National Hospital Organization Mito Medical Center

In a recent report, [Zhang et al. (2003) N. Engl. J. Med. 348, 203-213], the presence of CD3+ tumor-infiltrating lymphocytes (TILs) was found to correlate with improved survival in epithelial ovarian cancer. We performed immunohistochemical analysis for TILs and cancer testis antigens in 117 cases of epithelial ovarian cancer. The interrelationship between subpopulations of TILs and expression of cancer testis antigens was investigated, as well as between TILs and overall survival. The median follow-up of the patients was 31 months. Patients with higher frequencies of intraepithelial CD8+ T cells demonstrated improved survival compared with patients with lower frequencies [median = 55 versus 26 months; hazard ratio = 0.33; confidence interval (C.I.) = 0.18-0.60; P = 0.0003]. No association was found for CD3+ TILs or other subtypes of intraepithelial or stromal TILs. However, the subgroups with high versus low intraepithelial CD8+/CD4+ TIL ratios had median survival of 74 and 25 months, respectively (hazard ratio = 0.30; C.I. = 0.16-0.55; P = 0.0001). These results indicate that CD4+ TILs influence the beneficial effects of CD8+ TIL. This unfavorable effect of CD4+ T cells on prognosis was found to be due to CD25+ forkhead box P3 (FOXP3)+ regulatory T cells (Treg; suppressor T cells), as indicated by survival of patients with high versus low CD8+/Treg ratios (median = 58 versus 23 months; hazard ratio = 0.31; C.I. = 0.17-0.58; P = 0.0002). The favorable prognostic effect of intraepithelial CD8+ TILs did not correlate with concurrent expression of NY-ESO-1 or MAGE antigens. We conclude that intraepithelial CD8+ TILs and a high CD8+/Treg ratio are associated with favorable prognosis in epithelial ovarian cancer.

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.

IMPORTANCE: Whether intravenous thrombolysis is needed in combination with mechanical thrombectomy in patients with acute large vessel occlusion stroke is unclear. OBJECTIVE: To examine whether mechanical thrombectomy alone is noninferior to combined intravenous thrombolysis plus mechanical thrombectomy for favorable poststroke outcome. DESIGN, SETTING, AND PARTICIPANTS: Investigator-initiated, multicenter, randomized, open-label, noninferiority clinical trial in 204 patients with acute ischemic stroke due to large vessel occlusion enrolled at 23 hospital networks in Japan from January 1, 2017, to July 31, 2019, with final follow-up on October 31, 2019. INTERVENTIONS: Patients were randomly assigned to mechanical thrombectomy alone (n = 101) or combined intravenous thrombolysis (alteplase at a 0.6-mg/kg dose) plus mechanical thrombectomy (n = 103). MAIN OUTCOMES AND MEASURES: The primary efficacy end point was a favorable outcome defined as a modified Rankin Scale score (range, 0 [no symptoms] to 6 [death]) of 0 to 2 at 90 days, with a noninferiority margin odds ratio of 0.74, assessed using a 1-sided significance threshold of .025 (97.5% CI). There were 7 prespecified secondary efficacy end points, including mortality by day 90. There were 4 prespecified safety end points, including any intracerebral hemorrhage and symptomatic intracerebral hemorrhage within 36 hours. RESULTS: Among 204 patients (median age, 74 years; 62.7% men; median National Institutes of Health Stroke Scale score, 18), all patients completed the trial. Favorable outcome occurred in 60 patients (59.4%) in the mechanical thrombectomy alone group and 59 patients (57.3%) in the combined intravenous thrombolysis plus mechanical thrombectomy group, with no significant between-group difference (difference, 2.1% [1-sided 97.5% CI, -11.4% to ∞]; odds ratio, 1.09 [1-sided 97.5% CI, 0.63 to ∞]; P = .18 for noninferiority). Among the 7 secondary efficacy end points and 4 safety end points, 10 were not significantly different, including mortality at 90 days (8 [7.9%] vs 9 [8.7%]; difference, -0.8% [95% CI, -9.5% to 7.8%]; odds ratio, 0.90 [95% CI, 0.33 to 2.43]; P > .99). Any intracerebral hemorrhage was observed less frequently in the mechanical thrombectomy alone group than in the combined group (34 [33.7%] vs 52 [50.5%]; difference, -16.8% [95% CI, -32.1% to -1.6%]; odds ratio, 0.50 [95% CI, 0.28 to 0.88]; P = .02). Symptomatic intracerebral hemorrhage was not significantly different between groups (6 [5.9%] vs 8 [7.7%]; difference, -1.8% [95% CI, -9.7% to 6.1%]; odds ratio, 0.75 [95% CI, 0.25 to 2.24]; P = .78). CONCLUSIONS AND RELEVANCE: Among patients with acute large vessel occlusion stroke, mechanical thrombectomy alone, compared with combined intravenous thrombolysis plus mechanical thrombectomy, failed to demonstrate noninferiority regarding favorable functional outcome. However, the wide confidence intervals around the effect estimate also did not allow a conclusion of inferiority. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: UMIN000021488.

BACKGROUND AND PURPOSE: The natural history and optimal management of incidentally found small unruptured aneurysms <5 mm in size remain unclear. A prospective study was conducted to determine the optimal management for incidentally found small unruptured aneurysms. METHODS: From September 2000 to January, 2004, 540 aneurysms (446 patients) were registered. Four hundred forty-eight unruptured aneurysms <5 mm in size (374 patients) have been followed up for a mean of 41.0 months (1306.5 person-years) to date. We calculated the average annual rupture rate of small unruptured aneurysms and also investigated risk factors that contribute to rupture and enlargement of these aneurysms. RESULTS: The average annual risks of rupture associated with small unruptured aneurysms were 0.54% overall, 0.34% for single aneurysms, and 0.95% for multiple aneurysms. Patient <50 years of age (P=0.046; hazard ratio, 5.23; 95% CI, 1.03 to 26.52), aneurysm diameter of >or=4.0 mm (P=0.023; hazard ratio, 5.86; 95% CI, 1.27 to 26.95), hypertension (P=0.023; hazard ratio, 7.93; 95% CI, 1.33 to 47.42), and aneurysm multiplicity (P=0.0048; hazard ratio, 4.87; 95% CI, 1.62 to 14.65) were found to be significant predictive factors for rupture of small aneurysms. CONCLUSIONS: The annual rupture rate associated with small unruptured aneurysms is quite low. Careful attention should be paid to the treatment indications for single-type unruptured aneurysms <5 mm. If the patient is <50 years of age, has hypertension, and multiple aneurysms with diameters of >or=4 mm, treatment should be considered to prevent future aneurysmal rupture.

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.

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.

The present retrospective study was performed to evaluate the clinicopathological characteristics associated with distant metastasis from non-small-cell lung cancer (NSCLC). The records of NSCLC patients with metastasis at the time of diagnosis between 1999 and 2012 were reviewed. Of the consecutive 1,542 NSCLC patients diagnosed during the study period, 729 (47.3%) patients presented with distant metastasis. Among those 729 metastatic NSCLC patients, 250 (34.3%), 234 (32.1%), 207 (28.4%), 122 (16.7%), 98 (13.4%) and 69 (9.5%) had bone, lung, brain, adrenal gland, liver and extrathoracic lymph node metastasis, respectively. In a multivariate analysis using the Cox proportional hazards model, liver and adrenal gland metastases were unfavorable prognostic factors. However, brain and bone metastases were not statistically significant prognostic factors. Using a logistic regression analysis, metastasis to the adrenal glands and the presence of pleural and/or pericardial fluid effusion were correlated with a poor performance status. Therefore, when planning the treatment of NSCLC patients, particularly those with liver and adrenal gland metastases, we should take into consideration information regarding these unfavorable organ metastases.

Human colorectal cancer tissues are infiltrated by various immune/inflammatory cells, usually along the invasive margin. These responses tend be regarded as "non-specific". However, it is now clear that these cellular responses, particularly lymphocytic reactions, are independent prognostic factors for a better survival. Immunohistochemical subset analyses have generally disclosed that the number of T-lymphocytes is important. The effects of these T cells tend to be more manifest when the observation periods are longer. These data suggest that some degrees of anti-tumor immunity exist in human colorectal carcinomas. However, human tumors are generally composed of various histologic subtypes, which sometimes complicates these analyses and simple explanations may be misleading. Considered with precaution, these morphologic analyses on immune cell subtypes are important tools to understand the immune responses in human cancers.

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.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

Background: Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous “more versus less statins” trials. However, no clear evidence for more versus less statins has been established in an Asian population. Methods: In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) &lt;120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. Results: The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group ( P &lt;0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69–0.95; P =0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73–0.93; P =0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (&lt;95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups. Conclusions: High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01042730.

The aim of this meta-analysis was to compare the association of waist-to-height ratio (WHtR) with risk of incident diabetes with the associations of 3 other conventional obesity indicators (body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR)) with risk of incident diabetes. Literature searches in MEDLINE (January 1950 to April 27, 2011) and EMBASE (January 1974 to April 27, 2011) were conducted for prospective studies that made it possible to estimate the relative risk of diabetes per 1-standard deviation increase in WHtR, in addition to the RR of BMI, WC, or WHR. Strength of the estimated pooled relative risk for a 1-standard deviation increase of each indicator (expressed as RR(WHtR), RR(BMI), RR(WC), and RR(WHR)) was compared with a bivariate random-effects model. Pooled relative risks of the 15 eligible studies with 6,472 diabetes cases were 1.62 (95% CI: 1.48, 1.78) for RR(WHtR), 1.55 (95% CI: 1.43, 1.69) for RR(BMI), 1.63 (95% CI: 1.49, 1.79) for RR(WC), and 1.52 (95% CI: 1.40, 1.66) for RR(WHR). WHtR had an association stronger than that of BMI (P<0.001) or WHR (P<0.001). The present meta-analysis showed that WHtR has a modestly but statistically greater importance than BMI and WHR in prediction of diabetes. Nevertheless, measuring height in addition to WC appeared to have no additional benefit.

OBJECTIVE: The association between habitual physical activity (PA) and lowered risk of all-cause mortality (ACM) and cardiovascular disease (CVD) has been suggested in patients with diabetes. This meta-analysis summarizes the risk reduction in relation to PA, focusing on clarifying dose-response associations. RESEARCH DESIGN AND METHODS: Electronic literature searches were conducted for cohort studies that examined relative risk (RR) of ACM or CVD in relation to PA in patients with diabetes. For the qualitative assessment, RR for the highest versus the lowest PA category in each study was pooled with a random-effects model. We added linear and spline regression analyses to assess the quantitative relationship between increases in PA and ACM and CVD risk. RESULTS: There were 17 eligible studies. Qualitatively, the highest PA category had a lower RR [95% CI] for ACM (0.61 [0.52-0.70]) and CVD (0.71 [0.60-0.84]) than the lowest PA category. The linear regression model indicated a high goodness of fit for the risk of ACM (adjusted R(2) = 0.44, P = 0.001) and CVD (adjusted R(2) = 0.51, P = 0.001), with the result that a 1 MET-h/day incrementally higher PA was associated with 9.5% (5.0-13.8%) and 7.9% (4.3-11.4%) reductions in ACM and CVD risk, respectively. The spline regression model was not significantly different from the linear model in goodness of fit (P = 0.14 for ACM risk; P = 0.60 for CVD risk). CONCLUSIONS: More PA was associated with a larger reduction in future ACM and CVD risk in patients with diabetes. Nevertheless, any amount of habitual PA was better than inactivity.

T-cell infiltration into human cancer tissues can be a manifestation of host immune responses to cancer cells. The present study was undertaken to explore the clinicopathological significance of intraepithelial CD8(+) T cells using 371 consecutively sampled human colorectal carcinomas. By univariate analysis, we noted that the survival curves by intraepithelial CD8(+) T cells became separated only after 1 to 2 years postoperation. Multivariate analyses revealed that the beneficial effect of this factor becomes significant only after a longer (more than 2 year), but not after a shorter (less than 2 year) follow-up period. Furthermore, the number of intraepithelial CD8(+) T cells was significantly higher in patients alive for more than 5 years than in patients who either died of cancer after a curative operation or patients who underwent a noncurative operation. Patients' cancer-specific death long after a curative operation is thought to be caused by the growth of micrometastases in other organs or near the primary sites. The effects of intraepithelial CD8(+) T cells, therefore, may be mediated by suppression of micrometastasis, rather than suppression of growth in the primary tumour. In conclusion, our data support a hypothesis on the presence of systemic immunosurveillance against micrometastasis of cancer cells.

INTRODUCTION: Our aim in this study was to assess whether the new Glasgow Coma Scale, Age, and Systolic Blood Pressure (GAP) scoring system, which is a modification of the Mechanism, Glasgow Coma Scale, Age, and Arterial Pressure (MGAP) scoring system, better predicts in-hospital mortality and can be applied more easily than previous trauma scores among trauma patients in the emergency department (ED). METHODS: This multicenter, prospective, observational study was conducted to analyze readily available variables in the ED, which are associated with mortality rates among trauma patients. The data used in this study were derived from the Japan Trauma Data Bank (JTDB), which consists of 114 major emergency hospitals in Japan. A total of 35,732 trauma patients in the JTDB from 2004 to 2009 who were 15 years of age or older were eligible for inclusion in the study. Of these patients, 27,154 (76%) with complete sets of important data (patient age, Glasgow Coma Scale (GCS) score, systolic blood pressure (SBP), respiratory rate and Injury Severity Score (ISS)) were included in our analysis. We calculated weight for the predictors of the GAP scores on the basis of the records of 13,463 trauma patients in a derivation data set determined by using logistic regression. Scores derived from four existing scoring systems (Revised Trauma Score, Triage Revised Trauma Score, Trauma and Injury Severity Score and MGAP score) were calibrated using logistic regression models that fit in the derivation set. The GAP scoring system was compared to the calibrated scoring systems with data from a total of 13,691 patients in a validation data set using c-statistics and reclassification tables with three defined risk groups based on a previous publication: low risk (mortality < 5%), intermediate risk, and high risk (mortality > 50%). RESULTS: Calculated GAP scores involved GCS score (from three to fifteen points), patient age < 60 years (three points) and SBP (> 120 mmHg, six points; 60 to 120 mmHg, four points). The c-statistics for the GAP scores (0.933 for long-term mortality and 0.965 for short-term mortality) were better than or comparable to the trauma scores calculated using other scales. Compared with existing instruments, our reclassification tables show that the GAP scoring system reclassified all patients except one in the correct direction. In most cases, the observed incidence of death in patients who were reclassified matched what would have been predicted by the GAP scoring system. CONCLUSIONS: The GAP scoring system can predict in-hospital mortality more accurately than the previously developed trauma scoring systems.

Intra-abdominal infections (IAI) are an important cause of morbidity and are frequently associated with poor prognosis, particularly in high-risk patients. The cornerstones in the management of complicated IAIs are timely effective source control with appropriate antimicrobial therapy. Empiric antimicrobial therapy is important in the management of intra-abdominal infections and must be broad enough to cover all likely organisms because inappropriate initial antimicrobial therapy is associated with poor patient outcomes and the development of bacterial resistance. The overuse of antimicrobials is widely accepted as a major driver of some emerging infections (such as C. difficile), the selection of resistant pathogens in individual patients, and for the continued development of antimicrobial resistance globally. The growing emergence of multi-drug resistant organisms and the limited development of new agents available to counteract them have caused an impending crisis with alarming implications, especially with regards to Gram-negative bacteria. An international task force from 79 different countries has joined this project by sharing a document on the rational use of antimicrobials for patients with IAIs. The project has been termed AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections). The authors hope that AGORA, involving many of the world's leading experts, can actively raise awareness in health workers and can improve prescribing behavior in treating IAIs.

PURPOSE This study evaluated the continuous use of trastuzumab beyond progression (TBP) in human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastroesophageal junction (G/GEJ) cancer. PATIENTS AND METHODS Patients with HER2-positive advanced G/GEJ cancer refractory to first-line chemotherapy with trastuzumab in combination with fluoropyrimidine and platinum were eligible. Patients were randomly assigned to the paclitaxel (80 mg/m 2 , days 1, 8, and 15, every 4 weeks) or paclitaxel with trastuzumab (PT; initially 8 mg/kg followed by 6 mg/kg, every 3 weeks) arms. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rate, and safety. Biomarkers such as HER2 expression status in tumor tissue after first-line treatment, HER2 amplification evaluated in serum cell-free DNA, and soluble HER2 levels were analyzed. RESULTS Overall, 91 patients were allocated to the paclitaxel (n = 46) and PT (n = 45) arms. The median PFS in the paclitaxel and PT arms was 3.2 and 3.7 months, respectively (hazard ratio [HR], 0.91; 80% CI, 0.67 to 1.22; P = .33), and the median OS in both arms was 10 months (HR, 1.2; 95% CI, 0.75 to 2.0; P = .20). The overall response rates in the paclitaxel and PT arms were 32% and 33%, respectively ( P = 1.00), and safety was comparable between the 2 arms. On exploratory analyses, HER2 positivity of tumor tissues was lost after first-line chemotherapy in 11 (69%) of 16 patients whose tumor tissues were available, and circulating HER2 DNA amplification was detected in 41 (60%) of 68 patients. However, no biomarkers associated with efficacy of TBP were found. CONCLUSION The TBP strategy failed to improve PFS in patients with HER2-positive advanced G/GEJ cancer, and no beneficial biomarkers were found.

The aim of our retrospective study was to evaluate the clinicopathological features associated with distant metastasis from small cell lung cancer (SCLC). We reviewed patients diagnosed with SCLC metastasis at the time of presentation between 1999 and 2010. Among the consecutive 251 SCLC patients diagnosed, 152 (60.6%) patients had distant metastasis, of which 20.3, 18.3, 15.5, 10.0 and 6.0% of patients had liver, bone, brain, lung and adrenal gland metastasis, respectively. In a multivariate analysis using Cox's proportional hazards model, we identified that liver, bone and brain metastasis as well as the presence of pleural and/or pericardial fluids were unfavorable prognostic factors. However, lung, adrenal gland and extrathoracic lymph node metastasis were not statistically significant prognostic factors. With regard to the treatment of SCLC patients, particularly those with liver, bone and brain metastasis or pleural and/or pericardial fluids, we should take the metastasizing organs into consideration.

OBJECTIVE: To build a prediction model that estimates the 3-year rupture risk of unruptured saccular cerebral aneurysms. METHODS: Survival analysis was done using each aneurysm as the unit for analysis. Derivation data were from the Unruptured Cerebral Aneurysm Study (UCAS) in Japan. It consists of patients with unruptured cerebral aneurysms enrolled between 2000 and 2004 at neurosurgical departments at tertiary care hospitals in Japan. The model was presented as a scoring system, and aneurysms were classified into 4 risk grades by predicted 3-year rupture risk: I, < 1%; II, 1 to 3%; III, 3 to 9%, and IV, >9%. The discrimination property and calibration plot of the model were evaluated with external validation data. They were a combination of 3 Japanese cohort studies: UCAS II, the Small Unruptured Intracranial Aneurysm Verification study, and the study at Jikei University School of Medicine. RESULTS: The derivation data include 6,606 unruptured cerebral aneurysms in 5,651 patients. During the 11,482 aneurysm-year follow-up period, 107 ruptures were observed. The predictors chosen for the scoring system were patient age, sex, and hypertension, along with aneurysm size, location, and the presence of a daughter sac. The 3-year risk of rupture ranged from <1% to >15% depending on the individual characteristics of patients and aneurysms. External validation indicated good discrimination and calibration properties. INTERPRETATION: A simple scoring system that only needs easily available patient and aneurysmal information was constructed. This can be used in clinical decision making regarding management of unruptured cerebral aneurysms.

Summary This meta‐analysis quantified the risk of type 2 diabetes mellitus ( T2DM ) preceded by body weight ( BW ) gain in the general population. Systematic literature searches retrieved 15 eligible studies. The BW gain was divided into early weight‐gain, which was defined as BW gain from early adulthood (18–24 years of age) to cohort entry (≥25 years of age), and late weight‐gain, which was defined as BW gain from cohort entry. The pooled relative risk ( RR ; 95% confidence interval [ CI ]) of T2DM for an increment of BW gain standardized into a 5‐kg m −2 increment in the body mass index ( BMI ) was 3.07 (2.49–2.79) for early weight‐gain and 2.12 (1.74–2.58) for late weight‐gain. When limiting analysis to studies that concurrently examined T2DM risk for current BMI (defined in both groups as BMI at cohort entry), a larger magnitude of T2DM risk was revealed for early weight‐gain compared with current BMI ( RR [95% CI ], 3.38 [2.20–5.18] vs. 2.39 [1.58–3.62]), while there was little difference between late weight‐gain ( RR [95% CI ], 2.21 [1.91–2.56]) and current BMI ( RR [95% CI ], 2.47 [1.97–3.30]). The meta‐analysis suggested that BW gain was a quantifiable predictor of T2DM , as well as current obesity in adults. Particularly, BW gain in early rather than middle‐to‐late adulthood played an important role in developing T2DM .