are listed by class-definitions and TG18 severity grade I, II, and III subcategorized by clinical settings. In the era of emerging and increasing antimicrobial resistance, monitoring and updating local antibiograms is underscored. Prudent antimicrobial usage and early de-escalation or termination of antimicrobial therapy are now important parts of decision-making. What is new in TG18 is that the duration of antimicrobial therapy for both acute cholangitis and cholecystitis is systematically reviewed. Prophylactic antimicrobial usage for elective endoscopic retrograde cholangiopancreatography is no longer recommended and the section was deleted in TG18. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

Analysis of the contour of the peripheral pulse to assess arterial properties was first described in the nineteenth century. With the recognition of the importance of arterial stiffness there has been a resurgence of interest in pulse wave analysis, particularly the analysis of the radial pressure pulse acquired using a tonometer. An alternative technique utilizes a volume pulse. This may conveniently be acquired optically from a finger (digital volume pulse). Although less widely used, this technique deserves further consideration because of its simplicity and ease of use. As with the pressure pulse, the contour of the digital volume pulse is sensitive to changes in arterial tone induced by vasoactive drugs and is influenced by ageing and large artery stiffness. Measurements taken directly from the digital volume pulse or from its second derivative can be used to assess these properties. This review describes the background to digital volume pulse contour analysis, how the technique relates to contour analysis of the pressure pulse, and current and future applications.

Since the publication of the Tokyo Guidelines in 2007 and their revision in 2013, appropriate management for acute cholecystitis has been more clearly established. Since the last revision, several manuscripts, especially for alternative endoscopic techniques, have been reported; therefore, additional evaluation and refinement of the 2013 Guidelines is required. We describe a standard drainage method for surgically high-risk patients with acute cholecystitis and the latest developed endoscopic gallbladder drainage techniques described in the updated Tokyo Guidelines 2018 (TG18). Our study confirmed that percutaneous transhepatic gallbladder drainage should be considered the first alternative to surgical intervention in surgically high-risk patients with acute cholecystitis. Also, endoscopic transpapillary gallbladder drainage or endoscopic ultrasound-guided gallbladder drainage can be considered in high-volume institutes by skilled endoscopists. In the endoscopic transpapillary approach, either endoscopic naso-gallbladder drainage or gallbladder stenting can be considered for gallbladder drainage. We also introduce special techniques and the latest outcomes of endoscopic ultrasound-guided gallbladder drainage studies. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

Vaccination could be a key protective measure against coronavirus disease 2019 (COVID-19), and it is important to understand the acceptability of the COVID-19 vaccine among the general public. However, there is no study on the acceptance of a COVID-19 vaccine in Japan. Therefore, this study aimed to describe the COVID-19 vaccine acceptance and hesitancy situation in Japan and assess the factors associated with such issues. This was a cross-sectional study based on an internet survey completed by 2956 people. Participants were asked to indicate how likely they were to get vaccinated for COVID-19. In addition, the participants responded to questions regarding sociodemographic factors, attitudes, and beliefs regarding COVID-19 infection and vaccination. The proportion of participants with a high likelihood of getting a COVID-19 vaccine was 62.1%. Multiple logistic regression analysis showed that vaccine acceptance was lower among several sociodemographic groups, such as women, adults aged 20-49 years, and those with a low-income level. Several psychological factors, especially the perceived effectiveness of the COVID-19 vaccine, and willingness to protect others by getting oneself vaccinated, were associated with vaccine acceptance. Our results indicate that the perceived effectiveness of the vaccine and willingness to protect others may play an important role in the acceptance of the COVID-19 vaccine.

Management bundles that define items or procedures strongly recommended in clinical practice have been used in many guidelines in recent years. Application of these bundles facilitates the adaptation of guidelines and helps improve the prognosis of target diseases. In Tokyo Guidelines 2013 (TG13), we proposed management bundles for acute cholangitis and cholecystitis. Here, in Tokyo Guidelines 2018 (TG18), we redefine the management bundles for acute cholangitis and cholecystitis. Critical parts of the bundles in TG18 include the diagnostic process, severity assessment, transfer of patients if necessary, and therapeutic approach at each time point. Observance of these items and procedures should improve the prognosis of acute cholangitis and cholecystitis. Studies are now needed to evaluate the dissemination of these TG18 bundles and their effectiveness. Free full articles and mobile app of TG18 are available at: http://www.jshbps.jp/modules/en/index.php?content_id=47. Related clinical questions and references are also included.

OBJECTIVE: The optimal management of acute cholecystitis in patients at very high risk for cholecystectomy is uncertain. The aim of the current study was to compare endoscopic ultrasound (EUS)-guided gallbladder drainage (EUS-GBD) to percutaneous cholecystostomy (PT-GBD) as a definitive treatment in these patients under a randomised controlled trial. DESIGN: Consecutive patients suffering from acute calculous cholecystitis but were at very high-risk for cholecystectomy were recruited. The primary outcome was the 1-year adverse events rate. Secondary outcomes include technical and clinical success, 30-day adverse events, pain scores, unplanned readmissions, re-interventions and mortalities. RESULTS: Between August 2014 to February 2018, 80 patients were recruited. EUS-GBD significantly reduced 1 year adverse events (10 (25.6%) vs 31 (77.5%), p<0.001), 30-day adverse events (5 (12.8%) vs 19 (47.5%), p=0.010), re-interventions after 30 days (1/39 (2.6%) vs 12/40 (30%), p=0.001), number of unplanned readmissions (6/39 (15.4%) vs 20/40 (50%), p=0.002) and recurrent cholecystitis (1/39 (2.6%) vs 8/40 (20%), p=0.029). Postprocedural pain scores and analgesic requirements were also less (p=0.034). The technical success (97.4% vs 100%, p=0.494), clinical success (92.3% vs 92.5%, p=1) and 30-day mortality (7.7% vs 10%, p=1) were statistically similar. The predictor to recurrent acute cholecystitis was the performance of PT-GBD (OR (95% CI)=5.63 (1.20-53.90), p=0.027). CONCLUSION: EUS-GBD improved outcomes as compared to PT-GBD in those patients that not candidates for cholecystectomy. EUS-GBD should be the procedure of choice provided that the expertise is available after a multi-disciplinary meeting. Further studies are required to determine the long-term efficacy. TRIAL REGISTRATION NUMBER: NCT02212717.

The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed by the National Cancer Institute as an adverse event assessment system to evaluate patients’ symptoms, which tend to be underestimated in cancer clinical trials. The aim of this study was to assess the psychometric properties of the Japanese version of the PRO-CTCAE and the degree of adverse event assessment discordance between clinicians and patients. A total of 187 cancer patients receiving systemic therapy were enrolled. Reproducibility, criterion validity, and responsiveness of the Japanese version of PROCTCAE were assessed. The EORTC QLQ-C30 was used as an external anchor. Discordance of assessment of adverse events between clinician and patients were also assessed using the CTCAE and PRO-CTCAE. A total of 187 participants (187 for criterion validity, 80 for reproducibility, and 100 for responsiveness), were analyzed (Mage = 62.4 years). All patients responded to at least one symptom item (M = 16). The mean (SD) intra-class correlation coefficients of overall reproducibility for the Japanese PRO-CTCAE was 0.63 (0.02). The correlation coefficient for the corresponding items in the EORTC QLQ-C30 and the Japanese PRO-CTCAE was high (Pearson r = 0.56–0.76). The analysis of responsiveness revealed significant dose-response trends (Jonckheere-Terpstra test, ps < 0.001). Depending on the adverse events, a discrepancy was observed in evaluation between the clinician and patient. These results revealed that there is underestimation in the assessment of adverse events in Japan, and that the Japanese version of the PRO-CTCAE had acceptable reliability and validity for common and clinically important symptoms.

Although much promising data that interleukin (IL)-12 could be a powerful therapeutic agent against cancer were reported in animal models, its excessive toxicity has become a problem for its clinical application. IL-27 is a novel IL-12 family member that plays a role in the early regulation of T helper cell 1 initiation, including induction of T-bet and IL-12 receptor beta 2 expression. In the present study, we have evaluated the antitumor activity of IL-27 against a murine tumor model of colon carcinoma C26. C26 cells, which were transduced with the single-chain IL-27 cDNA and became secreting IL-27 (C26-IL-27), exhibited minimal tumor growth in vivo, and all of the mice inoculated with these cells survived healthily with complete tumor remission. Inoculation of mice with C26-IL-27 induced enhanced IFN-gamma production and cytotoxic T-lymphocyte activity against C26 tumor in spleen cells. Recovered mice from the inoculation showed a tumor-specific protective immunity to the following challenge with parental C26 tumor. The antitumor activity of IL-27 was almost diminished in nude mice, and depletion of CD8(+) T cells and neutralization of IFN-gamma in immunocompetent mice reduced greatly the antitumor activity. Moreover, the antitumor activity was abolished in T-bet-deficient mice, whereas it was observed unexpectedly in mice deficient of signal transducer and activator of transcription (STAT) 4. These results suggest that IL-27 has potent abilities to induce tumor-specific antitumor activity and protective immunity and that the antitumor activity is mediated mainly through CD8(+) T cells, IFN-gamma, and T-bet but not through STAT4.