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We investigated the efficacy of a Wilms' tumor gene 1 (WT1) vaccine combined with gemcitabine (GEMWT1) and compared it with gemcitabine (GEM) monotherapy for advanced pancreatic ductal adenocarcinoma (PDAC) in a randomized phase II study. We randomly assigned HLA-A*02:01– or HLA-A*24:02–positive patients with advanced PDAC to receive GEMWT1 or GEM. We assessed WT1-specific immune responses via delayed-type hypersensitivity (DTH) to the WT1 peptide and a tetramer assay to detect WT1-specific cytotoxic T lymphocytes (WT1-CTL). Of 91 patients enrolled, 85 were evaluable (GEMWT1: n = 42; GEM: n = 43). GEMWT1 prolonged progression-free survival [PFS; hazard ratio (HR), 0.66; P = 0.084] and improved overall survival rate at 1 year (1-year OS%; GEMWT1: 35.7%; GEM: 20.9%). However, the difference in OS was not significant (HR: 0.82; P = 0.363). These effects were particularly evident in metastatic PDAC (PFS: HR 0.51, P = 0.0017; 1-year OS%: GEMWT1 27.3%; GEM 11.8%). The combination was well tolerated, with no unexpected serious adverse events. In patients with metastatic PDAC, PFS in the DTH-positive GEMWT1 group was significantly prolonged, with a better HR of 0.27 compared with the GEM group, whereas PFS in the DTH-negative GEMWT1 group was similar to that in the GEM group (HR 0.86; P = 0.001). DTH positivity was associated with an increase in WT1-CTLs induced by the WT1 vaccine. GEM plus the WT1 vaccine prolonged PFS and may improve 1-year OS% in advanced PDAC. These clinical effects were associated with the induction of WT1-specific immune responses. Cancer Immunol Res; 6(3); 320–31. ©2018 AACR.

FACT-G subscale by treatment group

e12576 Background: From the results of ACOSOG Z0011, IBCSG23-01 and AMAROS trials, axilla surgery in node-positive breast cancer (BC) tends to be less invasive with sentinel node biopsy (SNB) followed by adjuvant therapy and regional node irradiation (RNI). However, optimized axilla treatment including SNB without RNI is still debated. The Japanese Society for Sentinel Node Navigation Surgery conducted a multi-institutional prospective cohort study to compare SNB with SNB followed by axillary lymph node dissection (ALND) in cases with positive-sentinel lymph nodes (SLN)(UMIN No. 000011782, Jpn J Clin Oncol, p.876-9, 2014). Methods: Female BC patients with cT1-3N0-1M0 were eligible. When 1 to 3 positive micrometastases or macrometastases in SLN were confirmed by histological or molecular diagnosis, SNB alone or additional ALND had been decided by physician’s discretion. Primary chemotherapy before or after SNB was acceptable for registration. Lymph node sampling was also allowed in the SNB group. Cases with bilateral BC, isolated tumor cells only in SLN, past history of invasive cancer within 5 years at the registration were ineligible. The primary endpoint was the 5-year recurrence rate of regional node (RN) in the SNB group. The secondary endpoint was overall survival (OS). We planned to collect 240 patients to reject that the 5-year recurrence rate of RN was more than 10% assuming the rate 5%. To compare the SNB group and ALND group, the propensity score matching (PSM) was performed. Matching variables were initial treatment, metastatic size and numbers of SLN, clinical stage, age, body mass index, menopausal status, family history, past history of invasive cancer, breast surgery. Results: Eight-hundred eighty cases had been registered between 2013 and 2016. In the 871 eligible cases, 308 cases were the SNB group. At the median follow-up of 6.3 years, 5-year recurrence rate of RN was 2.7% [95% confidence interval, 1.4% to 5.4%] and 5-year OS was 97.6% [94.9% to 98.8%]. After PSM, 209 cases were matched in the SNB and ALND group. Among them, 343 cases (82%) received operation at initial treatment. Partial and total mastectomy was performed in 225 (54%) and 193 cases (46%), respectively. One-positive SLN was recorded in 366 cases (88%), 2 in 48 (11%) and 3 in 4 (1%). Macrometastases and micrometastases in SLN were diagnosed in 271 (65%) and 147 cases (35%), respectively. Three-hundred seventy-six cases (90%) belonged to luminal-like subtype. RNI was underwent in 42 cases (20%) of the SNB group and 13 cases (6%) of the ALND group. Five-year recurrence rate of RN was 2.1% [0.8% to 5.5%] and 2.0% [0.8% to 5.3%] for the SNB and ALND group, respectively. Conclusions: Our series suggests that RNI is not necessary for regional control in cases with 1 to 3 positive SLN. In conclusion, SNB alone is acceptable in cases with fewer metastatic SLN. Clinical trial information: UMIN No. 000011782.

Background: Eighty percent of children with steroid-sensitive nephrotic syndrome (SSNS) relapse within 2 years and 40-50% patients show frequently-relapsing nephrotic syndrome (FRNS). Patients showing a relapse within 6 months after initial remission are at high risk of FRNS. Since frequent prednisolone treatment for FRNS induces severe prednisolone side effects, development of a treatment to prevent patients from shifting to FRNS is desirable. Mizoribine is an immunosuppressive drug with fewer side effects than prednisolone. Recent studies reported the efficacy of high-dose mizoribine in children with FRNS. Methods/design: We conduct a multicenter, open, randomized controlled trial to investigate the efficacy and safety of standard prednisolone plus high-dose mizoribine therapy in children with SSNS showing a relapse within 6 months after an initial remission. Patients are allocated to either standard prednisolone alone treatment group, or standard prednisolone plus high-dose mizoribine group. For the former group, mizoribine is administered at a dose of 10 mg/kg/day once daily and continued for 2 years. The primary endpoint is the duration to frequent relapse. Discussion: The results provide important data on use of high-dose mizoribine to prevent SSNS patients from shifting to FRNS. Since blood concentrations of mizoribine have not been investigated in detail until now, there is a possibility that mizoribine is underestimated in favor of other immunosuppressive drugs. In future, high-dose mizoribine therapy may lead to prevention of relapse in children at high risk of FRNS, and to decreased total dose of prednisolone., 論文

1026 Background: The Federation of Asian Clinical Oncology (FACO) conducted an international retrospective cohort study of oligometastatic breast cancer (BC) (OLIGO-BC1) (UMIN No.000030047). At ASCO2020, we demonstrated that locoregional and systemic therapy prolonged overall survival (OS) for patients with oligometastatic BC, especially for cases with some type of systemic therapy, younger age, ECOG performance status 0, stage I BC, non-triple negative subtype, fewer metastatic sites, local recurrence and longer disease-free interval from a multivariate analysis (#1025). Although BC is heterogeneous and a retrospective dataset has many kinds of bias, we attempted a subset analysis based on intrinsic subtype and several prognostic factors. Methods: Oligometastatic BC patients diagnosed from 2007 to 2012 were registered from CSCO, KSMO and JSCO. OS period was measured from the diagnosis of oligometastases to the latest follow-up. ER, PgR and HER2 status were determined by immunohistochemistry and/or in situ hybridization. A hazard ratio (HR) of OS was calculated by using a univariate analysis. Results: In 1200 eligible cases, one oligometastatic site was found in 578 cases, two in 289, three in 154, four in 102 and five in 77. Bone metastases were recorded in 301 cases, visceral metastases in 387, locoregional recurrence in 25, local recurrence in 83 and multiple metastatic sites in 404. Luminal subtype was recorded in 526 cases (44%), luminal-HER2 in 189 (16%), HER2 in 154 (13%), triple-negative in 166 (14%) and others in 165 (13%). In any subtype, locoregional and systemic therapy and ECOG performance status 0 were beneficial for OS. Stage I BC, one oligometastatic site and longer disease-free interval were also related to favorable prognosis in luminal and HER2 subtype. However, triple-negative subtype had no survival advantage with these 3 factors. On the other hand, pathological negative or micrometastatic lymph nodes at primary BC and one oligometastatic site of lymph node, lung, liver and bone were favorable prognostic factors. In addition, cases treated locally with surgical resection and conventional radiation therapy were expected to prolong OS. Discussions: Locoregional therapy for oligometastatic BC may be considered in luminal and HER2 subtype with some conditions. As reported in ASCO2020, triple-negative BC should be managed with systemic therapy. Conclusions: Oligometastatic BC is diagnosed by chance, but some cases seem to survive with multidisciplinary treatment. It is worthwhile to consider locoregional therapy in oligometastatic BC after evaluating favorable prognostic factors.

1025 Background: Systemic therapy is the standard care in metastatic breast cancer (BC). However, retrospective studies demonstrated survival benefits of locoregional and systemic (combination) therapy in oligometastatic BC. To clarify it, the Federation of Asian Clinical Oncology conducted an international retrospective cohort study (OLIGO-BC1) (UMIN No.000030047). Methods: Oligometastatic BC patients diagnosed from 2007 to 2012 were registered. “Oligometastases” is defined as low volume metastatic disease with limited number and size of metastatic lesions up to five and not necessarily in the same organ by the ABC guidelines. Overall survival (OS) from the diagnosis of oligometastases was the primary endpoint and compared between combination and systemic therapy using a log-rank test. Assuming the 5-year OS of 50% and 40%, respectively, 698 patients were required to achieve 80% power to detect the superiority of combination therapy, at a two-sided significance level. A multivariable Cox regression model with stratification by country was performed to estimate hazard ratio (HR) for therapy and other risk factors. Results: While 1,262 cases had been registered from February 2018 to May 2019, 1,200 remained for analysis after exclusion of unavailable cases. Among them, 573, 529 and 98 cases were registered from China, Japan and Korea, respectively. Luminal BC was recorded in 526 cases (44%), luminal-HER2 BC in 189 (16%), HER2 BC in 154 (13%), triple-negative BC in 166 (14%) and others in 165 (13%). One oligometastatic BC was found in 578 cases, 2 in 289, 3 in 154, 4 in 102 and 5 in 77. Bone metastases were recorded in 301 cases, visceral metastases in 387, locoregional recurrence in 25, local recurrence in 83 and multiple metastatic sites in 404. Combination therapy was performed in 595 cases and systemic therapy in 404. At median follow-up of 4.9 years, 5-year OS was 59.6% and 41.9%, respectively (p < 0.01). An adjusted HR was 0.61 (95% CI: 0.51, 0.74). Type of systemic therapy, younger age, ECOG performance status 0, stage I BC, non-triple negative subtype, fewer metastatic sites, local recurrence and longer disease-free interval were significantly favorable prognostic factors. Discussions: Oligometastatic BC under some conditions seems to be curable. Taken together with recent molecular targeted therapy, locoregional therapy will be advantageous to conquer it. Conclusions: Combination therapy is a promising strategy for patients with oligometastatic BC.

e19323 Background: Although the incidence of VTE is known to be high in cancer patients, many details of the frequency, risk factors, and management of VTE in patients with cancer remain unclear, especially in Asian populations. Methods: The multicenter, prospective, Cancer-VTE Registry study (UMIN000024942) aimed to clarify the actual status of VTE in cancer patients. The study enrolled patients diagnosed with colorectal, lung, stomach, breast, gynecological, or pancreatic cancer in Japan. Patients underwent VTE screening before initiating cancer treatment and were observed for 1 year. Registry objectives included the assessment of VTE prevalence and risk factors for VTE before initiating cancer treatment, real-world treatment of VTE, and frequency of new-onset events during the observation period. DVT screening was waived for those with a normal D-dimer level. Using a multivariate logistic regression model, we examined risk factors for DVT in cancer patients prior to initiating cancer treatment. Results: Of the 9726 patients enrolled, 3661 patients underwent DVT screening and 549 subjects were diagnosed with DVT. The risk factors for DVT among patients who underwent DVT screening (n=3661) are shown in the Table. Conclusions: The risk of DVT before initiating cancer treatment was clarified, and the factors strongly influencing DVT risk included age, sex, VTE history, D-dimer concentration, and hemoglobin concentration. [Table: see text]

Persistent proteinuria seems to be a risk factor for progression of renal disease. Its reduction by angiotensin-converting inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) is renoprotective. Our previous pilot study showed that 2-year lisinopril therapy is effective and safe for children with mild IgA nephropathy. When combined with ACEI and ARB, reported results are of greater decrease in proteinuria than monotherapy in chronic glomerulonephritis, including IgA nephropathy. To date, however, there have been no randomized controlled trials in children. This is an open-label, multicenter, prospective, and randomized phase II controlled trial of 63 children with biopsy-proven proteinuric mild IgA nephropathy. We compared efficacy and safety between patients undergoing lisinopril monotherapy and patients undergoing combination therapy of lisinopril and losartan to determine better treatment for childhood proteinuric mild IgA nephropathy. There was no difference in proteinuria disappearance rate (primary endpoint) between the two groups (cumulative disappearance rate of proteinuria at 24 months: 89.3% vs 89% [combination vs monotherapy]). Moreover, there were no significant differences in side effects between the two groups. We propose lisinopril monotherapy as treatment for childhood proteinuric mild IgA nephropathy as there are no advantages of combination therapy. Clinical trial registry, UMIN ID C000000006, https://www.umin.ac.jp .

We determined the predicting factors of early-onset group B streptococcal (EOGBS) infection in neonates who were born to GBS carrier mothers with inadequate intrapartum antibiotic prophylaxis (IAP). Medical records of all neonates born from January 1, 2008 to April 1, 2010 were reviewed. Inadequate IAP was defined as delivery less than 4 hours (h) after the first administration of antimicrobial. Of 1910 neonates, 273 were born from mothers colonized with GBS, including 69 who received inadequate IAP. Of 69 neonates, nine showed symptoms, including respiratory distress, fever, tachycardia, vomiting, and irritability. Abnormalities in complete blood count (CBC) and C-reactive protein (CRP) were noted in three and four neonates, respectively. Three infants were diagnosed with EOGBS infection confirmed by positive rectal and throat cultures, and all three presented with respiratory distress and CRP abnormalities. Respiratory distress (p=0.0004) and CRP (p=0.0001) offered reliable indicators for detecting EOGBS infections.

Summary Background and objectives An open-label, multicenter, randomized phase II trial was conducted from July 1, 2005 to March 29, 2011 to compare two protocols for treating children with frequently relapsing nephrotic syndrome using microemulsified cyclosporine. Design, setting, participants, & measurements Ninety-three children with frequently relapsing nephrotic syndrome were randomly assigned to group A (n=46) or group B (n=47). In both groups, the 2-hour postdose cyclosporine level was monitored. For group A, the cyclosporine target was set to 600–700 ng/ml for the first 6 months and 450–550 ng/ml for the next 18 months; for group B, it was set to 450–550 ng/ml for the first 6 months and 300–400 ng/ml for the next 18 months. The primary end point was the sustained remission rate. At the end of the study, if there was no difference in safety profile between the two groups and the sustained remission rate in group A was superior to group B with a decision threshold of 8%, then the regimen for group A would be determined the better treatment. Results Eight children from an ineligible institution, where cyclosporine levels were not measured, were excluded from all analyses. At 24 months, the sustained remission rate was nonsignificantly higher in group A (n=43) than group B (n=42; 64.4% versus 50.0%; hazard ratio, 0.57; 95% confidence interval, 0.29 to 1.11; P=0.09), and the progression-free survival rate was significantly higher (88.1% versus 68.4%; hazard ratio, 0.33; 95% confidence interval, 0.12 to 0.94; P=0.03). The relapse rate was significantly lower in group A than group B (0.41 versus 0.95 times/person-year; hazard ratio, 0.43; 95% confidence interval, 0.19 to 0.84; P=0.02). The rate and severity of adverse events were similar in both treatment groups. Conclusion The sustained remission rate was not significantly different between the two treatment groups, but the regimen with the higher 2-hour postdose cyclosporine level target improved progression-free survival and reduced the relapse rate.