Nationwide Multi-institutional Study Research Articles

Oncological outcomes of prophylactic urethrectomy at the time of radical cystectomy for bladder cancer: A nationwide multi-institutional study.

To determine the effects of prophylactic urethrectomy (PU) on oncological and perioperative outcomes in patients with bladder cancer (BC) undergoing radical cystectomy (RC). This retrospective study analyzed data on 1976 evaluable patients with BC who underwent RC. Patients were drawn from 36 institutions within the Japanese Urological Oncology Group. Oncological outcomes were compared using restricted mean survival times (RMSTs) based on inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves for non-urinary tract recurrence-free survival (NUTRFS), cancer-specific survival (CSS), and overall survival (OS). Interaction terms within IPTW-adjusted Cox regression models were examined to assess the heterogeneity of treatment effect based on the risk of urethral recurrence (UR). The association between PU, estimated blood loss (EBL), and the incidence of severe postoperative surgical complications (SPSCs) (Clavien-Dindo grade 3 or higher) was analyzed. Of 1976 patients, 1448 (73.3%) received PU. IPTW adjustment was used to balance baseline characteristics between the treatment groups. Within the 107-month window of patient monitoring, PU showed no survival benefits (NUTRFS difference: 0.2 months [95% confidence interval: -6.8 to 7.3]; CSS, 1.2 [-4.9 to 7.3]; OS, 0 [-6.5 to 6.5]). No significant interactions were observed with factors associated with UR, and PU was associated with unfavorable perioperative outcomes (EBL, 1179 mL vs. 983 mL; SPSC, 14.6% vs. 7.0%). This study showed that (1) PU was not associated with survival in patients with BC undergoing RC, regardless of UR-associated factors, and (2) PU was associated with unfavorable perioperative outcomes.

Effect of Four Main Gastrectomy Procedures for Proximal Gastric Cancer on Patient Quality of Life: A Nationwide Multi-Institutional Study.

This study aimed to examine the effects of 4 main types of gastrectomy for proximal gastric cancer on postoperative symptoms, living status, and quality of life (QOL) using the Postgastrectomy Syndrome Assessment Scale-45 (PGSAS-45). We surveyed 1,685 patients with upper one-third gastric cancer who underwent total gastrectomy (TG; n=1,020), proximal gastrectomy (PG; n=518), TG with jejunal pouch reconstruction (TGJP; n=93), or small remnant distal gastrectomy (SRDG; n=54). The 19 main outcome measures (MOMs) of the PGSAS-45 were compared using the analysis of means (ANOM), and the general QOL score was calculated for each gastrectomy type. Patients who underwent TG experienced the lowest postoperative QOL. ANOM showed that 10 MOMs were worse in patients with TG. Four MOMs improved in patients with PG, while 1 worsened. One MOM was improved in patients with TGJP versus 8 MOMs in patients with SRDG. The general QOL scores were as follows: SRDG (+39 points), TGJP (+6 points), PG (+3 points), and TG (-1 point). The TG group experienced the greatest decline in postoperative QOL. SRDG and PG, which preserve part of the stomach without compromising curability, and TGJP, which is used when TG is required, enhance the postoperative QOL of patients with proximal gastric cancer. When selecting the optimal gastrectomy method, it is essential to understand the characteristics of each and actively incorporate guidance to improve postoperative QOL.

A comparison of the effects of anti-reflux procedures during esophagogastrostomy after proximal gastrectomy on the postoperative quality of life.

To investigate the postoperative quality of life (QOL) in patients with proximal gastric cancer (PGC) or esophago-gastric junction cancer, a nationwide multi-institutional study (PGSAS NEXT trial) was conducted. Patients who had undergone radical resection more than 6months previously were enrolled from 70 Japanese institutions between July 2018 and June 2020. The Postgastrectomy Syndrome Assessment Scale (PGSAS)-45 questionnaire was distributed to eligible patients, and responses were collected by mail. The main outcome measures of the PGSAS-45 were then calculated and compared. Questionnaires were retrieved from 1950 participants, and data from 300 patients who had undergone a proximal gastrectomy (PG) with esophagogastrostomy for PGC were analyzed. The mean esophageal reflux subscale value was 1.9 among the 276 patients who underwent an anti-reflux procedure, which was significantly better than the mean value (2.6) for the 21 patients who did not undergo an anti-reflux procedure (p = 0.002). The esophageal reflux subscale values were also compared among 3 major anti-reflux procedures: the double-flap technique (N = 153), the pseudo-fornix and/or His angle formation (N = 67), and fundoplication (N = 44); no statistically significant differences were observed. An anti-reflux procedure during esophagogastrostomy after PG for PGC is necessary to improve postoperative esophageal reflux symptoms, regardless of the type of procedure. The PGSAS NEXT study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; registration number: 000032221).

Delays in melanoma presentation during the COVID-19 pandemic: A nationwide multi-institutional cohort study

Delays in melanoma presentation during the COVID-19 pandemic: A nationwide multi-institutional cohort study

Defecation disorders are crucial sequelae that impairs the quality of life of patients after conventional gastrectomy.

BACKGROUNDDefecation disorders are obscure sequelae that occurs after gastrectomy, and its implication on daily lives of patients have not been sufficiently investigated.AIMTo examine the features of defecation disorders after gastrectomy and to explore its implication on daily lives of patients in a large cohort using the Postgastrectomy Syndrome Assessment Scale (PGSAS)-45.METHODSWe conducted a nationwide multi-institutional study using PGSAS-45 to examine the prevalence of postgastrectomy syndrome and its impact on daily lives of patients after various types of gastrectomy. Data were obtained from 2368 eligible patients at 52 institutions in Japan. Of these, 1777 patients who underwent total gastrectomy (TG; n = 393) or distal gastrectomy (DG; n = 1384) were examined. The severity of defecation disorder symptoms, such as diarrhea and constipation, and their correlation with other postgastrectomy symptoms were examined. The importance of defecation disorder symptoms on the living states and quality of life (QOL) of postgastrectomy patients, and those clinical factors that affect the severity of defecation disorder symptoms were evaluated using multiple regression analysis.RESULTSAmong seven symptom subscales of PGSAS-45, the ranking of diarrhea was 4th in TG and 2nd in DG. The ranking of constipation was 5th in TG and 1st in DG. The symptoms that correlated well with diarrhea were dumping and indigestion in both TG and DG; while those with constipation were abdominal pain and meal-related distress in TG, and were meal-related distress and indigestion in DG. Among five main outcome measures (MOMs) of living status domain, constipation significantly impaired four MOMs, while diarrhea had no effect in TG. Both diarrhea and constipation impaired most of five MOMs in DG. Among six MOMs of QOL domain, diarrhea impaired one MOM, whereas constipation impaired all six MOMs in TG. Both diarrhea and constipation equally impaired all MOMs in DG. Male sex, younger age, division of the celiac branch of vagus nerve, and TG, independently worsened diarrhea, while female sex worsened constipation.CONCLUSIONDefecation disorder symptoms, particularly constipation, impair the living status and QOL of patients after gastrectomy; therefore, we should pay attention and adequately treat these relatively modest symptoms to improve postoperative QOL.

The evaluation of the postoperative quality of life in patients undergoing radical gastrectomy for esophagogastric junction cancer using the Postgastrectomy Syndrome Assessment Scale-45: a nationwide multi-institutional study.

This retrospective nationwide survey investigated the quality of life (QOL) of patients with esophagogastric junction cancer after gastrectomy using the Postgastrectomy Syndrome Assessment Scale-45. The Postgastrectomy Syndrome Assessment Scale-45 comprises 45 questions classified into symptoms, living status, and QOL domains. A total of 1950 gastrectomized patients with upper-third gastric or esophagogastric junction cancer returned the completed forms. Among them, 224 eligible patients with esophagogastric junction cancer were selected, including 86, 120, and 18 patients who underwent total gastrectomy, proximal gastrectomy (reconstruction-esophagogastrostomy: 56; double-tract method: 51), and other procedures, respectively. The postoperative period was significantly shorter (47 ± 30 vs. 34 ± 30months, p = 0.002), and the rates of early-stage disease and minimally invasive approaches significantly higher (both p < 0.001) in the proximal gastrectomy group than in the total gastrectomy group. Despite advantageous background factors for proximal gastrectomy, the postoperative QOL did not differ markedly between the groups. Compared to patients who underwent reconstruction with the double-tract method, patients who underwent esophagogastrostomy had significantly larger remnant stomachs but a similar QOL. Even with total gastrectomy, a postoperative QOL comparable to that with proximal gastrectomy can be maintained. Clarifying the optimal reconstruction methods for proximal gastrectomy for esophagogastric junction cancer is warranted. This study was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; registration number: 000032221).

Optimizing External Beam Radiotherapy as per the Risk Group of Localized Prostate Cancer: A Nationwide Multi-Institutional Study (KROG 18-15).

Simple SummaryThis multi-institutional study analyzed the patterns of care and outcomes of external beam radiotherapy (EBRT) in localized prostate cancer to identify the optimal EBRT strategy for each risk-stratified patient subgroup for clinical practice implementation. In 1573 patients from 17 institutions, EBRT treated prostate cancer effectively. Also, among various risk classification tools, NCCN classification revealed the highest predictive power. The modern RT techniques and dose escalation (≥179 Gy1.5) enhanced therapeutic effects of RT significantly, especially in the high-risk group. On the other hand, modest doses (≥170 Gy1.5) was a significant factor in the intermediate-risk group and no significant impact of dose was observed in the low-risk group. IMRT+ ≥179 Gy1.5+ hypofractionation resulted in higher biochemical failure-free survival in all risk groups, and it translated into survival benefits in the high-risk group. Therefore, risk-adapted RT (more intense RT, high-risk patients; moderate-dose RT, low-risk patients) can be considered, although further prospective studies are warranted.Purpose: This nationwide multi-institutional study analyzed the patterns of care and outcomes of external beam radiotherapy (EBRT) in localized prostate cancer patients. We compared various risk classification tools and assessed the need for refinements in current radiotherapy (RT) schemes. Methods and Materials: We included non-metastatic prostate cancer patients treated with primary EBRT from 2001 to 2015 in this study. Data of 1573 patients from 17 institutions were analyzed and re-grouped using a risk stratification tool with the highest predictive power for biochemical failure-free survival (BCFFS). We evaluated BCFFS, overall survival (OS), and toxicity rates. Results: With a median follow-up of 75 months, 5- and 10-year BCFFS rates were 82% and 60%, and 5- and 10-year OS rates were 95% and 83%, respectively. NCCN risk classification revealed the highest predictive power (AUC = 0.556, 95% CI 0.524–0.588; p < 0.001). Gleason score, iPSA < 12 ng/mL, intensity-modulated RT (IMRT), and ≥179 Gy1.5 (EQD2, 77 Gy) were independently significant for BCFFS (all p < 0.05). IMRT and ≥179 Gy1.5 were significant factors in the high-risk group, whereas ≥170 Gy1.5 (EQD2, 72 Gy) was significant in the intermediate-risk group and no significant impact of dose was observed in the low-risk group. Both BCFFS and OS improved significantly when ≥179 Gy1.5 was delivered using IMRT and hypofractionation in the high-risk group without increasing toxicities. Conclusions: With NCCN risk classification, dose escalation with modern high-precision techniques might increase survivals in the high-risk group, but not in the low-risk group, although mature results of prospective studies are awaited.

Recurrent Genomic Aberrations of D-Type Cyclins Are Therapeutic Targets of CDK4/6 Inhibitors in t(8;21) and MLL-Rearranged Acute Myeloid Leukemia

Background:Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease, characterized by expansion of undifferentiated myeloid precursor cells. The outcome for AML has improved through optimal treatment protocols, new drugs, and better supportive care; however, relapse remains common and patients with relapsed AML have poor prognosis. Recent genome-wide analyses revealed several recurrently mutated genes in AML, however, few of these driver mutations have been developed as therapeutic targets to date. In AML, t(8;21) and MLL (KMT2A) rearrangements are among the most frequent chromosomal abnormalities; however, knowledge of the genetic landscape is limited.Patients and Methods:The AML-05 study is a Japanese nationwide multi-institutional study of children (age < 18 years old) with de novo AML, conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG). The trial was registered with the UMIN Clinical Trials Registry (UMIN-CTR; http://www.umin.ac.jp/ctr/index.htm; number UMIN000000511) and conducted in accordance with the principles set down in the Declaration of Helsinki, and approved by the Ethics Committees of all participating institutions. All patients, or their parents / guardians, provided written informed consent. For whole-exome sequencing (WES), whole-exome capture was accomplished by liquid phase hybridization of sonicated genomic DNA using a bait cRNA library (SureSelect Human ALL Exon V5 or V5 Inc RNA 5 kit), following the manufacturer's protocol. Massively parallel sequencing of the captured targets was performed using a HiSeq 2000/2500 (Illumina) with the paired-end 126-133 bp read option. For targeted sequencing, target enrichment was performed using a SureSelect custom kit (Agilent) designed to capture all coding exons of the 338 genes. Similarly, CCND1, CCND2, and CCND3 were also captured and sequenced in t(8;21) AML samples. For cell cycle analysis, cell lines were treated with DMSO, palbociclib (500 nM), or abemaciclib (500 nM) for 24 h. Then, cells were stained with propidium iodide and analyzed using a FACS Canto II flow cytometer (BD Biosciences).Results and Discussion:First, we analyzed paired AML tumor and germline samples from nine pediatric MLL-rearranged AML patients by WES. In total, 52 mutations (mean, 5.8 mutations/patient) were identified, including known mutational targets in AML, such as FLT3, BRAF, SETD2, BCORL1, and WT1. Moreover, novel CCND3 mutation was detected in one patient. Next, we analyzed 56 samples from patients with pediatric MLL-rearranged AML enrolled in the JPLSG AML-05 study, using targeted sequencing. We selected 338 genes, among which were previously reported and putative driver genes, including CCND3, for targeted sequencing. We identified eight mutations in CCND3 in five pediatric MLL-rearranged AML patients (8.9%). All mutations were clustered in the PEST domain. Four of the eight mutations were R271fs, which is a known hot-spot mutation in lymphoid malignancies. Mutations of the other D-type cyclins (CCND1, CCND2) have been reported in t(8;21) AML (Leukemia, 2017); therefore, we also searched for mutations in CCND1, CCND2, and CCND3 by targeted sequencing of samples from pediatric t(8;21) AML patients (n=105). CCND1 (n=3, 2.9%) and CCND2 (n=8, 7.6%) mutations were detected; however, no mutations of CCND3 were detected. By contrast, there were no mutations of CCND1 or CCND2 in MLL-rearranged AML (n=56), suggesting that mutations of D-type cyclins exhibit a subtype-specific pattern in AML. A recent study demonstrated that genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4/6 inhibitor (Cancer Cell, 2017), therefore, we also examined the effects of CDK4/6 inhibitors (abemaciclib and palbociclib) on two t(8;21) AML cell lines (Kasumi-1 and SKNO-1) and five MLL-rearrangement AML cell lines (ML-2, MV4-11, MOLM-13, THP-1, and NOMO-1) were analyzed. All cell lines described above exhibited impaired proliferation after treatment with CDK4/6 inhibitors. Furthermore, treatment of these cell lines with CDK4/6 inhibitors resulted in detection of lower frequencies of S/G2/M phase cells by flow cytometry, suggesting that cells were arrested in G1 phase via CDK4/6 inhibition. These data provide further insights into the genetic basis of, and potential therapeutic strategies in t(8;21) and MLL-rearranged acute myeloid leukemia. DisclosuresNo relevant conflicts of interest to declare.

Chemotherapy for metastatic testicular cancer: The first nationwide multi-institutional study by the Cancer Registration Committee of the Japanese Urological Association.

To assess clinicopathological data and oncological outcomes focused on metastatic testicular cancer patients, who received chemotherapy as the initial treatment, in the nationwide multi-institutional study by the Cancer Registration Committee of the Japanese Urological Association. A testicular cancer survey was carried out by the Japanese Urological Association in 2011 to register newly diagnosed testicular cancers in 2005 and 2008. Among 1121 registered patients, 278 patients with metastases who received chemotherapy as the initial treatment and could be categorized by the Japanese Urological Association classification were eligible for the analysis. As first-line chemotherapy, bleomycin, etoposide and cisplatin, and etoposide and cisplatin therapies were chosen for 260 patients (93.5%). As second-line therapy, vinblastine, ifosfamide and cisplatin/etoposide, ifosfamide and cisplatin; and paclitaxel, ifosfamide and cisplatin/paclitaxel, ifosfamide and nedaplatin therapies were carried out in 23 out of 63 (36.5%) and 29 out of 63 (46.0%) patients, respectively. The response rate and serum tumor marker normalization rate were 93.4% and 81.3% at first line, 75.4% and 60.7% at second line, and 41.7% and 16.7% at third line, respectively. The Japanese Urological Association classification (≥IIIB2 vs ≤IIIB1) and choriocarcinoma component in primary histology were independent prognostic factors of overall survival before starting chemotherapy. Furthermore, in patients with non-seminomatous germ cell tumors, serum tumor marker normalization was an independent factor that was associated with better outcome of overall survival after completion of the initial series of chemotherapies. The initial accurate diagnosis and risk stratification is an important prognostic factor to achieve better oncological outcomes. In patients with non-seminomatous germ cell tumors, aiming for serum tumor marker normalization with continuous sequential chemotherapy could improve overall survival.

Pulmonary Oligometastases Treated by Stereotactic Body Radiation Therapy: A Nationwide Multi-institutional Study of 1,378 Subjects

Pulmonary Oligometastases Treated by Stereotactic Body Radiation Therapy: A Nationwide Multi-institutional Study of 1,378 Subjects

Factors affecting the quality of life of patients after gastrectomy as assessed using the newly developed PGSAS-45 scale: A nationwide multi-institutional study.

AIMTo identify certain clinical factors other than the type of gastrectomy which affect the postoperative quality of life (QOL) of patients after gastrectomy.METHODSThe postgastrectomy syndrome assessment scale (PGSAS)-45 was designed to assess the severity of symptoms, the living status and the QOL of gastrectomized patients. It consists of 45 items, of which 22 are original items while 23 were retrieved from the SF-8 and Gastrointestinal Symptoms Rating Scale questionnaires with permission. A nationwide surveillance study to validate PGSAS was conducted and 2368 gastric cancer patients who underwent various types of gastrectomy at 52 medical institutions were enrolled. Of these, 1777 patients who underwent total gastrectomy (TG) reconstructed with Roux-Y (n = 393), distal gastrectomy (DG) reconstructed with Billroth-I (n = 909), or DG reconstructed with Roux-Y (n = 475) were evaluated in the current study. The influence of the type of gastrectomy and other clinical factors such as age, sex, duration after surgery, the symptom severity, the degree of weight loss, dietary intake, and the ability for working on the postoperative QOL (i.e., dissatisfaction for daily life subscale, physical component summary and mental component summary of the SF-8) were examined by multiple regression analysis (MRA). In addition, importance of various symptoms such as esophageal reflux, abdominal pain, meal-related distress, indigestion, diarrhea, constipation and dumping on the postoperative living status and QOL were also appraised by MRA.RESULTSThe postoperative QOL were significantly deteriorated in patients who underwent TG compared to those after DG. However, the extent of gastrectomy was not an influential factor on patients’ QOL when adjusted by the MRA. Among various clinical factors, the symptom severity, ability for working, and necessity for additional meals were the most influential factors to the postoperative QOL. As for the individual symptoms, meal-related distress, dumping, abdominal pain, and esophageal reflux significantly affected the postoperative QOL in that order, while the influence of indigestion, diarrhea and constipation was insignificant.CONCLUSIONSeveral clinical factors such as the symptom severity (especially in meal-related distress and dumping), ability for working and necessity for additional meals were the main factors which affected the patients’ well-being after gastrectomy.

Double CEBPA Mutations Are Not Associated With Favorable Clinical Outcome In Pediatric AML: A Report From The Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

BackgroundCCAAT/enhancer binding protein alpha (CEBPA) is a transcription factor that coordinates cellular differentiation. Mutations in the CEBPA genes are found in about 10% of patients with AML and are associated with favorable prognosis. However, recent data suggests that the favorable prognosis is restricted only to the patients with double CEBPA mutations and normal karyotype. These data have large implications for risk-stratified therapy and require confirmation. In this study, we investigated CEBPA mutation status and clinical outcome of the pediatric AML patients treated in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study. Patients & MethodsAML-05 study, registered at http://www.umin.ac.jp/ctr/as UMIN000000511, is a nation-wide multi-institutional study for children (age <18 years) with de novo AML enrolled from 11/1/2006 to 12/31/2010. Cases with acute promyelocytic leukemia or Down syndrome were excluded. Patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups; CBF-AML patients to the low risk (LR) group, those with either unfavorable cytogenetics (-7, 5q-, t(16;21)(p11;q22), Ph1, FLT3-ITD) or poor induction responders to the high risk (HR) group, and the rest to the intermediate risk (IR) group. In this trial, morphology was prospectively diagnosed by a central review system. Cytogenetic tests were carried out in regional laboratories, but the reports were reviewed centrally. FLT3-internal tandem duplication (ITD) was examined for all patients. Using the surplus RNA from the AML-05 study, CEBPA gene mutation was analyzed by RT-PCR and direct sequencing. ResultsOf the 317 evaluable patients, 73 patients (23.0%) had normal karyotype, 42 patients (13.2%) were FLT3-ITD positive, and 19 patients (6.0%) had both normal karyotype and FLT3-ITD. Among the 54 cases with normal karyotype and negative FLT3-ITD, 16 patients (29.6%) had a single CEBPA mutation and 17 patients (31.5%) had double or more (hereafter described as Double) CEBPA mutations. Between the CEBPA wild type (WT) and Double mutated patients, there were no statistically significant differences in relapse-free survival (RFS) (53.9% vs. 71.1%, P=0.27) nor overall survival (OS) (68.9% vs. 64.7%, P=0.57).An in-frame insertion of 6bp (ACCCGC) in CEBPAtrans-activator (TAD2) domain, resulting in a His-Pro duplication (HP196-197 ins), was detected in 131 patients (41.3% of all patients) in the current study, a considerably high incidence. However, this insertion was previously reported as polymorphism in adult AML (Leukemia 2008). When categorizing this insertion cases as CEBPA WT, 24 patients were CEBPA mutated among the 54 cases with normal karyotype and negative FLT3-ITD; 11 patients (20.4%) with single CEBPA mutation and 13 patients (24.1%) with Double CEBPA mutations. Although not statistically significant, there was a tendency of higher RFS (83.3% vs. 55.5%, P=0.20) and OS (79.1% vs. 63.3%, P=0.39) in patients with Double CEBPA mutations versus WT patients. ConclusionsThe current study is the first Japanese nation-wide investigation of the clinical significance of CEBPA mutations in pediatric AML. Our results suggest that CEBPA mutations have no prognostic impact on children with AML. Disclosures:No relevant conflicts of interest to declare.

Poor Prognosis With Different Induction Rate Was Observed In Children With Acute Myeloid Leukemia and FLT3-ITD According To The ITD/WT Allelic Ratio: A Result From The Japanese Pediatric Leukemia/Lymphoma Study Group

BackgroundAcute myeloid leukemia harboring internal tandem duplication of fms-like tyrosine kinase 3 (AMLFLT3-ITD) is associated with poor prognosis, but the previous studies have reported that the inferior outcome is only confined to those with high allelic ratio (AR) of ITD/wild type (WT). In our previous AML99 study (2000-2002), AMLFLT3-ITD showed a poor outcome compared to the WT cases (5-year OS; 35% vs. 84%, P<0.0001). We, therefore, assigned all the patients with AMLFLT3-ITD to receive hematopoietic stem cell transplantation (HSCT) in first remission (1CR) in the JPLSG AML-05 study. Patients & MethodsAML-05 study, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, is a Japanese nation-wide multi-institutional study for children (age<18 years) with de novo AML and enrolled 443 eligible patients from Nov. 2006 to Dec. 2010. Cases with acute promyelocytic leukemia or Down syndrome were excluded. FLT3-ITD was examined centrally for all the patients. After the 2 consecutive induction chemotherapies [(ECM: etoposide, Ara-C, and mitoxantrone) and (HCEI: HD Ara-C, etoposide, and idarubicin)], all the AMLFLT3-ITD patients were allocated to the high risk group and further received intensification therapy including HD Ara-C followed by HSCT in 1CR. All DNA samples were extracted from the first diagnostic bone marrow or peripheral blood and subjected to PCR and direct sequencing. AR of FLT3-ITD/WT was examined by GeneScan, and defined AR >0.4 as high and AR ≤ 0.4 as low as previously reported (Meshinchi S. Blood2006). ResultsWe found 47 patients (10.6%) with AMLFLT3-ITD in this study (30 males, 17 females, and median age of 11 years at diagnosis). The median WBC count was 65,300/ml (3,690 - 522,050/mL). FAB classification included M1 (n=10), M2 (n=9), M4 (n=9), and M5 (n=11), and AML with normal karyotype was dominant (19/47, 40.4%).Of the 29 patients (61.7%) who achieved CR, twenty-seven received HSCT in 1CR and 19 patients survived (19/27, 70.4%). On the other hand, 14/16 non-CR patients received HSCT, but only 4 survived. The only demographic difference between the 29 CR and 16 non-CR cases was the median WBC count at diagnosis (19,000 vs. 124,000/μL, P<0.001), and rapid clearance of bone marrow blasts after single induction course was observed in the CR group (median blast percentage dropped from 73% to 1.1% in the CR group, while that was 85% to 30.6% in the non-CR group). Finally, five-year OS, DFS and EFS for all 47 AMLFLT3-ITD patients were 41.3%, 58.4% and 36.1%, respectively.AR was analyzed in 44 patients with median ratio of 0.68 (range, 0.11 to 4.47). Median AR was not different between CR vs. non-CR cases (0.53 vs. 0.72). There were no difference in 5-year OS (52.8% vs. 42.5%, P=0.302), DFS (54.5% vs. 64.5%, P=0.524), and EFS (50.0% vs. 34.4%, P=0.283) between patients with low (n=12) and high AR (n=32), however, induction rate was significantly higher in the low AR patients (91.7% vs. 53.1%, P=0.018).It was rather surprising that all FLT3-ITDs were found only in JM domain and not in TKI domain in the current trial. In addition, six of 47 (12.8%) AMLFLT3-ITD patients had NPM1mutation simultaneously, and all received HSCT at 1CR and survived. Discussion and ConclusionWe observed a different induction rate between AMLFLT3-ITD patients with low and high AR, but poor final outcomes in both. Regardless of the level of AR, patients with AMLFLT3-ITD, especially who fail to achieve remission, have dismal outcome and effective therapy combined with novel FLT3 inhibitor is urgently needed to overcome the disease. Disclosures:No relevant conflicts of interest to declare.

Excess Reduction of Anthracyclines Results in Inferior Event-Free Survival in Core Binding Factor Acute Myeloid Leukemia in Children; A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

AbstractAbstract ▪409▪This icon denotes a clinically relevant abstract Background:Intensive combination chemotherapy of Ara-C and anthracyclines, together with optimal risk stratification, led to 70% probability of survival (pOS) in childhood acute myeloid leukemia (AML) nowadays. Therefore, one of the main subjects for AML chemotherapy in children is to reduce anthracyclines to avoid late cardiotoxicity which could occur in lower cumulative dose compared to adults. High-dose (HD) Ara-C has contributed to improved survival especially in core binding factor (CBF)-AML, and we hypothesized that the intensive use of HD Ara-C could compensate for reduction of anthracycline dose in children with CBF-AML. Patients & Methods:JPLSG AML-05, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, is a nation-wide multi-institutional study and recruited 447 eligible children (age <18 years) with de novo AML from 11/1/2006 to 12/31/2010 (acute promyelocytic leukemia and Down syndrome patients excluded). Three patients including 2 children with t(8;21) who discontinued from the study during induction therapy are excluded from the efficacy analyses: one protocol violation, 1 changing to non-JPLSG member hospital at the patient’s request, and 1 withdrawal of the JPLSG institutional membership. After 2 courses of common induction therapies, patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups. Patients with CBF-AML, t(8;21) or inv(16), and good bone marrow response to the first induction course were stratified to the low risk (LR) group, and further received 3 courses of chemotherapy; 4/5 courses consisted of HD Ara-C, and the total cumulative dose of anthracyclines, Mitoxantrone and Idarubicin, was reduced from 300 to 225 mg/m2 compared to the LR chemotherapy in the previous AML99 study (Tsukimoto I. J Clin Oncol 2009;27:4007–13). Conversion rate of 5:1 was used to compare the cumulative dose of Daunorubicin and Mitoxantrone/Idarubicin. Results:Three-year probability of event-free survival (pEFS) and 3y-pOS of all 444 patients was 55.3% (95%CI, 50.2 – 60.1%) and 73.2% (68.3 – 77.5%), respectively. The median follow-up period for living patients was 3.06 years (range, 0.84 – 5.36 years).One hundred fifty-five CBF-AML patients [34.9%; t(8;21), N=123 (27.7%); inv(16), N=32 (7.2%)] in the AML-05 and 89 patients [37.0%; t(8;21), N=77 (32.0%); inv(16), N=12 (5.0%)] in AML99 were compared. There were no differences in basic characteristics such as sex and age/WBC at diagnosis. CR rate was identical between the 2 cohorts (95.5% vs. 97.8%, p = 0.36). There was a tendency of lower 3y-pEFS in the AML-05 cohort [69.3% (95%CI, 60.8 – 76.3%) vs. 80.9% (71.1 – 87.7%), p = 0.078], however, 3y pOS did not differ [92.2% (85.8 – 95.8%) vs. 92.1% (84.2 – 96.2%), p= 0.94].One hundred thirty-six CBF-AML patients were stratified to the LR group in AML-05; 8 patients were stratified to the HR group and allocated to allogeneic hematopoietic transplantation in 1CR because of poor treatment response (N=5) or FLT3-ITD positivity (N=3), and 11 patients were off protocol therapy before risk stratification because of various reasons. These 136 LR patients were compared with 83 CBF-AML patients in AML99 who fulfilled AML-05 LR criteria; 7/83 t(8;21) cases with WBC ≥ 50,000/μL in AML99 received intermediate risk (IR) chemotherapy with 375 mg/m2 of anthracyclines according to the protocol. The 3y-pEFS was significantly lower in the AML-05 cohort [69.6% (60.6 – 77.0%) vs. 83.1% (73.2 – 89.6%), p = 0.041], although the 3y-pOS was not different [92.6% (85.6 – 96.3%) vs. 94.0% (86.1 – 97.5%), p= 0.74]. Conclusions:The pEFS of children with CBF-AML treated with very low cumulative dose of anthracyclines were inferior to the historical control even treated with intensive use of HD Ara-C, therefore, caution is needed to reduce cumulative anthracycline doses to below 300mg/m2. However, the fact that nearly 70% of the CBF-AML patients are cured with lower dose of anthracyclines suggest the presence of underlying biological factors to be identified for future stratification of CBF-AML in children. Disclosures:No relevant conflicts of interest to declare.

Appropriate Dose Modification in Induction Therapy Is Essential for the Treatment of Infants with Acute Myeloid Leukemia; A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).

AbstractAbstract 2615▪▪This icon denotes a clinically relevant abstract Background:Infants (age <1 year) with AML are naturally vulnerable to intensive cytotoxic therapy, and we have previously reported unacceptably high early death rate mainly due to pulmonary complications among the first 32 infants (28 eligible) enrolled in the JPLSG AML-05 study, which prompted us to suspension of patient accrual and protocol amendment (Tomizawa D. 52ndASH abstract #2146). Seventeen additional infants were enrolled after the amendment, and here we report the final outcome of total 45 infants with AML treated on AML-05 study. Patients & Methods:JPLSG AML-05 study, registered at http://www.umin.ac.jp/ctr/as UMIN000000511, is a nation-wide multi-institutional study and recruited 447 eligible children (age <18 years) with de novo AML from 11/1/2006 to 12/31/2010 (acute promyelocytic leukemia and Down syndrome patients excluded). Three patients who discontinued from the study during induction therapy are excluded from the efficacy analyses: one protocol violation, 1 changing to non-JPLSG member hospital at the patient’s request, and 1 withdrawal of the JPLSG institutional membership. After 2 courses of common induction therapies, patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups. For patients <2 years old, drug dosages were reduced by calculating on body weight basis, and after the study amendment, additional dose reduction by 33% in initial induction course was made for infants <1 year old. Results:The median follow-up period for living patients was 3.06 years (range, 0.84 – 5.36 years). Although, there was no difference in 3-year probability of event-free survival (pEFS) between infants and patients ≥1 year old [56.0% (95%CI, 38.7 – 70.1%) vs. 55.2% (49.8 – 60.2%) (p = 0.63)], 3-year probability of overall survival (pOS) in infants was inferior; 56.0% (95%CI, 37.9 – 70.7%) vs. 75.0% (70.0 – 79.4%) (p = 0.011). When the outcome of infants were compared with patients 1 - <2 years old (N=58) and ≥2 year old (N=341), again, there was no difference in 3y-pEFS [56.0% (95%CI, 38.7 – 70.1%) vs. 55.2% (40.6 – 67.6%) vs. 55.3% (49.5 – 60.7%) (p = 0.83)], but worse 3y-pOS was observed in infants [56.0% (95%CI, 37.9 – 70.7%) vs. 77.0% (62.8 – 86.4%) vs. 74.8% (69.2 – 79.5%) (p= 0.037)].The inferiority of pOS in infants compared to the patients 1 - <2 years old and ≥2 year old was because of higher early death and non-relapse death observed in infants: 11.1% (5/45) vs. 1.7% (1/58) vs. 0.3% (1/341) (p < 0.001) and 22.2% (10/45) vs. 6.9% (4/58) vs. 9.4% (32/341) (p = 0.033), respectively. However, reduction of both early death and non-relapse death was observed after the study amendment, although not statistically significant because of small numbers; 17.9% (5/28) to 0.0% (0/17) (p = 0.14) and 32.1% (9/28) to 5.9% (1/17) (p = 0.064). Notably, in spite of dose reduction in the first induction course, CR rate [pre-amendment vs. post-amendment; 67.9% (19/28) vs. 82.4% (14/17) (p = 0.28)], 2y-pEFS [58.6% (35.1 – 76.1%) vs. 49.0% (22.0 – 71.4%) (p = 0.56)], and 2y-pOS [67.8% (47.3 – 81.8%) vs. 74.1% (44.0 – 89.6%) (p= 0.41)] did not deteriorate. Conclusions:Our experience suggests that appropriate chemotherapeutic dose modification in induction therapy to avoid early deaths is essential in treating infants with de novo AML. As dose intensification approach is difficult to apply for this age subgroup, incorporation of less toxic targeted agents based on biological features is needed to attain better outcome for infants with AML. Disclosures:No relevant conflicts of interest to declare.

Attempts to Optimize Post-Induction Treatment in Childhood Acute Myeloid Leukemia without Core Binding Factors: A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

AbstractAbstract ▪3545▪This icon denotes a clinically relevant abstract Background:With intensive chemotherapy and optimal risk stratification, 80–90 % of children with acute myeloid leukemia (AML) achieve complete remission (CR) which translates into a long-term disease-free survival in as many as 50–60% of patients. We have previously reported that risk stratified therapy and intensive use of cytarabine improved the outcome of childhood AML in AML99 study with 5-year event free survival (EFS) of 61.6% and 5-year overall survival (OS) of 75.6% (Tsukimoto I. J Clin Oncol 2009;27:4007–13), which gave us an additional impetus to reduce the number of consolidation courses with more restrictive indication for stem cell transplantation (SCT). We here report the outcome of successor nation-wide multi-institutional study AML-05, focusing on the AML patients without core binding factor (CBF). Patients & Methods:47 eligible children (age <18 years) with de novo AML (acute promyelocytic leukemia and Down syndrome patients were excluded). Three patients were excluded from the efficacy analyses: one protocol violation, 1 changing to non-JPLSG member hospital at the patient’s request, and 1 withdrawal of the JPLSG institutional membership. After 2 courses of common induction therapies, patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups. Low risk (LR) children were defined as those with t(8;21) or inv(16), and good bone marrow response (BMR) to the first induction course. High risk (HR) children were those with abnormalities of monosomy 7, 5q-, t(16;21)(p11;q22), t(9;22), FLT3-ITD, and/or poor BMR to the first induction course. Intermediate risk (IR) children were those who were neither LR or HR group. Only patients assigned to HR were candidate for SCT in first CR in AML-05, whereas patients with IR were also allocated to SCT, if HLA-matched siblings were available in the former AML99. Patients with CR after two courses of induction therapy further received 3 courses of consolidation chemotherapy in AML-05; whereas 4 courses of consolidation therapy were given in AML99. The total cumulative dose of anthracyclines, Mitoxantrone and Idarubicin, was 375 mg/m2 in the IR/HR chemotherapy both in AML-05 and AML99. Conversion rate of 5:1 was used to compare the cumulative dose of Daunorubicin and Mitoxantrone/Idarubicin. Results:Three-year EFS and 3y-OS of all 444 patients was 55.3% (95%CI, 50.2 – 60.1%) and 73.2% (68.3 – 77.5%), respectively. The median follow-up period for living patients was 3.1 years (range, 0.8 – 5.4 years). Two hundred eighty-nine non-CBF-AML patients [t(9;11), N=39 (13.5%); 11q23, N=27 (9.3%); Normal, N=81 (28.0%); Others, N=137 (47.4%)] in the AML-05 and 151 patients [t(9;11), N=15 (9.9%); 11q23, N=26 (17.2%); Normal, N=53 (35.1%); Others, N=55 (36.4%)] in AML99 were compared. There were no significant differences in basic characteristics such as sex and age/WBC at diagnosis. Incidence of FLT3-ITD in AML-05 cohort were identical to that in AML99 [AML-05 cohort, N= 42/289 (14.5%); AML99, N= 15/82 (18.2%), p=0.41]. CR rate in AML-05 was inferior to that in AML99 (81.0% vs. 90.7%, p = 0.008). There was no significant differences in 3y-EFS of non-CBF AML among 2 cohort [47.5% in AML-05 (95%CI, 41.2– 53.6%) vs. 49.7% in AML99 (41.5 – 57.3%), p= 0.43], however, there was a tendency of lower 3y-OS among them [62.8% in AML-05 (95%CI, 56.2– 68.7%) vs. 70.9% in AML99 (62.9 – 77.4%), p = 0.083]. The early death within 42 days in AML-05 (2.1%) were equivalent to that of AML99 (2.0%), whereas non-relapsed mortality were significantly increased in AML-05 compared with that of AML99 [44/289 (15.2%) in AML-05; 11/151 (7.3%) in AML99, p=0.022], which was due to increased mortality among infants. SCT rate in the 1stCR was lower in the non-CBF AML-05 compared with that in AML99 [47/289 (16.3%) in AML-05; 40/151 (26.4%) in AML99, p=0.011]. Conclusions:Reduction on consolidation chemotherapy courses from four to three, together with incorporation of repetitive cycles of high-dose cytarabine were adequate for non-CBF childhood AML, and did not compromise the treatment results in AML-05 despite of adaptation of more restrictive indication for SCT in 1st CR. Non-CBF-AML is a cytogenetically heterogeneous disease, hence the mechanism underlying these prognostic differences should be studied. Disclosures:No relevant conflicts of interest to declare.

Myelodysplasia-Related Changes Have Adverse Prognostic Significance in Children with Acute Myeloid Leukemia; A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG).

AbstractAbstract 2583▪▪This icon denotes a clinically relevant abstract Background:The 2008 WHO classification expanded the category of acute myeloid leukemia (AML) with multilineage dysplasia of the 2001 WHO classification into AML with myelodysplasia-related changes (AML-MRC). Although AML with multilineage dysplasia (AML-MLD) is diagnosed based on morphological features alone, AML-MRC includes AML with a previous history of myelodysplastic syndrome or myeloproliferative neoplasms and AML with a myelodysplasia-related cytogenetic abnormality as well as AML-MLD. Since this category of AML has been believed to be rare in children, its clinical impact on children remains unknown. We developed a comprehensive and prospective central review system in a clinical trial for pediatric AML, in which unexpected high incidence of AML-MRC was found. Thus, we evaluated the clinical characteristics and prognostic significance of AML-MRC in children. Patients & Methods:JPLSG AML-05, registered at http://www.umin.ac.jp/ctr/as UMIN000000511, is a nation-wide multi-institutional study for children (age <18 years) with de novo AML from 11/1/2006 to 12/31/2010 (acute promyelocytic leukemia and myeloid leukemia associated with Down syndrome excluded). On the trial, morphology was prospectively diagnosed by a central review system. A diagnosis of AML-MLD was made by the presence of dysplasia in 50% or more of the cells in 2 or more lineages. Cytogenetic tests were carried out in regional laboratories, but reports were reviewed centrally. Mutations of FLT3 were examined for all patients. Results:Among 447 eligible patients recruited, a total of 93 patients (20.8%) were diagnosed as AML-MRC; 34 from morphological features, 65 from myelodysplasia-related cytogenetic abnormalities and six from the both. The cases with AML-MRC included 48 boys and 45 girls with a median age of 3 years (range; 0–17 years). Ten patients with AML-MRC had FLT3-internal tandem duplication (ITD). Three-year probability of event-free survival (3y-pEFS) and 3-year probability of overall survival (3y-pOS) at the 93 patients was 37.1% (95%CI, 26.9 – 47.3%) and 56.8% (95%CI, 45.2 – 66.8%), respectively. The median follow-up of alive patients as of May 2012 was 3.4 years (range;1.3–5.3 years). Comparison of the clinical outcome of AML-MRC with AML, not otherwise specified (AML-NOS)(n=111), showed that AML-MRC had a lower complete remission rate after two induction courses(67.7% vs 85.6%, p<0.01), and worse 3y-pEFS (37.1% vs 53.8%, p= 0.02), but that 3y-pOS (56.8% vs 68.9%, p= 0.05) and 3 year probability of relapse-free survival after achieving complete remission (46.9.% vs 62.8%, p= 0.06) were similar. Although no differences were seen in sex and WBC count at diagnosis between AML-MRC and AML-NOS, the median age or the incidence of FLT3-ITD positivity of AML-MRC was lower than that of AML-NOS. In Cox regression analysis, adjusted hazard ratio (HR) of patients diagnosed with AML-MRC for EFS was significantly worse compared to those diagnosed with AML-NOS after controlling for these baseline patients and disease characteristics (HR 1.7,p<0.01). Conclusions:Our study suggests that AML-MRC is not rare in children. AML-MRC had adverse prognostic significance in children partly due to the low induction rate. Induction chemotherapy awaits further improvement for children with AML-MRC. Disclosures:No relevant conflicts of interest to declare.

Results of a Japanese Nationwide Multi-Institutional Study on Lateral Pelvic Lymph Node Metastasis in Low Rectal Cancer

To evaluate whether lateral pelvic lymph nodes (LNs) in low rectal cancer are metastatic disease or part of regional LNs that are amenable to curative resection. It is highly controversial whether lateral pelvic LNs should be considered as regional or distant disease, although the American Joint Committee on Cancer (AJCC) defines internal iliac LNs as regional LNs of rectal cancer. Data of patients with stage I to III low rectal cancer who underwent curative resection from 1978 to 1998 were extracted from the multi-institutional registry of large bowel cancer in Japan. Patients with only mesorectal LN metastasis were classified as the mesorectal-LN group. Patients with lateral pelvic LN metastasis localized to or extending beyond the internal iliac area were classified as the internal lateral pelvic lymph nodes (LPLN) group and external-LPLN group, respectively. Overall survival (OS) and cancer-specific survival (CSS) were compared between the groups. Lateral pelvic LN dissection was performed in 5789 (50%) of 11,567 patients. Overall, 3905 (34%), 411 (3.6%), and 244 (2.1%) patients were classified as the mesorectal-LN, internal-LPLN, and external-LPLN groups, respectively. When the mesorectal LN group was subdivided as defined by the AJCC, both 5-year OS and CSS were not significantly different between the N2a and internal-LPLN groups (OS: 45% vs 45%, P = 0.9585; CSS: 51% vs 49%, P = 0.5742), and the N2b and external-LPLN groups (OS: 32% vs 29%, P = 0.3342; CSS: 37% vs 34%, P = 0.4347). OS and CSS were significantly better in the external-LPLN group than in stage IV patients who underwent curative resection (OS: 29% vs 24%, P = 0.0240; CSS: 34% vs 27%, P = 0.0117). Lateral pelvic LNs can be considered as regional LNs in low rectal cancer, although metastasis extending beyond the internal iliac area is associated with poorer survival.

A multi-institutional feasibility study of induction pemetrexed (Pem) plus cisplatin (Cis) followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation (RT) for malignant pleural mesothelioma (MPM): Japan Mesothelioma Research Center (JMRC) 001001 trial.

TPS285 Background: Trimodality treatment consisting of preoperative induction chemotherapy with Pem plus Cis (PC), EPP, and postoperative RT might be a promising treatment option for potentially resectable MMP, but its safety as well as efficacy remains unclear, especially in Asian population, as only limited information is currently available from a few Western studies. Methods: The Japan Mesothelioma Research Center (JMRC), supported by the Special Coordination Funds for Promoting Science and Technology from the Japanese Ministry of Education, Culture, Sports, Science, and Technology, has planned a nationwide prospective study to assess the feasibility of trimodality treatment for potentially resectable clinical stage I-III MPM patients. Based on the results of a phase I/II study of PC for unresectable MPM conducted in Japan and a single-institution pilot study of induction PC for resectable MPM, we adopted Cis at the dose of 60 mg/m2 in combination with Pem (500 mg/m2). After 3 cycles of PC, patients received EPP followed by RT (54 Gy in 30 fractions of 1.8 Gy per day). The primary endpoints are macroscopic complete resection rate and treatment-related mortality, and secondary endpoints included completion rate of trimodality treatment, adverse events, radiographic response rate of induction chemotherapy, and 2-year disease-free survival and overall survival. A total of 40 patients will be accrued over 3 years. Patient accrual rate continues as planned after activation of this trial on May 15, 2008, with registration at the UMIN Clinical Trials Registry (No. 000001154). 19 eligible patients have been enrolled as of December 31, 2009. We expect that patient registration will be completed in 2011, and this nationwide multi-institutional study will provide a variety of information on trimodality treatment in the Japanese population, which contributes to planning future prospective studies for resectable MPM. No significant financial relationships to disclose.

Diagnosis of brain death in children.

During the last two decades, criteria have been developed for the diagnosis of brain death that are applicable to adults and children over 5 years of age. To identify brain death, EEG and evoked potentials (EPs) have been extensively used as diagnostic tools in conjunction with the clinical examination and other laboratory procedures such as four-vessel cerebral angiograms or radionuclide scans. In this report, we review the criteria for the determination of brain death. In addition, the question of applying these criteria to children under 5 years of age is critically assessed, with special emphasis on the role of EEG and EPs in confirming the cessation of all brain activities. We propose that the criteria that pertain to adults may be appropriate for children under 5 years of age as well; however, this premise needs to be validated by a large nationwide multi-institutional study.