Kenichi Yoshimura

Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration

BACKGROUND Comparative assessment of treatment results in paediatric hepatoblastoma trials has been hampered by small patient numbers and the use of multiple disparate staging systems by the four major trial groups. To address this challenge, we formed a global coalition, the Childrens Hepatic tumors International Collaboration (CHIC), with the aim of creating a common approach to staging and risk stratification in this rare cancer. METHODS The CHIC steering committee-consisting of leadership from the four major cooperative trial groups (the International Childhood Liver Tumours Strategy Group, Childrens Oncology Group, the German Society for Paediatric Oncology and Haematology, and the Japanese Study Group for Paediatric Liver Tumours)-created a shared international database that includes comprehensive data from 1605 children treated in eight multicentre hepatoblastoma trials over 25 years. Diagnostic factors found to be most prognostic on initial analysis were PRETreatment EXTent of disease (PRETEXT) group; age younger than 3 years, 3-7 years, and 8 years or older; α fetoprotein (AFP) concentration of 100 ng/mL or lower and 101-1000 ng/mL; and the PRETEXT annotation factors metastatic disease (M), macrovascular involvement of all hepatic veins (V) or portal bifurcation (P), contiguous extrahepatic tumour (E), multifocal tumour (F), and spontaneous rupture (R). We defined five clinically relevant backbone groups on the basis of established prognostic factors: PRETEXT I/II, PRETEXT III, PRETEXT IV, metastatic disease, and AFP concentration of 100 ng/mL or lower at diagnosis. We then carried the additional factors into a hierarchical backwards elimination multivariable analysis and used the results to create a new international staging system. RESULTS Within each backbone group, we identified constellations of factors that were most predictive of outcome in that group. The robustness of candidate models was then interrogated using the bootstrapping procedure. Using the clinically established PRETEXT groups I, II, III, and IV as our stems, we created risk stratification trees based on 5 year event-free survival and clinical applicability. We defined and adopted four risk groups: very low, low, intermediate, and high. INTERPRETATION We have created a unified global approach to risk stratification in children with hepatoblastoma on the basis of rigorous statistical interrogation of what is, to the best of our knowledge, the largest dataset ever assembled for this rare paediatric tumour. This achievement provides the structural framework for further collaboration and prospective international cooperative study, such as the Paediatric Hepatic International Tumour Trial (PHITT). FUNDING European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission (grant number 261474); Childrens Oncology Group CureSearch grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research; and Swiss Cancer Research grant.

Irradiance heterogeneity within crown affects photosynthetic capacity and nitrogen distribution of leaves in Cedrela sinensis

Because light conditions in the forest understory are highly heterogeneous, photosynthetic acclimation to spatially variable irradiance within a crown is important for crown-level carbon assimilation. The effect of variation in irradiance within the crown on leaf nitrogen content and photosynthetic rate was examined for pinnate compound leaves in saplings of Cedrela sinensis, a pioneer deciduous tree. Five shading treatments, in which 0, 25, 50, 75 and 100% of leaves were shaded, were established by artificial heavy shading using shade screen umbrellas with 25% transmittance. Although the nitrogen content of leaves was constant regardless of shading treatment, ribulose 1.5-bisphosphate carboxylase/oxygenase (Rubisco) content and light-saturated photosynthetic capacity were lower in shade leaves within partially shaded crowns than within fully shaded crowns. Shade leaves within partially shaded crowns contained higher amount of amino acids. Most shade leaves died in partially shaded crowns, whereas more than half of shade leaves survived in totally shaded crowns. Assumptions on photosynthetic acclimation to local light conditions cannot explain why shade leaves have different photosynthetic capacities and survival rates in between partially and totally shaded crowns. Irradiance heterogeneity within the crown causes a distinct variation in photosynthetic activity between sun and shaded leaves within the crown.

Next-generation narrow band imaging system for colonic polyp detection: a prospective multicenter randomized trial

PurposePrevious studies have yielded conflicting results on the colonic polyp detection rate with narrow-band imaging (NBI) compared with white-light imaging (WLI). We compared the mean number of colonic polyps detected per patient for NBI versus WLI using a next-generation NBI system (EVIS LUCERA ELITE; Olympus Medical Systems) used with standard-definition (SD) colonoscopy and wide-angle (WA) colonoscopy.MethodsDesign: this study is a 2 × 2 factorial, prospective, multicenter randomized controlled trial. Setting: this study was conducted at five academic centers in Japan. Interventions: patients were allocated to one of four groups: (1) WLI with SD colonoscopy (H260AZI), (2) NBI with SD colonoscopy (H260AZI), (3) WLI with WA colonoscopy (CF-HQ290), and (4) NBI with WA colonoscopy (CF-HQ290). Main outcome: the mean numbers of polyps detected per patient were compared between the four groups: WLI with/without WA colonoscopy and NBI with/without WA colonoscopy.ResultsOf the 454 patients recruited, 431 patients were enrolled. The total numbers of polyps detected by WLI with SD, NBI with SD, WLI with WA, and NBI with WA were 164, 176, 188, and 241, respectively. The mean number of polyps detected per patient was significantly higher in the NBI group than in the WLI group (2.01 vs 1.56; P = 0.032). The rate was not higher in the WA group than in the SD group (1.97 vs 1.61; P = 0.089).ConclusionsAlthough WA colonoscopy did not improve the polyp detection, next-generation NBI colonoscopy represents a significant improvement in the detection of colonic polyps.

Impact of EUS-FNA for preoperative para-aortic lymph node staging in patients with pancreatobiliary cancer

BACKGROUND AND AIMS In patients with pancreatobiliary cancer, para-aortic lymph node (PALN) metastasis is considered to be the involvement beyond the regional lymph nodes, namely, distant metastasis. Effective methods for preoperative PALN staging, however, are not established. This study aimed to compare the diagnostic capability for PALN metastasis between EUS-FNA and (18)F-fluorodeoxyglucose positron emission tomography with CT (PET/CT). METHODS We performed a prospective, nonrandomized, single-center trial. Between December 2010 and March 2014, 208 patients with pancreatobiliary cancer without apparent distant metastasis except for PALNs were assessed for study eligibility before surgery. Among them, 52 consecutive patients with PALN enlargement were enrolled in the study. (18)F-Fluorodeoxyglucose PET/CT and EUS-FNA were performed sequentially as a single combined procedure to evaluate PALN metastases. The primary outcome was to compare the diagnostic capability of EUS-FNA and PET/CT for PALN metastasis. RESULTS Of 71 enlarged PALNs in the 52 patients, 30 (42.3%) were finally diagnosed as metastases in 21 patients (40.4%). Of the 21 patients with PALN metastases, preoperative EUS-FNA or PET/CT made a correct diagnosis in 20 (95.2%) or 12 (57.1%), respectively. EUS-FNA had higher sensitivity and specificity for the diagnosis of PALN metastasis (sensitivity, 96.7% [29/30]; 95% confidence interval, 82.2%-99.9%; specificity, 100% [39/39]; 95% confidence interval, 91.0%-100%) than PET/CT. CONCLUSIONS EUS-FNA is superior to PET/CT for preoperative PALN staging in patients with pancreatobiliary cancer. Because of the clinical benefit of EUS-FNA to reduce unnecessary surgery, it should be part of the standard preoperative examination for patients with pancreatobiliary cancer. (UMIN clinical trials registry number: 000006408.).

Risk factors for postoperative recurrence of intraductal papillary mucinous neoplasms of the pancreas based on a long-term follow-up study: proposals for follow-up strategies

The aim of this study was to examine the associations between postoperative clinicopathological features of intraductal papillary mucinous neoplasm (IPMN) and recurrence over a long follow‐up period.

Convergence of leaf display and photosynthetic characteristics of understory Abies amabilis and Tsuga heterophylla in an old-growth forest in southwestern Washington State,USA

We compared the morphological and physiological characteristics of understory trees of Abies amabilis (Dougl. ex Loud.) Dougl. ex J. Forbes and Tsuga heterophylla (Raf.) Sarg. growing adjacent to each other in an old-growth forest in southwestern Washington State, USA. We hypothesized that, despite contrasting branching patterns and crown architectures, the two species should exhibit convergence in leaf display and photosynthetic gain per light intercepting area, because these are important properties determining their survival in the light-limited understory. The branching pattern of A. amabilis was regular (normal shoot-length distribution, less variable branching angle and bifurcation ratio), whereas that of T. heterophylla was more plastic (positively skewed shoot-length distribution, more variable branching angle and bifurcation ratio). The two species had similar shoot morphologies: number of leaves per unit shoot length and leaf to axis dry mass ratio. Leaf morphology, in contrast, was significantly different. Leaves of A. amabilis were larger and heavier than those of T. heterophylla, which resulted in lower mass-based photosynthetic rate for A. amabilis. Despite these differences, the two species had similar levels of leaf overlap and area-based photosynthetic characteristics. Needle longevity of A. amabilis was nearly twice that of T. heterophylla. The leaf N contents of current and 1-year-old leaves were lower for A. amabilis than for T. heterophylla. However, the leaf N content of A. amabilis did not change from current leaves to 6-year-old leaves, whereas that of T. heterophylla decreased with increasing leaf age. Abies amabilis had deeper crowns than T. heterophylla and retained branches with low relative growth rates. Longer branch retention may compensate for the lower branch-level assimilation rate of A. amabilis. We inferred that the convergence of leaf display and photosynthetic characteristics between A. amabilis and T. heterophylla may contribute to the persistence of both species in the understory of this forest.

Mogamulizumab for Relapsed Adult T-Cell Leukemia–Lymphoma: Updated Follow-up Analysis of Phase I and II Studies

The present study sought to elucidate the prognosis of adult T‐cell leukemia–lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti‐CCR4 monoclonal antibody. Progression‐free survival (PFS) and overall survival (OS) of ATL patients enrolled in two studies are herein updated, namely NCT00355472 (phase I study of mogamulizumab in relapsed patients with ATL and peripheral T‐cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived >3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1‐year PFS was 26%, whereas median OS was 14.4 months, and 3‐year OS was 23%. For patients without a rash or who developed a grade 1 rash only, median PFS was 0.8 months, and 1‐year PFS was zero, with a median OS of 6.0 months, and 3‐year OS of 8%. In contrast, for patients who developed a rash ≥grade 2, median PFS was 11.7 months, and 1‐year PFS was 50%, with a median OS of 25.6 months, and 3‐year OS of 36%. Thus, we conclude that mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune‐related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of mogamulizumab.

A phase II study of neoadjuvant chemotherapy with S‐1 and cisplatin for stage III gastric cancer: KUGC03

A multi‐center phase II study was conducted to evaluate the safety and efficacy of neoadjuvant chemotherapy (NAC) with S‐1 plus cisplatin for advanced gastric cancer.

Pharmacokinetic Study of Adjuvant Gemcitabine Therapy for Biliary Tract Cancer following Major Hepatectomy (KHBO1101).

Background Biliary tract cancer (BTC) patients who have undergone surgical resection with major hepatectomy cannot tolerate the standard gemcitabine regimen (1,000 mg/m2 on days 1, 8, and 15 every 4 weeks) due to severe toxicities such as myelosuppression. Our dose-finding study of adjuvant gemcitabine therapy for biliary tract cancer following major hepatectomy determined that the recommended dose is 1,000 mg/m2 on days 1 and 15 every 4 weeks. Here, we evaluate the pharmacokinetics and pharmacodynamics of gemcitabine in these subjects. Methods We evaluated BTC patients scheduled to undergo surgical resection with major hepatectomy followed by gemcitabine therapy. A pharmacokinetic evaluation of gemcitabine and its main metabolite, 2′,2′-difluorodeoxyuridine (dFdU), was conducted at the initial administration of gemcitabine, which was given by intravenous infusion over 30 min at a dose of 800–1,000 mg/m2. Physical examination and adverse events were monitored for 12 weeks. Results Thirteen patients were enrolled from August 2011 to January 2013, with 12 ultimately completing the pharmacokinetic study. Eight patients had hilar cholangiocarcinoma, three had intrahepatic cholangiocarcinoma, and one had superficial spreading type cholangiocarcinoma. The median interval from surgery to first administration of gemcitabine was 65.5 days (range, 43–83 days). We observed the following toxicities: neutropenia (n = 11, 91.7%), leukopenia (n = 10, 83.3%), thrombocytopenia (n = 6, 50.0%), and infection (n = 5, 41.7%). Grade 3 or 4 neutropenia was observed in 25% (n = 3) of patients. There were differences in clearance of gemcitabine and dFdU between our subjects and the subjects who had not undergone hepatectomy. Conclusion Major hepatectomy did not affect the pharmacokinetics of gemcitabine or dFdU. Trial Registration UMIN-CTR in (JPRN) UMIN000005109

Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma.

Lung adenocarcinoma in the young is a rare entity, and the oncogenic genetic alterations (GAs) and clinical characteristics associated with this disease are poorly understood. Conversely, it has been demonstrated that young age at diagnosis defines unique biology in other cancers. For this report, the effects of young age on lung adenocarcinoma are reported.