Ramucirumab Plus Docetaxel for Patients with Non-small cell Lung Cancer with Brain Metastases: A Multicenter, Open-Label Single-Arm Phase II Trial.

BACKGROUND: Ramucirumab plus docetaxel combination therapy (DOC/RAM) for advanced non-small cell lung cancer (NSCLC) achieves favorable outcomes; however, efficacy and safety for patients with brain metastases are still unclear. METHODS: Eligible patients included those with advanced NSCLC with measurable asymptomatic brain metastases that progressed after chemotherapy. Patients were intravenously administered ramucirumab (10 mg/kg) and docetaxel (60 mg/m2) every 21-day cycle. RESULTS: Due to difficulties in accumulating the planned 65 participants, enrollment was terminated early when 25 patients were enrolled. Primary endpoint: Median progression-free survival (PFS) was 3.9 months (95% CI, 1.8-5.3). Secondary endpoints: Median intracranial progression-free survival was 4.6 months (95% CI, 2.5-5.9); median overall survival was 20.9 months (95% CI, 6.6-not possible to estimate); objective response rate was 20% (95% CI, 6.8-40.7); disease control rate was 68% (95% CI, 46.5-85.1). The most common grade 3 or higher toxicities were neutropenia in 10 patients (40%). Neither intracranial hemorrhage nor grade 5 adverse events were observed. Patients with higher serum soluble vascular endothelial growth factor receptor 2 concentrations at the start of treatment had slightly longer PFS. CONCLUSION: No clinical concerns were identified with DOC/RAM for NSCLC with brain metastases in this study. Further investigation with a larger sample size is needed to determine the tolerability and safety of these populations (Trial Identifiers: University Hospital Medical Information Network in Japan [UMIN000024551] and Japan Registry of Clinical Trials [jRCTs071180048]).

Impact of tumor shrinkage pattern with biweekly triplet gemcitabine+cisplatin+S-1 regimen for biliary tract cancers: Implications for neoadjuvant therapy from the data of KHBO1401 (KHBO1401-1A study).

BACKGROUND: The multicenter randomized phase III KHBO1401 study (gemcitabine+cisplatin+S-1 [GCS] versus GC in biliary tract cancers [BTC]) demonstrated that GCS not only prolonged patient survival but also achieved a high response rate and that it should be good for neoadjuvant therapy. Therefore, to explore the possibilities of neoadjuvant therapy, we investigated the tumor shrinkage pattern. METHODS: Among the total of 246 patients enrolled in the KHBO1401, the tumor shrinkage pattern and survival were investigated in patients with measurable BTC (n=183, 74%; GCS, n=91; GC, n=92). RESULTS: The tumor shrinkage pattern could be divided to 4 categories based on the response at 100 days after enrollment: category A (<-30% in size), B (-30% to 0%), C (0% to +20%), and D (>+20%). The GCS arm included more category A and B cases (61 [67%] vs. 33 [36%], P<0.0001). Each category predicted best response and overall survival (P<0.0001). Category A showed sustained tumor response compared with category B; in GCS, the time to maximum tumor response was 165 ± 76 days in category A and 139 ± 78 in category B. Categories C and D did not achieve tumor shrinkage. The maximum tumor shrinkage size in category A was -53% in the GCS arm and -65% in the GC arm (P=0.0892). Twenty percent of patients in the GCS showed tumor regrowth 154 ± 143 days later. CONCLUSION: GCS provided faster and greater tumor shrinkage with better survival in comparison to GC, although 20% of patients showed re-growth after 6 cycles.

Effect of Low-Density Lipoprotein Apheresis on Quality of Life in Patients with Diabetes, Proteinuria, and Hypercholesterolemia.

INTRODUCTION: Treating diabetic nephropathy with low-density lipoprotein (LDL) apheresis reduces proteinuria and improves prognosis. However, its impact on patients' quality of life (QoL) is unclear. This study evaluated the effect of LDL apheresis on QoL in patients with diabetes, proteinuria, and hypercholesterolemia. METHODS: In this nationwide multicenter prospective study, we enrolled 40 patients with diabetes. Inclusion criteria were proteinuria (defined as an albumin/creatinine ratio ≥3 g/g), serum creatinine levels <2 mg/dL, and serum LDL ≥120 mg/dL despite drug treatment. LDL apheresis was performed 6-12 times within 12 weeks. The 36-item Short Form Health Survey (SF-36) was used to analyze QoL. RESULTS: The study enrolled 35 patients (27 men and 8 women; mean age 58.9 ± 11.9 years). A comparison of baseline SF-36 values with those at the end of the course of apheresis found an improvement in the mean physical component summary (37.9 ± 11.4 vs. 40.6 ± 10.5, p = 0.051) and a significant increase in the mean mental component summary (MCS) (49.4 ± 8.4 vs. 52.5 ± 10.9, p = 0.026). A multivariable linear regression analysis revealed a history of coronary heart disease negatively correlated with the MCS increase at the end of the course of apheresis (ß coefficient -6.935, 95% confidence interval, 13.313 to-0.556, p = 0.034). CONCLUSION: Our results suggest that LDL apheresis may improve the mental and physical QoL in patients with diabetes, proteinuria, and hypercholesterolemia.

First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors.

BACKGROUND: The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. METHODS: This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle = 28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. RESULTS: Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. CONCLUSIONS: This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. LAY SUMMARY: This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.

Serum Laminin γ2 Monomer as a Diagnostic and Predictive Biomarker for Hepatocellular Carcinoma.

BACKGROUNDS AND AIMS: Structural dynamics of basement membrane components are still to be elucidated in the process of hepatocarcinogenesis. We evaluated the characteristics of HCC expressing laminin γ2 monomer (LG2m), a basement membrane component not detected in normal tissues, for HCC diagnosis. We further determined whether elevated serum LG2m is a risk factor for HCC development in patients with chronic hepatitis C (CHC). APPROACH AND RESULTS: In HCC cell lines, LG2m was expressed in alpha-fetoprotein (AFP)-negative, CD90-positive cells characterized by highly metastatic natures. Using 14 cell lines and 258 HCC microarray data, we identified that LG2m gene signature was associated with Hoshida's S1/Boyault's G3 molecular subclasses with poor prognosis, which could not be recognized by AFP. Serum LG2m was assessed in 24 healthy donors, 133 chronic liver disease patients, and 142 HCC patients, and sensitivity and specificity of LG2m testing for HCC diagnosis were 62.9% and 70.5%, respectively (cutoff, 30 pg/mL). We evaluated the consequence of LG2m elevation in two independent HCC cohorts (n = 47 and n = 81), and LG2m-high HCC showed poor prognosis with later development of distant organ metastasis (cutoff, 60 pg/mL). LG2m was slightly elevated in a subset of CHC patients, and Kaplan-Meier analysis indicated a high incidence of HCC (n = 70). For validation, we enrolled 399 CHC patients with sustained virological response (SVR) as a multicenter, prospective study, and serum LG2m elevation correlated with a high incidence of HCC in the CHC patients with SVR (P < 0.0001). CONCLUSIONS: LG2m is a predictive biomarker for the development of metastatic HCC. Elevated serum LG2m is an HCC risk in CHC patients who have achieved SVR.

Phase I/II clinical trial of high-dose [131I] meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding single myeloablative chemotherapy and haematopoietic stem cell transplantation.

PURPOSE: Paediatric high-risk neuroblastoma has poor prognosis despite modern multimodality therapy. This phase I/II study aimed to determine the safety, dose-limiting toxicity (DLT), and efficacy of high-dose 131I-meta-iodobenzylguanidine (131I-mIBG) therapy combined with single high-dose chemotherapy (HDC) and haematopoietic stem cell transplantation (HSCT) in high-risk neuroblastoma in Japan. METHODS: Patients received 666 MBq/kg of 131I-mIBG and single HDC and HSCT from autologous or allogeneic stem cell sources. The primary endpoint was DLT defined as adverse events associated with 131I-mIBG treatment posing a significant obstacle to subsequent HDC. The secondary endpoints were adverse events/reactions, haematopoietic stem cell engraftment and responses according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) and 123I-mIBG scintigraphy. Response was evaluated after engraftment. RESULTS: We enrolled eight patients with high-risk neuroblastoma (six females; six newly diagnosed and two relapsed high-risk neuroblastoma; median age, 4 years; range, 1-10 years). Although all patients had adverse events/reactions after high-dose 131I-mIBG therapy, we found no DLT. Adverse events and reactions were observed in 100% and 25% patients during single HDC and 100% and 12.5% patients during HSCT, respectively. No Grade 4 complications except myelosuppression occurred during single HDC and HSCT. The response rate according to RECIST 1.1 was observed in 87.5% (7/8) in stable disease and 12.5% (1/8) were not evaluated. Scintigraphic response occurred in 62.5% (5/8) and 37.5% (3/8) patients in complete response and stable disease, respectively. CONCLUSION: 131I-mIBG therapy with 666 MBq/kg followed by single HDC and autologous or allogeneic SCT is safe and efficacious in patients with high-risk neuroblastoma and has no DLT. TRIAL REGISTRATION NUMBER: jRCTs041180030. NAME OF REGISTRY: Feasibility of high-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and haematopoietic stem cell transplantation (High-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma). URL OF REGISTRY: https://jrct.niph.go.jp/en-latest-detail/jRCTs041180030 . DATE OF ENROLMENT OF THE FIRST PARTICIPANT TO THE TRIAL: 12/01/2018.

Establishing a whole blood CD4+ T cell immunity measurement to predict response to anti-PD-1.

BACKGROUND: Biomarkers that can accurately predict the efficacy of immune checkpoint inhibitors (ICIs) against programmed death 1 (PD-1) ligand in cancer immunotherapy are urgently needed. We have previously reported a novel formula that predicts the response to treatment with second-line nivolumab with high sensitivity and specificity in patients with non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The formula was based on the percentages of CD62LlowCD4+ T cells (effector T cells; %Teff) and CD4+CD25+FOXP3+ T cells (regulatory T cells; %Treg) in the peripheral blood before treatment estimated using the peripheral blood mononuclear cell (PBMC) method. Here, we investigated the applicability of the formula (K-index) to predict the response to treatment with another ICI to expand its clinical applicability. Furthermore, we developed a simpler assay method based on whole blood (WB) samples to overcome the limitations of the PBMC method, such as technical difficulties, in obtaining the K-index. METHODS: The K-index was evaluated using the PBMC method in 59 patients with NSCLC who received first-line pembrolizumab treatment. We also assessed the K-index using the WB method and estimated the correlation between the measurements obtained using both methods in 76 patients with lung cancer. RESULTS: This formula consistently predicted the response to first-line pembrolizumab therapy in patients with NSCLC. The WB method correlated well with the PBMC method to obtain %Teff, %Treg, and the formula value. The WB method showed high repeatability (coefficient of variation, < 10%). The data obtained using WB samples collected in tubes containing either heparin or EDTA-2K and stored at room temperature (18-24 °C) for one day after blood sampling did not differ. Additionally, the performance of the WB method was consistent in different flow cytometry instruments. CONCLUSIONS: The K-index successfully predicted the response to first-line therapy with pembrolizumab, as reported earlier for the second-line therapy with nivolumab in patients with NSCLC. The WB method established in this study can replace the cumbersome PBMC method in obtaining the K-index. Overall, this study suggests that the K-index can predict the response to anti-PD-1 therapy in various cancers, including NSCLC.

Feasibility of dose-dense cisplatin-based chemotherapy in Japanese children with high-risk hepatoblastoma: Analysis of the JPLT3-H pilot study.

BACKGROUND: The SIOPEL-4 study has demonstrated that dose-dense cisplatin-based chemotherapy dramatically improves outcome in children with high-risk hepatoblastoma in western countries. However, the feasibility and safety of this regimen have not been clarified in Japanese patients. METHODS: A pilot study, JPLT3-H, was designed to evaluate the safety profile of the SIOPEL-4 regimen in Japanese children with newly diagnosed hepatoblastoma with either metastatic disease or low alpha-fetoprotein. RESULTS: A total of 15 patients (three female) were enrolled. Median age was 2 years (range, 0-14). Three patients were PRETEXT II (where PRETEXT is PRETreatment EXTent of disease), six PRETEXT III, and six PRETEXT IV. All patients had lung metastasis, none had low alpha-fetoprotein. Eight patients completed the prescribed treatment, and seven patients discontinued therapy prematurely, four due to progressive disease and three due to causes other than severe toxicity. Grade 4 neutropenia was documented in most patients in preoperative cycles A1-3 (11/15 in A1, 9/11 in A2, and 7/11 in A3) and in all considering all cycles. Grade 3-4 thrombocytopenia and grade 3 anemia were also frequently observed. Patients experienced several episodes of grade 3 febrile neutropenia, but none had grade 4 febrile neutropenia or severe infections. One patient had grade 3 heart failure only in the first cycle. Other grade 3 or 4 toxicities were hypomagnesemia, anorexia, nausea, mucositis, liver enzyme elevation, fever, infection, and fatigue. There were no unexpected severe toxicities. CONCLUSION: The toxicity profile of JPLT3-H was comparable to that of SIOPEL-4. Dose-dense cisplatin-based chemotherapy may be feasible among Japanese patients with high-risk hepatoblastoma.

Effect of ice water injection toward the duodenal papilla for preventing post-ERCP pancreatitis: study protocol for a multicenter, single-blinded, randomized controlled trial (EUTOPIA study).

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is an essential procedure in the diagnosis and treatment of biliopancreatic diseases. The most common adverse event of ERCP is post-ERCP pancreatitis (PEP), which can sometimes be severe. Our previous study suggested that injecting ice water at the end of ERCP suppressed PEP, and we decided to investigate this effect in a multicenter randomized controlled trial. METHODS: This study is being conducted at eight hospitals in Japan starting in April 2022. Patients undergoing ERCP will be randomized to ice water group and control group. In the ice water group, 250 ml of ice water is injected toward the papilla at the end of ERCP. The next morning, a physical examination and blood tests are performed to evaluate for the development of pancreatitis. The goal is to have 440 cases in each group. DISCUSSION: The main cause of PEP is thought to be papilla edema. Cooling the papilla, as everyone naturally does at the time of a burn, is expected to prevent its inflammation and edema. Various methods to suppress PEP have been reported, but so far none of them are reliable. The method we have devised is very simple, easy, and safe. We hope that our study will change the world's ERCP common practice. TRIAL REGISTRATION: UMIN000047528. Registered 20 April 2022, https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000053209.

Stent placement above the sphincter of Oddi is a useful option for patients with inoperable malignant hilar biliary obstruction.

BACKGROUND AND AIMS: Endoscopic biliary drainage (EBD) is essential for the management of malignant hilar biliary obstruction (MHBO). We prospectively evaluated the efficacy and safety of "inside-stent" therapy, where a plastic stent is placed above the sphincter of Oddi without endoscopic sphincterotomy, in patients with inoperable MHBO. METHODS: This study was a multicenter, single-blinded, randomized controlled trial at three centers. Patients with inoperable MHBO were enrolled in this study, and randomly assigned to receive an inside-stent or conventional-stent therapy. The primary endpoint was cumulative stent patency of the initial stent. The secondary endpoints were second stent patency, technical and clinical success rate, adverse events, re-intervention rate, and overall patient survival. RESULTS: Forty-three patients were randomly assigned to the inside-stent group (n = 21) or the conventional-stent group (n = 22). The median cumulative stent patency of the initial stent was 123 days in the inside-stent group and 51 days in the conventional-stent group (P = .031). For patients with the initial stent dysfunction in the conventional-stent group, the inside-stent was placed as a second stent, and its patency was significantly longer than that of the initial stent (P = .0001). The technical and clinical success rate, re-intervention rate, second stent patency, adverse events, and survival probability did not differ between the groups. CONCLUSIONS: Inside-stent therapy appears to be useful not only as an initial stent but also as a second stent for patients with inoperable MHBO. TRIAL REGISTRATION NUMBER: UMIN000004587.

Factors for conversion risk of colorectal endoscopic submucosal dissection: a multicenter study.

BACKGROUND: Endoscopic submucosal dissection (ESD) has become a widely accepted treatment method for colorectal tumors; however, there are some persistent problems. This multi-center study aimed to characterize the risk factors for incomplete resection and perforation in standardized colorectal ESD procedures. METHODS: This study included 2423 consecutive patients who underwent ESD for 2592 colorectal tumors between August 2013 and December 2018 at 11 institutions (1 academic hospital and 10 affiliated hospitals) from the Hiroshima GI Endoscopy Research Group. We evaluated the risk factors for interruption, piecemeal resection, and perforation of standardized colorectal ESD in relation to clinicopathologic and endoscopic characteristics. RESULTS: The incidences of interruption, piecemeal resection, and perforation were 0.7%, 2.9%, and 3.0%, respectively. Multivariate analysis identified the following risk factors for interruption: perforation during the procedure, deep submucosal invasion (> 1000 µm), poor scope operability, and severe submucosal fibrosis. The risk factors for piecemeal resection included poor scope operability, severe submucosal fibrosis, and procedure time (≥ 85 min). The risk factors for perforation during the procedure were severe submucosal fibrosis, poor scope operability, procedure time (≥ 85 min), and tumor size (≥ 40 mm). Independent risk factors for severe submucosal fibrosis included a history of biopsy and lesions located on the fold or flexure. CONCLUSIONS: Severe submucosal fibrosis and poor scope operability are the common risk factors for interruption, piecemeal resection, and perforation in standardized colorectal ESD.

Triaging of COVID-19 patients using low dose chest CT: Incidence and factor analysis of lung involvement on CT images.

INTRODUCTION: Despite an increase in CT studies to evaluate patients with coronavirus disease 2019 (COVID-19), their indication in triage is not well-established. The purpose was to investigate the incidence of lung involvement and analyzed factors related to lung involvement on CT images for establishment of the indication for CT scans in the triaging of COVID-19 patients. METHODS: Included were 192 COVID-19 patients who had undergone CT scans and blood tests for triaging. Two radiologists reviewed the CT images and recorded the incidence of lung involvement. The prediction model for lung involvement on CT images using clinico-laboratory variables [age, gender, body mass index, oxygen saturation of the peripheral artery (SpO2), comorbidities, symptoms, and blood data] were developed by multivariate logistic regression with cross-validation. RESULTS: In 120 of the 192 patients (62.5%), CT revealed lung involvement. The patient age (odds ratio [OR]; 4.95, 95% confidence interval [CI]; 0.93-26.49), albumin (OR; 4.66, 95%CI; 1.37-15.84), lactate dehydrogenase (OR; 5.79, 95%CI; 1.43-23.38) and C-reactive protein (OR; 8.93, 95%CI; 4.13-19.29) were selected for the final prediction model for lung involvement on CT images. The cross-validated area under the receiver operating characteristics (ROC) curve was 0.83. CONCLUSIONS: The high incidence of lung involvement (62.5%) was confirmed on CT images. The proposed prediction model that includes the patient age, albumin, lactate dehydrogenase, and C-reactive protein may be useful for predicting lung involvement on CT images and may assist in deciding whether triaged COVID-19 patients should undergo CT.

Early gastric cancer detection in high-risk patients: a multicentre randomised controlled trial on the effect of second-generation narrow band imaging.

OBJECTIVE: Early detection of gastric cancer has been the topic of major efforts in high prevalence areas. Whether advanced imaging methods, such as second-generation narrow band imaging (2G-NBI) can improve early detection, is unknown. DESIGN: This open-label, randomised, controlled tandem trial was conducted in 13 hospitals. Patients at increased risk for gastric cancer were randomly assigned to primary white light imaging (WLI) followed by secondary 2G-NBI (WLI group: n=2258) and primary 2G-NBI followed by secondary WLI (2G-NBI group: n=2265) performed by the same examiner. Suspected early gastric cancer (EGC) lesions in both groups were biopsied. Primary endpoint was the rate of EGC patients in the primary examination. The main secondary endpoint was the positive predictive value (PPV) for EGC in suspicious lesions detected (primary examination). RESULTS: EGCs were found in 44 (1.9%) and 53 (2.3%; p=0.412) patients in the WLI and 2G-NBI groups, respectively, during primary EGD. In a post hoc analysis, the overall rate of lesions detected at the second examination was 25% (n=36/145), with no significant differences between groups. PPV for EGC in suspicious lesions was 13.5% and 20.9% in the WLI (50/371 target lesions) and 2G-NBI groups (59/282 target lesions), respectively (p=0.015). CONCLUSION: The overall sensitivity of primary endoscopy for the detection of EGC in high-risk patients was only 75% and should be improved. 2G-NBI did not increase EGC detection rate over conventional WLI. The impact of a slightly better PPV of 2G-NBI has to be evaluated further. TRIAL REGISTRATION NUMBER: UMIN000014503.

Exploring the size of reference population for expected accuracy of genomic prediction using simulated and real data in Japanese Black cattle.

BACKGROUND: Size of reference population is a crucial factor affecting the accuracy of prediction of the genomic estimated breeding value (GEBV). There are few studies in beef cattle that have compared accuracies achieved using real data to that achieved with simulated data and deterministic predictions. Thus, extent to which traits of interest affect accuracy of genomic prediction in Japanese Black cattle remains obscure. This study aimed to explore the size of reference population for expected accuracy of genomic prediction for simulated and carcass traits in Japanese Black cattle using a large amount of samples. RESULTS: A simulation analysis showed that heritability and size of reference population substantially impacted the accuracy of GEBV, whereas the number of quantitative trait loci did not. The estimated numbers of independent chromosome segments (Me) and the related weighting factor (w) derived from simulation results and a maximum likelihood (ML) approach were 1900-3900 and 1, respectively. The expected accuracy for trait with heritability of 0.1-0.5 fitted well with empirical values when the reference population comprised > 5000 animals. The heritability for carcass traits was estimated to be 0.29-0.41 and the accuracy of GEBVs was relatively consistent with simulation results. When the reference population comprised 7000-11,000 animals, the accuracy of GEBV for carcass traits can range 0.73-0.79, which is comparable to estimated breeding value obtained in the progeny test. CONCLUSION: Our simulation analysis demonstrated that the expected accuracy of GEBV for a polygenic trait with low-to-moderate heritability could be practical in Japanese Black cattle population. For carcass traits, a total of 7000-11,000 animals can be a sufficient size of reference population for genomic prediction.

Efficacy of perioperative chemotherapy for synovial sarcoma: a retrospective analysis of a Nationwide database in Japan.

BACKGROUND: Synovial sarcoma is an aggressive but chemosensitive soft-tissue tumor. We retrospectively analyzed the efficacy of perioperative chemotherapy for synovial sarcoma with data from the nationwide database, Bone and Soft Tissue Tumor Registry in Japan. METHODS: This study included 316 patients diagnosed with synovial sarcoma between 2006 and 2012. Oncologic outcomes were analyzed using a Cox-hazard regression model. Moreover, the effects of perioperative chemotherapy on outcomes were evaluated using a matched-pair analysis. The oncologic outcomes of patients who did or did not receive chemotherapy were compared (cx + and cx-). RESULTS: Multivariate analysis revealed significant correlations of age (over 40, hazard ratio [HR] = 0.61, p = 0.043), margin status (marginal resection, HR = 0.18, p < 0.001 and intralesional resection, HR = 0.30, p = 0.013 versus wide resection) with overall survival; surgical margin type (marginal resection, HR = 0.14, p = 0.001 and intralesional resection, HR = 0.09, p = 0.035 versus wide resection) with local recurrence; and postoperative local recurrence (HR = 0.30, p = 0.027) and surgical margin (marginal resection, HR = 0.31, p = 0.023 versus wide resection) with distant relapse-free survival. Before propensity score matching, perioperative chemotherapy was mainly administered for young patients and patients with deeper tumor locations, larger tumors, more advanced-stage disease, and trunk location. The 3-year overall survival, local control, and distant relapse-free survival rates were 79.8%/89.3% (HR = 0.64, p = 0.114), 89.6%/93.0% (HR = 0.37, p = 0.171) and 71.4%/84.5% (HR = 0.60, p = 0.089) in the cx+/cx- groups, respectively. After propensity score matching, 152 patients were selected such that the patient demographics were nearly identical in both groups. The 3-year overall survival, local control, and distant relapse-free survival rates were 71.5%/86.0% (HR = 0.48, p = 0.055), 92.5%/93.3% (HR = 0.51, p = 0.436) and 68.4%/83.9% (HR = 0.47, p = 0.046) in the cx+/cx- groups, respectively. CONCLUSION: This large-sample study indicated that the margin status and postoperative disease control were associated directly or indirectly with improved oncologic outcomes. However, the efficacy of perioperative chemotherapy for survival outcomes in synovial sarcoma patients was not proven in this Japanese database analysis.

Effect of educational lecture on the diagnostic accuracy of Japan NBI Expert Team classification for colorectal lesions.

BACKGROUND: An educational and training program is required for generalization of Japan NBI Expert Team (JNET) classification. However, there is no detailed report on the learning curve of the diagnostic accuracy of endoscopists using JNET classification. We examined the effect of an educational lecture on beginners and less experienced endoscopists for improving their diagnostic accuracy of colorectal lesions by JNET classification. METHODS: Seven beginners with no endoscopy experience (NEE group), 7 less experienced endoscopists (LEE group), and 3 highly experienced endoscopists (HEE group) performed diagnosis using JNET classification for randomized NBI images of colorectal lesions from 180 cases (Type 1: 22 cases, Type 2A: 105 cases, Type 2B: 33 cases, and Type 3: 20 cases). Next, the NEE and LEE groups received a lecture on JNET classification, and all 3 groups repeated the diagnostic process. We compared the correct diagnosis rate and interobserver agreement before and after the lecture comprehensively and for each JNET type. RESULTS: In the HEE group, the correct diagnosis rate was more than 90% with good interobserver agreements (kappa value: 0.78-0.85). In the NEE and LEE groups, the correct diagnosis rate (NEE: 60.2 → 68.0%, P < 0.01; LEE: 66.4 → 86.7%, P < 0.01), high-confidence correct diagnosis rate (NEE: 19.6 → 37.2%, P < 0.01; LEE: 43.6 → 61.1%, P < 0.01), and interobserver agreement (kappa value, NEE: 0.32 → 0.43; LEE: 0.39 → 0.75) improved after the lecture. In the examination by each JNET type, the specificity and positive predictive value in the NEE and LEE groups generally improved after the lecture. CONCLUSION: After conducting an appropriate lecture, the diagnostic ability using JNET classification was improved in beginners or endoscopists with less experience in NBI magnifying endoscopy.

Randomized controlled study to examine the efficacy of hepatic arterial infusion chemotherapy with cisplatin before radiofrequency ablation for hepatocellular carcinoma.

AIM: Hepatic arterial infusion chemotherapy (HAIC) with cisplatin is beneficial to patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. This study aimed to examine the effect of HAIC with cisplatin before radiofrequency ablation (RFA) in patients with HCC. METHODS: This was a multicenter, single-blinded, randomized controlled study (UMIN000007267). Early-stage HCC patients were randomly assigned (1:1) to receive HAIC with cisplatin before RFA therapy (HAIC group) or RFA monotherapy (non-HAIC group). The primary end-point was recurrence-free survival. Efficacy analysis and safety analysis followed the intention-to-treat principle. RESULTS: Between August 2012 and July 2016, 74 patients were recruited. A total of 70 eligible patients were randomly assigned to the HAIC group (n = 35) and non-HAIC group (n = 35). Recurrence-free survival rates at 1 (3) year in the HAIC group and non-HAIC group were 82.9% (54.3%) and 74.3% (34.3%), respectively (hazard ratio [HR], 0.597; 95% confidence interval [CI], 0.320-1.091; p = 0.094]. Subgroup analysis showed that the beneficial effect of HAIC was observed in patients with a single nodule and Child-Pugh score 5. Intrahepatic distant recurrence-free survival rate in the HAIC group was significantly better than that in the non-HAIC group (HR, 0.468; 95% CI, 0.235-0.896; p = 0.022). Adverse events were observed in just two patients in the HAIC group (6%) - grade 2 cholecystitis and grade 2 hyperkalemia. CONCLUSIONS: HAIC with cisplatin before RFA did not significantly decrease recurrence in patients with early-stage HCC. However, it might be effective in preventing intrahepatic distant recurrence.

Risk of death due to other causes is lower among octogenarians with non-small cell lung cancer after wedge resection than lobectomy/segmentectomy.

OBJECTIVE: We aimed to determine the influences of surgical procedures on the postoperative death of octogenarians with clinical Stage IA non-small cell lung cancer excluding cT1mi. METHODS: We compared overall survival and the cumulative incidence of death due to all and other causes among 1 130 279, and 191 consecutive patients aged ≤79 and ≥80 years after lobectomy, segmentectomy and wedge resection at three institutions. Death due to other causes was defined as death due to any cause except non-small cell lung cancer. RESULTS: The median followup was 53 months. The 5-year overall survival rates for patients aged ≥ 80 and ≤ 79 years after lobectomy, segmentectomy and wedge resection were respectively, 78.0% (95% confidence interval, 63.8%-87.2%) versus 91.2% (95% confidence interval, 89.0%-92.9%), 68.1% (95% confidence interval, 45.2%-83.1%) versus 90.0% (95% confidence interval, 84.6%-93.5%), and 62.7% (95% confidence interval, 44.0-76.7%) versus 84.4% (95% confidence interval, 76.3%-89.9%) (P < 0.01 for all). The cumulative incidence of death due to other causes after wedge resection was similar between patients aged ≥ 80 and ≤ 79 years (P = 0.45), but significantly higher in those aged ≥ 80, than ≤ 79 years after lobectomy or segmentectomy (P = 0.00015 and 0.00091, respectively). CONCLUSIONS: The influence of wedge resection on death due to other causes was lower than that of lobectomy or segmentectomy in patients with non-small cell lung cancer aged ≥ 80 years. Wedge resection might be a useful option for octogenarians even if they can tolerate lobectomy/segmentectomy to avoid postoperative death due to causes other than non-small cell lung cancer.

A Phase I/IIa Study of Antidisialoganglioside Antibody Dinutuximab in Japanese Patients With Neuroblastoma.

Japanese patients with neuroblastoma completing induction therapy and high-dose chemotherapy received antidisialoganglioside antibody dinutuximab 17.5 mg/m2 for 4 days during each of 5 consecutive 28-day cycles. Patients also received macrophage colony-stimulating factor (M-CSF) or granulocyte colony-stimulating factor (G-CSF) during cycles 1, 3, and 5 combined with interleukin-2 teceleukin during cycles 2 and 4. A total of 25 patients (11 in the M-CSF group and 14 in the G-CSF group) were enrolled, and dose-limiting toxicity was assessed in the first 12 patients (6 in each group). The recommended doses of dinutuximab, M-CSF, and G-CSF were determined to be 17.5 mg/m2, 6.0×106 U/m2, and 5 µg/kg/d, respectively, whereas that of teceleukin was 0.75×106 IU/m2 during week 1 and 1×106 IU/m2 during week 2. The most common grade 3 or 4 adverse events in both groups were neutrophil count decreased, platelet count decreased, pyrexia, and alanine aminotransferase increased. Four patients (2 in each group) discontinued the treatment because of adverse events. At the end of the study, survival was confirmed in 22 patients (9 in the M-CSF group and 13 in the G-CSF group). From these results, we concluded that this combination regimen is a feasible treatment for Japanese patients with neuroblastoma.

Effects of LDL apheresis on proteinuria in patients with diabetes mellitus, severe proteinuria, and dyslipidemia.

BACKGROUND: Patients with diabetes mellitus and severe proteinuria present with poor renal prognoses, despite improvements in diabetes and kidney disease therapies. In this study, we designed a low-density lipoprotein (LDL)-cholesterol apheresis treatment for patients with diabetic nephropathy (DN)/diabetic kidney disease and severe proteinuria. This was a multicenter prospective LICENSE study to confirm the impact of LDL apheresis on proteinuria that exhibited hyporesponsiveness to treatment. In addition, we sought to determine the efficacy and safety of LDL apheresis by comparing the outcomes to those of historical controls in patients with diabetes, refractory hypercholesterolemia, and severe proteinuria. METHODS: This was a prospective, multicenter study, including 40 patients with diabetes, severe proteinuria, and dyslipidemia. LDL apheresis was performed 6-12 times over a 12-week period. The primary endpoint was the proportion of patients with a decrease in proteinuria excretion of at least 30% in the 6 months after starting therapy. The secondary endpoints included serum creatinine levels and laboratory variables, which were evaluated 4, 6, 12, 18, and 24 months after therapy initiation. RESULTS: LDL apheresis was performed on 40 registered patients with diabetes. The proportion of cases in which proteinuria decreased by 30% or more after 6 months of LDL apheresis was 25%, which was similar to that of historical controls. The overall survival and end-stage kidney disease-free survival rates were significantly higher in the LICENSE group compared to those in historical controls. CONCLUSION: Our results suggest that LDL apheresis may be effective and safe for patients with diabetes, proteinuria, and dyslipidemia. TRIAL REGISTRATION: Trial registration number: jRCTs042180076.